bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving Handoffs Between Operating Room and Pediatric Intensive Care Teams: Before and After Study
Authors: Malenka Emma C. , Nett Sholeen T. , Fussell Melissa , Braga Matthew S.
Published: October 2018

Introduction:

Patient transfer between teams and units is known to be a high-risk event for miscommunication and therefore error. We instituted a quality improvement initiative to formalize patient handoffs from the operating room (OR) to the Pediatric Intensive Care Unit (PICU). We hypothesized that measures of information transfer would improve.

Methods:

In this before and after study, a multidisciplinary team developed a standardized handoff protocol (including a checklist) instituted in the Dartmouth PICU over the summer of 2016. We directly observed pediatric admissions from OR to PICU and collected data on information transfer and patient outcome metrics both before and after the institution of the handoff protocol at the time of transfer (intervention).

Results:

We directly observed 52 handoffs (29 preintervention, 23 postintervention). The mean patient age was 9.3 years (SD, 6.5), with 55% male. Preintervention the average information transfer was 56% (upper control limit, 76%; lower control limit, 36%), whereas postintervention it was 81% (upper control limit, 97%, lower control limit, 65%). The improvement in information transfer postintervention was statistically significant (P < 0.001). There was no statistically significant change in maximum pain score in the first 6 hours after admission (preintervention, 4.5, SD 3.9; postintervention, 2.9, SD 1.3, P = 0.15). There was no difference in the time required for handoff pre- versus postintervention (8.7 minutes, SD 5.5 versus 10.1 minutes, SD 4.6, P = 0.34).

Conclusion:

Standardization of OR to PICU patient transfers using a predetermined checklist at the time of handoff can improve the completeness of information transfer without increasing the length of the handoff.
Using Quality Improvement to Change Testing Practices for Community-acquired Pneumonia
Authors: Rogers Amanda J. , Lye Patricia S. , Ciener Daisy A. , Ren Bixiang , Kuhn Evelyn M. , Morrison Andrea K.
Published: October 2018

Background:

National guidelines for pediatric community-acquired pneumonia (CAP) contain recommendations regarding diagnostic testing including chest radiographs (CXRs), complete blood counts (CBCs), and blood cultures. Local data indicated that our institution was not delivering care at standards outlined by these guidelines. This project aimed to decrease CXRs for children with CAP discharged from the emergency department (ED) by 10% and decrease CBCs and blood cultures for patients hospitalized with uncomplicated CAP by 20% within 1 year.

Methods:

This single-site quality improvement initiative targeted otherwise healthy children 3 months to 18 years who presented to the ED with uncomplicated CAP at a free-standing academic children’s hospital. A quality improvement team performed a series of interventions including guideline implementation, data sharing, and annual education. Process measures included CXR, CBC, and blood culture rates. Balancing measures included the number of patients diagnosed with CAP, the frequency of antibiotic use, length of stay, and ED and hospital return rates. The team used statistical process control charts to plot measures.

Results:

There was special cause improvement with a desirable downward shift in testing that correlated with the project’s interventions. The percentage of CXRs for discharged patients decreased from 79% to 57%. CBCs and blood cultures for hospitalized patients decreased from 30% to 19% and 24% to 14%, respectively. Balancing measures remained unchanged.

Conclusions:

We used elements of quality improvement methodology to reduce testing for uncomplicated CAP without impacting the number of patients diagnosed with CAP, the frequency of antibiotic use, length of stay, and reutilization rates.
Automated E-mail Reminders Linked to Electronic Health Records to Improve Medication Reconciliation on Admission
Authors: Johnson Kristen , Burkett Gregory S. , Nelson Daniel , Chen Allen R. , Matlin Carol , Garger Cathy , McMahan Steven , Hughes Helen , Miller Marlene , Kim Julia M.
Published: October 2018

Introduction:

Medication reconciliation can reduce medication discrepancies, errors, and patient harm. After a large academic hospital introduced a medication reconciliation software program, there was low compliance with electronic health record documentation of home medication reconciliation. This quality improvement project aimed to improve medication reconciliation on admission in 4 pediatric inpatient units by 50% over 3 months.

Methods:

We used Lean Sigma methodology to observe medication reconciliation processes; interview residents, nurses, pharmacists, and families; and perform swim lane process mapping and Ishikawa Cause and Effect analysis. The improvement plan included education and automated e-mails sent to admitting residents who had not completed medication reconciliation within 24 hours of admission. The daily percentage of patients without medication reconciliation within 24 hours of admission, indicated by the presence of old prescriptions in Sunrise Prescription Writer (RxWriter) (Allscripts Healthcare Solutions, Chicago, Ill.) from prior admissions, was assessed from March 2015-June 2016. We constructed statistical process control charts and identified special causes.

Results:

Key barriers included lack of knowledge about RxWriter and lack of accountability for completing medication reconciliation. The percentage of patients without medication reconciliation decreased from 32% at baseline to 22% with education (P < 0.001), to 15% with the use of automated e-mail reminders (P < 0.001). We sustained improvement over the following year. Statistical process control testing indicated shifts aligning with each stage of the study.

