Deciphering Heteroresistance to Colistin in a Klebsiella pneumoniae Isolate from Marseille, France.

Abstract: Here, we report the description of a colistin-heteroresistant Klebsiella pneumoniae isolate fortuitously isolated from the stool sample of a patient with suspicion of tuberculosis in a public hospital of Marseille, France. In the colistin-resistant subpopulation, a mutation in the mgrB gene leading to a premature stop codon was found, and the hypermucoviscous phenotype was lost. Susceptibility to other antibiotics remained unchanged. To our knowledge, this is the first identification of such a colistin-heteroresistant Klebsiella pneumoniae isolate in France.

Bardet|Lucie|L|
Baron|Sophie|S|
Leangapichart|Thongpan|T|
Okdah|Liliane|L|
Diene|Seydina M|SM|
Rolain|Jean-Marc|JM|

D000900:Anti-Bacterial Agents
D001426:Bacterial Proteins
D003091:Colistin
D024881:Drug Resistance, Bacterial
D005602:France
D007711:Klebsiella pneumoniae
D008826:Microbial Sensitivity Tests

heteroresistance
colistin
Klebsiella pneumoniae
mgrB


Development of job demands, decision authority and social support in industries with different gender composition - Sweden, 1991-2013.

Abstract:
BACKGROUND
This study aims to explore the development of job demands, decision authority and social support within and between industries with different gender composition in Sweden between 1991 and 2013.

METHODS
Cross-sectional data from 12 waves of the Swedish Work Environment Surveys (1991 to 2013), comprising in total 109,698 respondents, were used. Industries were classified in 7 categories according to its gender composition and main activity, comprising two female-dominated, three gender-mixed and two male-dominated industries. Proportions of workers reporting high job demands, low decision authority and poor social support between 1991 and 2013 were calculated. Logistic regression analyses were performed to estimate variation across time, using 1991 as the reference category, and between industries, using knowledge intensive services as the reference category. Estimates for high job demands, low decision authority and poor social support were presented as average marginal effects (AMEs).

RESULTS
The probabilities of reporting low decision authority were higher in education and health and social care during the whole study period, for both genders, compared with the reference category of knowledge intensive services. The probability of having high job demands were higher for men and women in education, and women in health and social care, compared with the reference category. Men in the male dominated industries had increased job demands over time, compared to the beginning of the study period (1991). The probability of reporting poor social support was higher in the later than in the earliest time period for women in the female-dominated industry health and social care as well as in the gender-mixed labour intensive services industry.

CONCLUSIONS
There has been a negative development of job demands and decision authority in the female-dominated industries education and health and social care in Sweden, whereas social support has developed more negatively for women in health and social care and in labour intensive services.

Job demands
Decision authority
Social support
Industry
Gender composition
Sweden
Average marginal effects
Development over time


Diffusion in hierarchical systems: A simulation study in models of healthy and diseased muscle tissue.

Abstract:
PURPOSE
To investigate the sensitivity of diffusion-MR signal to microstructural change in muscle tissue associated with pathology, and recommend optimal acquisition parameters.

METHODS
We employ Monte-Carlo simulation of diffusing spins in hierarchical tissue to generate synthetic diffusion-weighted signal curves over a wide range of scan parameters. Curves are analyzed using entropy-a measure of curve complexity. Entropy change between a baseline and various microstructural scenarios is investigated. We find acquisitions that optimize entropy difference in each scenario.

RESULTS
Permeability changes have a large effect on the diffusion-weighted signal curve. Muscle fiber atrophy is also important, although differentiating between mechanisms is challenging. Several acquisitions over a range of diffusion times is optimal for imaging microstructural change in muscle tissue. Sensitivity to permeability is optimized for high gradient strengths, but sensitivity to other scenarios is optimal at other values.

CONCLUSIONS
The diffusion-attenuated signal is sensitive to the microstructural changes, but the changes are subtle. Taking full advantage of the changes to the overall curve requires a set of acquisitions over a range of diffusion times. Permeability causes the largest changes, but even the very subtle changes associated with fiber radius distribution change the curves more than noise alone. Magn Reson Med 78:1187-1198, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

D038524:Diffusion Magnetic Resonance Imaging

muscle
Monte-Carlo simulation
entropy
Duchenne muscular dystrophy
diffusion MRI
pathology modeling


Sexual and reproductive health of adolescents in schools for people with disabilities.

Abstract:
Introduction
Persons with disabilities have the same sexual and reproductive health (SRH) needs as the abled people but they often face barriers to SRH information and services which are necessary for healthy and safe relationships, protection from HIV and other sexually transmitted infections (STIs). This study sought to access the SRH services among adolescents with disabilities in four Special Needs Schools in Ghana.

Methods
The study adopted a cross-sectional study design with a quantitative approach to data collection between the months of January to March, 2018. A structured and pretested questionnaire was used to collect data from adolescents with disabilities from selected schools in Ghana. Both descriptive and inferential statistics were performed using chi-square test and multivariate logistic regression.