Conclusion:

Provider-tailored, automated e-mail reminders linked to electronic health record with educational training significantly improved resident compliance with use of an electronic tool for documentation of home medication reconciliation on hospital admission.
Adherence to Daily Weights and Total Fluid Orders in the Pediatric Intensive Care Unit
Authors: Ahearn Marshall A. , Soranno Danielle E. , Stidham Timothy , Lusk Jennifer , Gist Katja M.
Published: October 2018

Background:

Fluid is central to the resuscitation of critically ill children. However, many pay limited attention to continued fluid accumulation. Fluid overload (FO) is associated with significant morbidity and mortality. The Volume Status Awareness Program (VSAP) is a multi-phase quality improvement initiative aimed at reducing iatrogenic FO. For baseline data, the authors examined a retrospective cohort of patients admitted to the pediatric intensive care unit.

Methods:

Cohort included diuretic-naive patients admitted to the pediatric intensive care unit at a tertiary care children’s hospital in 2014. Furosemide-exposure was used to indicate provider-perceived FO. Variables included daily weight and total fluid (TF) orders, and their timing, frequency, and adherence. Implementation of VSAP phase 1 (bundle of interventions to promote consistent use of patient weights) occurred in June 2017.

Results:

Forty-nine patients met criteria. Five (10%) had daily weight orders, and 41 (84%) had TF orders—although 7 of these orders followed furosemide administration. Adherence to TF orders was good with 32 (78%) patients exceeding TF limits by < 10%. Thirty (63%) had > 5% FO by day 1, and 22 (51%) had > 10% cumulative FO by day 3. Following phase 1 of the VSAP, the frequency of daily weight orders increased from 6% to 88%.

Conclusions:

In our institution, use of fluid monitoring tools is both inconsistent and infrequent. Early data from the VSAP project suggests simple interventions can modify ordering and monitoring practice, but future improvement cycles are necessary to determine if these changes are successful in reducing iatrogenic FO
Dissemination of a Novel Framework to Improve Blood Culture Use in Pediatric Critical Care
Authors: Woods-Hill Charlotte Z. , Lee Laura , Xie Anping , King Anne F. , Voskertchian Annie , Klaus Sybil A. , Smith Michelle M. , Miller Marlene R. , Colantuoni Elizabeth A. , Fackler James C. , Milstone Aaron M.
Published: October 2018

Introduction:

Single center work demonstrated a safe reduction in unnecessary blood culture use in critically ill children. Our objective was to develop and implement a customizable quality improvement framework to reduce unnecessary blood culture testing in critically ill children across diverse clinical settings and various institutions.

Methods:

Three pediatric intensive care units (14 bed medical/cardiac; 28 bed medical; 22 bed cardiac) in 2 institutions adapted and implemented a 5-part Blood Culture Improvement Framework, supported by a coordinating multidisciplinary team. Blood culture rates were compared for 24 months preimplementation to 24 months postimplementation.

Results:

Blood culture rates decreased from 13.3, 13.5, and 11.5 cultures per 100 patient-days preimplementation to 6.4, 9.1, and 8.3 cultures per 100 patient-days postimplementation for Unit A, B, and C, respectively; a decrease of 32% (95% confidence interval, 25–43%; P < 0.001) for the 3 units combined. Postimplementation, the proportion of total blood cultures drawn from central venous catheters decreased by 51% for the 3 units combined (95% confidence interval, 29–66%; P < 0.001). Notable difference between units included the identity and involvement of the project champion, adaptions of the clinical tools, and staff monitoring and communication of project progress. Qualitative data also revealed a core set of barriers and facilitators to behavior change around pediatric intensive care unit blood culture practices.

Conclusions:

Three pediatric intensive units adapted a novel 5-part improvement framework and successfully reduced blood culture use in critically ill children, demonstrating that different providers and practice environments can adapt diagnostic stewardship programs.
Patient-Reported Outcome Measures for Soft-Tissue Facial Reconstruction: A Systematic Review and Evaluation of the Quality of Their Measurement Properties
Authors: Dobbs Thomas D. , Gibson John A. G. , Hughes Sarah , Thind Arron , Patel Benjamin , Hutchings Hayley A. , Whitaker Iain S.
Published: October 2018

Background:

A patient’s health-related quality of life can be significantly impacted by facial scarring and disfigurement. Facial soft-tissue reconstruction should aim to improve this, with outcomes measured from the patient’s perspective using patient-reported outcome measures. This systematic review identifies patient-reported outcome measures for soft-tissue facial reconstruction and appraises their methodologic and psychometric properties using up-to-date methods.

Methods:

A systematic search of the MEDLINE, Embase, PsychINFO, and Cochrane databases was performed. Identified patient-reported outcome measures were assessed using the updated Consensus-Based Standards for the Selection of Health Measurement Instruments checklist. Psychometric properties were also assessed and a modified Grading of Recommendation Assessment, Development and Evaluation analysis was performed to aid in recommendations for future questionnaire use.

Results:

Thirty-four studies covering nine patient-reported outcome measures were included. Methodologic quality and psychometric evidence were variable. FACE-Q, Skin Cancer Index, Patient Outcome of Surgery–Head/Neck, and the Derriford Appearance Scale 59/24 all demonstrated high enough evidence to be recommended as having potential for inclusion in future studies.

Conclusions:

This is the first systematic review to identify and critically appraise patient-reported outcome measures for soft-tissue facial reconstruction using internationally accepted criteria. Four questionnaires were deemed to have adequate levels of methodologic and psychometric evidence, although further studies should be conducted before they are used routinely in patients undergoing facial reconstruction. Through the use of psychometrically well-validated questionnaires, it is hoped that patients’ concerns can be truly appreciated, the level of care improved, and the quality of reconstructive options offered advanced.
Synovial Chondromatosis and Calcium Pyrophosphate Deposition of the Temporomandibular Joint: Challenging Diagnosis
Authors: Vellone Valentino , Bracciolini Valeria , Ramieri Valerio , Pernazza Angelina , Della Rocca Carlo , Cascone Piero
Published: October 2018

Background:

The association between the synovial chondromatosis (SC) and the calcium pyrophosphate deposition (pseudogotta) in temporomandibular joint (TMJ) is very rare and has been described just 1 patient in the literature.

Clinical Presentation:

A 64-year-old woman was referred to Dipartimento di Scienze Odontostomatologiche e Maxillo-Facciali, Sapienza Università di Roma after complaining about right temporomandibular pain, limitation in mandibular movements, and tumefaction in the right preauricular region. The patient was hospitalized for the surgery. The microscopic examination of the excised material revealed calcium pyrophosphate dihydrate (CPPD) deposits crystals associated with cartilaginous proliferation.

Conclusion:

The association between the SC and the calcium pyrophosphate deposition (pseudogotta) is a challenging diagnosis among TMJ neoplasms.
Geomagnetic instruments at National Museums Scotland
Authors: Morrison-Low A. D.
Published: October 2018

In 1981, the sole book about historic geomagnetic instruments was by Anita McConnell. Using it as a timeline, the Royal Scottish Museum's temporary exhibition ‘The Earth is a Magnet’, was put on to coincide with an international congress held in Edinburgh that year. The curators were aware that this important story could be told only with borrowed material from a number of other collections and that, in some cases, crucial items no longer existed. Locating and borrowing such objects before the Internet proved tricky and time-consuming, but helped to form thinking about how the collections might grow. The paper will look at what there is, and something of what there is not, in the Scottish national collections.
Quality characteristics of Pleurotus eryngii, Lentinus edodes GNA01 and Grifola frondosa as affected by different drying methods
Authors: Je Hee-Jeong , Kim Hyeon Young , Ha Gi-Jeong , ha Injong , Cho Sung Rae
Published: October 2018

This study compared the quality and drying characteristics of dried king oyster mushroom (Pleurotus eryngii), shiitake mushroom (Lentinus edodes GNA01) and maitake mushroom (Grifola frondosa) slices obtained by sundrying, hot-air drying (40, 50, 60℃), low-temperature vacuum drying (20, 25, 30℃), heat-pump dehumidifying drying (30, 40, 50℃), and freeze drying. The quality changes investigted included color, browning degree, hardness, general components, β-glucan. Color changes in king oyster mushroom during freeze drying were less than that between control (raw) and treated mushrooms. Compared with other drying methods, low-temperature vacuum drying of shiitake mushroom resulted in less color changes. Browning degree differed significantly between the different drying methods. As temperature increased, low-temperature vacuum drying resulted in decreased browning while heat-pump dehumidifying drying resulted in increased browning. In king oyster mushroom, hardness increased with temperature under hot-air drying, low-temperature vacuum drying and heat-pump dehumidifying drying. In shiitake mushroom, hardness increased with increasing temperature under hot-air drying and heat-pump dehumidifying drying. β-glucan content after drying was found to be between 28.29 and 39.39% in king oyster mushroom, 23.05 and 29.48% in shiitake mushroom and 16.10 and 24.51% in maitake mushroom.
Evaluation of quality characteristics in commercial yogurt
Authors: Shin Kwang-Seup , Lee Jeung-Hee
Published: October 2018