Results
Majority of participants had hearing disability (52.1%). The average age at menarche among females was 13 years whiles the age at which puberty was attained among boys was 14 years. School teachers were the major source of information on SRH for the respondents (63.7%) followed by parents (12.2%). A majority (67.1%) of respondents had good knowledge of SRH. Factors which were significantly associated with knowledge level were age (p=0.026), religion (p=0.034), sources of information (p<0.001), guardians (p=0.049).

Conclusion
The majority of participants had good knowledge of SRH, although their knowledge of contraceptive and access were poor. Only condoms were mostly known. There is the need for increased awareness on the availability of other contraceptives methods and the removal of barriers to contraceptive methods.

Obasi|Mercy|M|
Manortey|Stephen|S|
Kyei|Kofi Adesi|KA|
Addo|Michael Kwabeng|MK|
Talboys|Sharon|S|
Gay|Lynette|L|
Baiden|Frank|F|

D007722:Health Knowledge, Attitudes, Practice

sexual
reproductive health
Adolescent
disability
assessment


Concept, mechanism, and applications of phenolic antioxidants in foods.

Abstract: In this review, the concept of phenolic antioxidants, mechanisms of action, and applications have been reviewed. Phenolic compounds (PCs) acts as an antioxidant by reacting with a variety of free radicals. The mechanism of antioxidant actions involved either by hydrogen atom transfer, transfer of a single electron, sequential proton loss electron transfer, and chelation of transition metals. In foods, the PCs act as antioxidants which are measured with several in vitro spectroscopic methods. The PCs have been found in milk and a wide range of dairy products with sole purposes of color, taste, storage stability, and quality enhancement. The role of PCs in three types of food additives, that is, antimicrobial, antioxidant, and flavoring agents have been critically reviewed. The literature revealed that PCs present in a variety of foods possess several health benefits such as antibacterial, antihyperlipidemic, anticancer, antioxidants, cardioprotective, neuroprotective, and antidiabetic properties. PRACTICAL APPLICATIONS: Phenolic compounds are strong antioxidants and are safer than synthetic antioxidants. The wide occurrence in plant foods warranted continuous review applications. This review, therefore, presented an updated comprehensive overview of the concept, mechanism, and applications of phenolic antioxidants in foods.

mechanism
applications
antioxidant
Phenolic compounds
free radicals
health benefits


Effect of (2)H and (18)O water isotopes in kinesin-1 gliding assay.

Abstract: We show for the first time the effects of heavy-hydrogen water ((2)H2O) and heavy-oxygen water (H2 (18)O) on the gliding speed of microtubules on kinesin-1 coated surfaces. Increased fractions of isotopic waters used in the motility solution decreased the gliding speed of microtubules by a maximum of 21% for heavy-hydrogen and 5% for heavy-oxygen water. We also show that gliding microtubule speed returns to its original speed after being treated with heavy-hydrogen water. We discuss possible interpretations of these results and the importance for future studies of water effects on kinesin and microtubules. We also discuss the implication for using heavy waters in biomolecular devices incorporating molecular motors.

Maloney|Andy|A|
Herskowitz|Lawrence J|LJ|
Koch|Steven J|SJ|

Kinesin-1
Microtubules
Gliding motility assay
Heavy-water


Circulating growth/differentiation factor 15 is associated with human CD56bright natural killer cell dysfunction and nosocomial infection in severe systemic inflammation.

Abstract:
BACKGROUND
Systemic inflammation induced by sterile or infectious insults is associated with an enhanced susceptibility to life-threatening opportunistic, mostly bacterial, infections due to unknown pathogenesis. Natural killer (NK) cells contribute to the defence against bacterial infections through the release of Interferon (IFN) γ in response to Interleukin (IL) 12. Considering the relevance of NK cells in the immune defence we investigated whether the function of NK cells is disturbed in patients suffering from serious systemic inflammation.

METHODS
NK cells from severely injured patients were analysed from the first day after the initial inflammatory insult until the day of discharge in terms of IL-12 receptor signalling and IFN-γ synthesis.

FINDINGS
During systemic inflammation, the expression of the IL-12 receptor β2 chain, phosphorylation of signal transducer and activation 4, and IFN-γ production on/in NK cells was impaired upon exposure to Staphylococcus aureus. The profound suppression of NK cells developed within 24 h after the initial insult and persisted for several weeks. NK cells displayed signs of exhaustion. Extrinsic changes were mediated by the early and long-lasting presence of growth/differentiation factor (GDF) 15 in the circulation that signalled through the transforming growth factor β receptor I and activated Smad1/5. Moreover, the concentration of GDF-15 in the serum inversely correlated with the IL-12 receptor β2 expression on NK cells and was enhanced in patients who later acquired septic complications.

INTERPRETATION
GDF-15 is associated with the development of NK cell dysfunction during systemic inflammation and might represent a novel target to prevent nosocomial infections. FUND: The study was supported by the Department of Orthopaedics and Trauma Surgery, University Hospital Essen.