Commercial yogurt can be classified as fermented milk (FM) and condensed fermented milk (CFM). A selection of commercial yogurt was collected from domestic markets and the quality characteristics were compared by analyzing total acidity, viscosity, organic acids, sugars, conjugated linoleic acid (CLA), and aroma pattern. Total acidity and viscosity in FM were significantly lower than those in CFM (p<0.05). The major organic acid of commercial yogurt was lactic acid, the content of which was 8.15-4.72 times and 26.83-47.20 times higher than that of citric acid and acetic acid, respectively. CFM contained 1.47 times more lactic acid and 2.53 times more citric acid than FM. The total sugar content in FM was two times higher than that in CFM and the major sugars measured were sucrose, lactose, glucose, and maltose. The sucrose content was the highest in FM. CFM contained 23.65 times more CLA and 10.81 times more lipid than FM. The aroma patterns of yogurt analyzed with an electronic nose were clustered into Therefore, among commercial yogurt, CFM had higher viscosity, organic acid and CLA content, but lower sugar content than FM, which resulted in a relatively strong sour and weak sweet taste.
Changes in the physicochemical characteristics and antioxidant activity of barley during germination using different pre-treatment methods
Authors: Park Ji-Hye , Kang Min-Jung , Kang Jae-Ran , Shin Jung-Hye
Published: October 2018

In this study, we established the pre-treatment conditions that could increase the γ-aminobutyric acid (GABA) content during barley germination. In the process, three different barley samples were prepared, which differed in the pre-treatedment processes. The specimens were stored at 50℃ for 1 h after being kept in water at room temperature for 4 h (HKW sample), kept in sufficient water for 4 h (KW sample), or left untreated (CO sample). After the pre-treatment, the barely samples were germinated for 35 h. A sample was taken from each batch in 5-h intervals, extracted with water, and physicochemical characteristics and radical scavenging activity were measured. As a result, we found that the contents of phenolic compounds (18.02-30.63 mg/100 g) and flavonoids (1.87­4.63 mg/100 g) were higher in HKW, showing similar trends. Also the GABA contents in the HKW and KW samples were higher than that in the CO sample. Furthermore, the radical scavenging activities of DPPH and ABTS were the highest in the HKW sample, having values in the ranges of 58.49-77.40% and 54.57-88.10%, respectively. All in all, we found that in order to increase the antioxidative activity and GABA content of the barley samples, it would be suitable to pre-treatment the specimens after the post-immersion heat treatment. In addition, pre-treating the KW samples is appropriate only after immersion time. Lastly, the optimum germination time of the batches was found to be 20-25 h.
Biological activity of wild Ligularia fischeri leaf extracts in the development of functional food materials
Authors: Lim Su-Bin , Kim Myung-Uk , Park Kyeung-Il , Lee Eun-Ho , Kim Ye-Jin , Cho Eun-Bi , Kim Byeong-Oh , Cho Young-Je
Published: October 2018

The objective of this study was to identify the anti-oxidation, astringent, and inhibition effects of wild Ligularia fischeri on hyaluronidase and angiotensin conerting enzyme (ACE). In order to identify the total phenolic compound (TPC), various solvents were used for extraction showing hot water extract with the highest value of 14.42 GAE mg/g. In addition, ABTS radical scavenging activity measurements revealed an anti-oxdiation effect of 98.64-99.84% a hot water extract concentration of 50-200 μg/mL and a radical scavenging activity of 95.14-98.96% at a 60% ethanol extract content. If expressed in antioxidant protection factors (PF), the hot water extract showed 0.59-1.02 PF and the 60% ethanol sample displayed 0.30-0.74 PF. To identify the bio-activity effect, the hyaluronidase inhibition effect was determined as 4.66-35.00% in a 50-200 μg/mL hot water extract. Considering ACE inhibition effect, the hot water extract and 60% ethanol sample showed 0-64.24% and 46.12-69.64% inhibition effect, respectively. Lastly, when taking into account the astringent effect, the hot water extract with 50-200 μg/mL TPC concentration showed 15.68-26.92% and the 60% ethanol sample with an equal concentration exhibited 49.48-86.84%, which indicates the possibility to apply this product as a cosmetic source for pore contraction. Therefore, wild Ligularia fischeri extract can be used for anti-inflammation, high-blood pressure prevention, and as a source for health functional food with anti-oxidative properties.
Characterization of Lactobacillus brevis SCML 432 isolated from Meju in Sunchang and optimization of its culture conditions by statistical methods
Authors: Seo Ji Won , Yang Hee-Jong , Jeong Su-Ji , Ryu Myeong Seon , Ha Gwangsu , Jeong Seong-Yeop , Jeong Do-Youn
Published: October 2018

When used as a starter in the manufacture of Meju, it is expected that the quality of the soup products can be improved. In this study, we isolated Lactobacillus strain having possible safety and food-industrial benefits as a starter. Four hundred and seven isolates were screened from Meju, and chemically characterized for their antibacterial activity against Bacillus cereus, non-productivity of biogenic amine, and hemolysis. Eight of the isolates were selected upon chemical characterization, and their antioxidant and β-glucosidase activity was measured. Finally, we selected, and measured its enzyme activity and antibiotic resistance. Next, we investigated its cell growth, showed maximum biomass of 3.5 g/L after 28 h of culture. The ingredients of the medium to improve biomass were selected using the Plackett-Burman design (PBD) and central composite design (CCD). The results obtained using PBD revealed molasses, yeast extract, and maltose to be significant factors determining the biomass of the L. brevis SCML 432 strain. The CCD was then applied with three variables found from PBD and the optimum values were predicted to be 5.5% molasses, 1.5% yeast extract, and 2.0% maltose, and the maximum biomass was predicted to be 11.2 g/L. Through model verification, we confirmed that the predicted and actual results were similar, with about 3.2-fold improvement in the biomass from 3.5 g/L to 11.3 g/L when compared to that obtained in basal medium. These results suggest that SCML 432 has high potential in the food industry as a starter.
Triterpenoids from the leaves of Dendropanax morbifera Léveille and its cytotoxic activity toward breast MCF-7 and lung A549 cancer cells
Authors: Park Soyi , Hwang Kwontack , Na Ju-ryun , Lee Kihoon , Jeong Eui-seon , Kim Sunoh
Published: October 2018

Dendropanax morbifera Léveille (Araliaceae) is an endemic species growing in the south-western part of South Korea and has been used in folk medicine and health functional food. Several studies have indicated that extract of D. morbifera (DP) has cytotoxic activities on a number of human cancers, such as, breast cancer, lung cancer, hepatoma, and chorioepithelioma. Recently, polyacetylene and triterpene compounds have been isolated from the DP and showed to have anti-complement activity. β-Amyrin, α-amyrin, dendropanoxide, and β-sitosterol are isolated from DP. However, its biological activities in cancer have not yet been clearly elucidated. In this study, we evaluated the anti-cancer activity of isolated triterpenoids from the DP leaves by measuring the levels of cytotoxicity against MCF-7 human breast cancer and A549 human lung cancer cells. Six triterpenoids were isolated from the n-hexane fraction of DP leaves along with the known compounds. β-amyrin (1), α-amyrin (2), olean-12-en-3,24 β-diol (3), dendropanoxide (4), β-sitosterol (5), and stigmasterol (6). Compound 3 and 6 were isolated from DP for the first time. Cytotoxic activities of six compounds were evaluated against two human cancer cell lines by using the MTT in vitro assay. Among them, five compounds (1, 2, 4, 5, and 6) showed moderate cytotoxic activities toward the tested cell lines, and were safe to normal cells. Western blot analysis showed a decreased expression of anti-apoptotic protein Bcl-2 and increased levels of pro-apoptotic protein Bax in MCF-7 and A549 cells treated by β-amyrin and α-amyrin. Flow cytometry analysis confirmed that five compounds (1, 2, 4, 5, and 6) treatment increased populations of sub-G1 (apoptosis) phase. The results of the present study revealed that triterpenoids from DP have the potential for further development as anticancer agents.
Comparison of ellagic acid contents in Korean and Chinese cultivated species of unripe black raspberries
Authors: Lee Ki Hoon , Kim Sunoh
Published: October 2018

The goal of this study was to investigate the extracts of ellagic acid in Korean and Chinese black raspberries according to harvest time and extraction solvent. This study was also performed to establish a simple and reliable high-performance liquid chromatography-ultraviolet (HPLC/UV) analytical method for the determination of ellagic acid for quality control and to establish baseline data of extracts of Rubus occidentalis (uRo) and Rubus chingii (uRc) fruits as healthy functional food ingredients. uRo and uRc were each extracted with 0%, 5%, 30%, and 70% ethanol. Among the extracts of these two varieties, the 5% ethanol extracts of uRo and uRc showed the highest contents of ellagic acid, 16.56 and 17.27 mg/g, respectively. The specificity was satisfied with retention time and photo-diode array (PDA) spectrum by analysis of ellagic acid using HPLC and comparison with a standard compound. Ellagic acid was validated for its limit of detection (LOD), limit of quantitation (LOQ), precision, and accuracy. It showed a high linearity in the calibration curve, with a coefficient of determination (R2) of 0.9999, and the LOD and LOQ values were 0.25 and 0.77 μg/mL, respectively. The results showed that R. occidentalis and R. chingii can be used simultaneously as healthy functional ingredients and natural medicines.
Conditions for hydrolysis of perilla seed meal protein for producing hydrolysates and ultrafiltered peptides and their antioxidant activity
Authors: Park Bo Yeon , Yoon Kyung Young
Published: October 2018

This study was conducted to investigate the antioxidant activity of perilla seed meal (PSM) protein hydrolysates and peptide fractions prepared using proteolytic enzymes and ultrafiltration to improve the usability of PSM as a functional food ingredient. Optimal conditions for producing PSM protein hydrolysate using Flavourzyme were determined to be pH 7.0, temperature 50℃, 10 unit of enzyme concentration, and 4 h hydrolysis time. The yield of each peptide fraction obtained by ultrafiltration was found to be the highest (45.65%) in the <1 kDa fraction, followed by 5-10 kDa (16.45%), >10 kDa (16.37%), 1-3 kDa (10.86%), and 3-5 kDa (10.67%), respectively. The DPPH radical scavenging activity was the highest in the hydrolysate, the reducing power was the highest in the 3-5 kDa fraction, and the superoxide dismutase-like activity was the highest in the <1 kDa fractions. The hydrolysate and peptide fractions produced from PSM protein showed different antioxidant activities, and thus they could potentially be used as functional food ingredients. Further evaluation as a functional food ingredient would allow the application of PSM protein hydrolysates as food materials.
Medium optimization for enhanced growth of Bacillus subtilis SRCM102046 possessing antibacterial activity using response-surface methodology
Authors: Ha Gwangsu , Yang Hee-Jong , Jeong Su-Ji , Ryu Myeong Seon , Kim JinWon , Yang HoYeon , Shin Su-Jin , Im Sua , Seo Ji Won , Jeong Seong-Yeop , Jeong Do-Youn
Published: October 2018

The aim of this study was to investigate the optimal conditions for increasing the growth yield of Bacillus subtilis SRCM102046, a strain possessing potential biopreservative properties. B. subtilis SRCM102046 showed remarkable antibacterial activity against a wide range of bacterial foodborne pathogens that cause serious food spoilage, as well as high antioxidant capacity. Response-surface methodology (RSM) was used to optimize medium composition to enhance B. subtilis SRCM102046 biomass. The effects of 14 different components on biomass production were investigated and three significant positive factors, molasses, sucrose, and peptone, were selected as the main factors for improving biomass based on a Plackett-Burman design (PBD). Next, we optimized the concentrations of these three factors using a central composite design. The predicted optimized concentrations were 7 g/L molasses, 7 g/L sucrose, and 2 g/L peptone. The coefficient of determination (R2, 0.9755) for the model and probability value showed that our model was highly significant. Finally, an overall approximate 9-fold increase in dry cell weight yield (22.03 g/L) was achieved using the optimized medium compared with the non-optimized medium (2.47 g/L). Furthermore, we confirmed that the antibacterial activity and antioxidant activity also increased by 140% and 100.41%, respectively. These research is expected to be useful data for the production of food preservatives by establishing optimal conditions for increasing the growth yield of microorganisms possessing excellent antimicrobial activity.
Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications
Authors: Ward Carl C. , Kleinman Jordan I. , Brittain Scott M. , Lee Patrick S. , Chung Clive Yik Sham , Kim Kenneth , Petri Yana , Thomas Jason R. , Tallarico John A. , McKenna Jeffrey M. , Schirle Markus , Nomura Daniel K.
Published: October 2018

Targeted protein degradation has arisen as a powerful strategy for drug discovery allowing the targeting of undruggable proteins for proteasomal degradation. This approach most often employs heterobifunctional degraders consisting of a protein-targeting ligand linked to an E3 ligase recruiter to ubiquitinate and mark proteins of interest for proteasomal degradation. One challenge with this approach, however, is that only few E3 ligase recruiters currently exist for targeted protein degradation applications, despite the hundreds of known E3 ligases in the human genome. Here, we utilized activity-based protein profiling (ABPP)-based covalent ligand screening approaches to identify cysteine-reactive small-molecules that react with the E3 ubiquitin ligase RNF4 and provide chemical starting points for the design of RNF4-based degraders. The hit covalent ligand from this screen reacted with either of two zinc-coordinating cysteines in the RING domain, C132 and C135, with no effect on RNF4 activity. We further optimized the potency of this hit and incorporated this potential RNF4 recruiter into a bifunctional degrader linked to JQ1, an inhibitor of the BET family of bromodomain proteins. We demonstrate that the resulting compound CCW 28-3 is capable of degrading BRD4 in a proteasome- and RNF4-dependent manner. In this study, we have shown the feasibility of using chemoproteomics-enabled covalent ligand screening platforms to expand the scope of E3 ligase recruiters that can be exploited for targeted protein degradation applications.
Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability
Authors: Reynolds Regina H , Botía Juan , Nalls Mike A ,   International Parkinson’s Disease Genomics Consortium (IPDGC),   System Genomics of Parkinson’s Disease (SGPD), Hardy John , Gagliano Sarah A , Ryten Mina
Published: October 2018

Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set specifically expressed in astrocytic and microglial subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes to which cell types may have varying vulnerability.
How face perception unfolds over time
Authors: Dobs Katharina , Isik Leyla , Pantazis Dimitrios , Kanwisher Nancy
Published: October 2018

Within a fraction of a second of viewing a face, we have already determined its gender, age and identity. A full understanding of this remarkable feat will require a characterization of the computational steps it entails, along with the representations extracted at each. To this end, we used magnetoencephalography to measure the time course of neural responses to faces, thereby addressing two fundamental questions about how face processing unfolds over time. First, using representational similarity analysis, we found that facial gender and age information emerged before identity information, suggesting a coarse-to-fine processing of face dimensions. Second, identity and gender representations of familiar faces were enhanced very early on, indicating that the previously-reported behavioral benefit for familiar faces results from tuning of early feed-forward processing mechanisms. These findings start to reveal the time course of face perception in humans, and provide powerful new constraints on computational theories of face perception.
Unbiased Atomistic Insight in the Mechanisms and Solvent Role for Globular Protein Dimer Dissociation
Authors: Brotzakis Faidon Z. , Bolhuis Peter G.
Published: October 2018

Association and dissociation of proteins are fundamental processes in nature. While this process is simple to understand conceptually, the details of the underlying mechanism and role of the solvent are poorly understood. Here we investigate the mechanism and solvent role for the dissociation of the hydrophilic β-lactoglobulin dimer by employing transition path sampling. Analysis of the sampled path ensembles indicates that dissociation (and association) occurs via a variety of mechanisms: 1) a direct aligned dissociation 2) a hopping and rebinding transition followed by unbinding 3) a sliding transition before unbinding. Reaction coordinate and transition state analysis predicts that, besides native contact and vicinity salt-bridge interactions, solvent degrees of freedom play an important role in the dissociation process. Analysis of the structure and dynamics of the solvent molecules reveals that the dry native interface induces enhanced populations of both disordered hydration water and hydration water with higher tetrahedrality, mainly nearby hydrophobic residues. Bridging waters, hydrogen bonded to both proteins, support contacts, and exhibit a faster decay and reorientation dynamics in the transition state than in the native state interface, which renders the proteins more mobile and assists in rebinding. While not exhaustive, our sampling of rare un-biased reactive molecular dynamics trajectories shows in full detail how proteins can dissociate via complex pathways including (multiple) rebinding events. The atomistic insight obtained assists in further understanding and control of the dynamics of protein-protein interaction including the role of solvent.

PACS numbers:
Deficient FGF signaling in the developing peripheral retina disrupts ciliary margin development and causes aniridia
Authors: Balasubramanian Revathi , Tao Chenqi , Polanco Karina , Zhong Jian , Wang Fen , Ma Liang , Zhang Xin
Published: October 2018

The mammalian ciliary margin is a part of the developing peripheral neural retina that differentiates into the ciliary body and the iris. Canonical WNT signaling plays a critical role in the specification of the ciliary margin at the peripheral retina in the presence of strong FGF signaling in the central retina. The mechanism of how the boundary between the central retina and the ciliary margin is created has not been previously elucidated. Using genetic ablation and epistasis experiments, we show that loss of FGF signaling gradient in the peripheral retina causes expansion of WNT signaling towards the central retina thereby disrupting the neurogenic boundary and compartmentalization of the ciliary margin. Loss of WNT signaling displays a complimentary effect with expansion of FGF signaling into the ciliary marginal space. Usingin vivoexperiments, we elucidate the FGF signaling cascade involved in development of the ciliary margin. We also identify the surface ectoderm as the source of WNT ligands in eliciting WNT response at the ciliary margin. We show that an interaction between FGF and WNT signaling is required for generation of the ciliary marginal cells. Taken together, our results reveal that a gradient intersection of FGF and WNT signaling is required for specification of the ciliary margin.
Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma
Authors: Ferguson Blake , Handoko Herlina Y. , Mukhopadhyay Pamela , Chitsazan Arash , Balmer Lois , Morahan Grant , Walker Graeme J.
Published: October 2018

Genetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanoma-prone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset toPrkdc, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit geneRrp15. Ribosome biogenesis was upregulated in skin shortly after UVR exposure, Mechanistically, variation in the “usual suspects” by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.
Perceptual phenotypes: Perceptual gains and losses in synesthesia and schizophrenia
Authors: van Leeuwen Tessa M. , Sauer Andreas , Jurjut Anna-Maria , Wibral Michael , Uhlhaas Peter J. , Singer Wolf , Melloni Lucia
Published: October 2018

Individual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in e.g. perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Different perceptual phenotypes may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients, synesthetes, and controls. Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors – introduced during the hysteresis experiment – lowered thresholds but did not normalize perception. Our results imply that distinct perceptual phenotypes might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.
Proteotoxic stress-induced Nrf1 transcriptional program requires a functional TIP60 complex
Authors: Vangala Janakiram R. , Radhakrishnan Senthil K.
Published: October 2018

In response to inhibition of the cellular proteasome, the transcription factor Nrf1 (also called NFE2L1) induces transcription of proteasome subunit genes resulting in the restoration of proteasome activity and thus enabling the cells to mitigate the proteotoxic stress. To identify novel regulators of Nrf1, we performed an RNA interference screen and discovered that the AAA+ ATPase RUVBL1 is necessary for its transcriptional activity. Given that RUVBL1 is part of different multi-subunit complexes that play key roles in transcription, we dissected this phenomenon further and found that the TIP60 chromatin regulatory complex is essential for Nrf1-dependent transcription of proteasome genes. Consistent with these observations, Nrf1, RUVBL1, and TIP60 proteins were co-recruited to the promoter regions of proteasome genes after proteasome inhibitor treatments. More importantly, depletion of RUVBL1 or TIP60 in various cancer cells sensitized them to cell death induced by proteasome inhibition. Our study provides a framework for manipulating the Nrf1-TIP60 axis to alter proteasome function in various human diseases including cancer.
Evolution of protein kinase substrate recognition at the active site
Authors: Bradley David , Beltrao Pedro
Published: October 2018

Protein kinases catalyse the phosphorylation of target proteins, controlling most cellular processes. The specificity of serine/threonine kinases is partly determined by interactions with a few residues near the phospho-acceptor residue, forming the so-called kinase substrate motif. Kinases have been extensively duplicated throughout evolution but little is known about when in time new target motifs have arisen. Here we show that sequence variation occurring early in the evolution of kinases is dominated by changes in specificity determining residues. We then analysed kinase specificity models, based on known target sites, observing that specificity has remained mostly unchanged for recent kinase duplications. Finally, analysis of phosphorylation data from a taxonomically broad set of 48 eukaryotic species indicates that most phosphorylation motifs are broadly distributed in eukaryotes but not present in prokaryotes. Overall, our results suggest that the set of eukaryotes kinase motifs present today was acquired soon after the eukaryotic last common ancestor and that early expansions of the protein kinase fold rapidly explored the space of possible target motifs.
Diverse chemical compounds target Plasmodium falciparum plasma membrane lipid homeostasis
Authors: Bhatnagar Suyash , Nicklas Sezin , Morrisey Joanne M. , Goldberg Daniel E. , Vaidya Akhil B.
Published: October 2018

Lipid homeostasis is essential for the maintenance of life. We previously reported that disruptions of the parasite Na+ homeostasis via inhibition of PfATP4 resulted in elevated cholesterol within the parasite plasma membrane as assessed by saponin sensitivity. A large number of compounds have been shown to target the parasite Na+ homeostasis. We therefore screened the same collection of 800 compounds to identify chemotypes that disrupted the parasite plasma membrane lipid homeostasis. Here, we show that the compounds disrupting parasite Na+ homeostasis also induced saponin sensitivity, an indication of parasite lipid homeostasis disruption. Remarkably, 13 compounds were identified that altered plasma membrane lipid composition independent of Na+ homeostasis disruption. Further studies suggest that these compounds target the Plasmodium falciparum Niemann-Pick Type C1-Related (PfNCR1) protein, which is hypothesized to be involved in maintaining plasma membrane lipid composition. PfNCR1, like PfATP4, appears to be targeted by multiple chemotypes with potential for drug discovery.
Biology and Bias in Cell Type-Specific RNAseq of Nucleus Accumbens Medium Spiny Neurons
Authors: Kronman Hope , Richter Felix , Labonté Benoit , Chandra Ramesh , Zhao Shan , Hoffman Gabriel , Lobo Mary Kay , Schadt Eric E. , Nestler Eric J.
Published: October 2018

Isolation of cell populations is untangling complex biological interactions, but studies comparing methodologies lack in vivo complexity and draw limited conclusions about the types of transcripts identified by each technique. Furthermore, few studies compare FACS-based techniques to ribosomal affinity purification, and none do so genome-wide. We addressed this gap by systematically comparing nuclear-FACS, whole cell-FACS, and RiboTag affinity purification in the context of D1 or D2 dopamine receptor-expressing medium spiny neuron (MSN) subtypes of the nucleus accumbens (NAc), a key brain reward region. We find that nuclear-FACS-seq generates a substantially longer list of differentially expressed genes between these cell types, and a significantly larger number of neuropsychiatric GWAS hits than the other two methods. RiboTag-seq has much lower coverage of the transcriptome than the other methods, but very efficiently distinguishes D1- and D2-MSNs. We also demonstrate differences between D1- and D2-MSNs with respect to RNA localization, suggesting fundamental cell type differences in mechanisms of transcriptional regulation and subcellular transport of RNAs. Together, these findings guide the field in selecting the RNAseq method that best suits the scientific questions under investigation.
CoCoScore: Context-aware co-occurrence scoring for text mining applications using distant supervision
Authors: Junge Alexander , Jensen Lars Juhl
Published: October 2018

Information extraction by mining the scientific literature is key to uncovering relations between biomedical entities. Most existing approaches based on natural language processing extract relations from single sentence-level co-mentions, ignoring co-occurrence statistics over the whole corpus. Existing approaches counting entity co-occurrences ignore the textual context of each co-occurrence. We propose a novel corpus-wide co-occurrence scoring approach to relation extraction that takes the textual context of each co-mention into account. Our method, called CoCoScore, scores the certainty of stating an association for each sentence that co-mentions two entities. CoCoScore is trained using distant supervision based on a gold-standard set of associations between entities of interest. Instead of requiring a manually annotated training corpus, co-mentions are labeled as positives/negatives according to their presence/absence in the gold standard. We show that CoCoScore outperforms previous approaches in identifying human disease-gene and tissue-gene associations as well as in identifying physical and functional protein-protein associations in different species. CoCoScore is a versatile text-mining tool to uncover pairwise associations via co-occurrence mining, within and beyond biomedical applications. CoCoScore is available at: https://github.com/JungeAlexander/cocoscore