Kleinertz|Holger|H|
Hepner-Schefczyk|Monika|M|
Ehnert|Sabrina|S|
Claus|Maren|M|
Halbgebauer|Rebecca|R|
Boller|Lea|L|
Huber-Lang|Markus|M|
Cinelli|Paolo|P|
Kirschning|Carsten|C|
Flohé|Sascha|S|
Sander|André|A|
Waydhas|Christian|C|
Vonderhagen|Sonja|S|
Jäger|Marcus|M|
Dudda|Marcel|M|
Watzl|Carsten|C|
Flohé|Stefanie B|SB|

D055436:Growth Differentiation Factor 15

D018746:Systemic Inflammatory Response Syndrome

Natural killer cells
Immunosuppression
Interferon gamma
Interleukin 12
Opportunistic infections
Transforming growth factor receptor


Effects of grain adaptation programs and antimicrobial feed additives on performance and nutrient digestibility of Bos indicus cattle fed whole shelled corn.

Abstract: Two experiments were conducted to evaluate the effects of feed additives [monensin (MON); 30 mg/kg of dry matter (DM), and virginiamycin (VM); 25 mg/kg DM] and grain adaptation programs [adding roughage (ROU; sugarcane bagasse) or not (NO-ROU) during the 20-d adaptation period] on performance, carcass characteristics, and nutrient digestibility of Bos indicus cattle fed finishing diets containing 85% whole shelled corn and 15% of a pelleted protein-mineral-vitamin supplement. In Exp.1, 105 Nellore bulls [initial body weight (BW) = 368 ± 25 kg] were used in a complete randomized block design with a 2 × 2 factorial arrangement of treatments, consisting of two feed additives (MON and VM) associated with two adaptation programs (ROU or NO-ROU during the 20-d adaptation period). Effects of feed additives × adaptation programs were not detected (P ≥ 0.13). Feed additives did not affect dry matter intake (DMI), average daily gain (ADG), and feed efficiency (G:F) during the 20-d adaptation period (P ≥ 0.35). During the total feeding period (105 d), feeding MON decreased DMI (P ≤ 0.03) compared to VM. Adding sugarcane bagasse to finishing diets during the 20-d adaptation period (ROU) increased ADG (P = 0.05) and G:F (P = 0.03), and tended to increase BW (P = 0.09) compared to NO-ROU. In Exp. 2, 10 ruminally cannulated Nellore steers (BW = 268 ± 38 kg) were used in a completely randomized design to evaluate the effects of the two feed additives used in the Exp. 1 (MON and VM; 5 steers/treatment) on DMI, total apparent digestibility of nutrients, and ruminal fermentation characteristics. No differences in DMI, total tract apparent digestibility of nutrients, and ruminal fermentation characteristics were observed between MON and VM (P ≥ 0.32). An effect of sampling day (P < 0.001) was observed for ruminal pH, which was greater on day 0 compared to day 7, 14, and 21 of the experimental period (P ≤ 0.05). In summary, supplementing monensin and virginiamycin for finishing Nellore bulls fed whole shelled corn diets, resulted in similar growth performance and carcass characteristics. Including sugarcane bagasse to adapt finishing bulls to no-roughage diets containing whole shelled corn is an alternative to increase growth performance.

adaptation
monensin
virginiamycin
roughage
beef cattle
feedlot


When student midwives are present during labour and childbirth in a peer-learning model: An interview study of parents in Sweden.

Abstract:
OBJECTIVE
For peer learning to be useful in clinical practice, we need to know how parents experience peer learning during labour and childbirth. This study explored how parents experienced having two students present during labour and childbirth in a peer-learning model.

DESIGN
A qualitative approach using individual interviews followed by thematic inductive analysis.

SETTING
Three hospitals and obstetric units in Stockholm, Sweden.

PARTICIPANTS
Eleven women and nine partners.

FINDINGS
The overarching theme was that of a fruitful model of health care, in which there were gains for both parents and students. Parents described feeling seen and cared for, being made aware of what was going on, and never being left alone (subtheme 1, Trustful relationship). Parents appreciated being able to observe student midwives' attendance to the tasks at hand and that they, the two students, learned from each other (subtheme 2, Advantages for students).

CONCLUSIONS
The parent couple was able to build a trustful relationship with both students. Furthermore, could parents only see advantages for students in a peer-learning model. Parents reported generous support and were willing to contribute to student education. Parents took advantage of the learning taking place between the two students. The model deserves to be incorporated in the midwifery-student internships to complement more individually assisted births.

Student midwives
Labour and childbirth
Peer learning
Clinical practice
Parent experiences


N-acetylglucosaminyltransferase V modulates radiosensitivity and migration of small cell lung cancer through epithelial-mesenchymal transition.

Abstract: N-acetylglucosaminyltransferase V (Gnt-V) has been linked to the migration of various human cancers. Recently we have found that inhibition of Gnt-V increases the radiosensitivity of cancer cells. However, the mechanisms by which Gnt-V mediates radiosensitivity and migration, especially in small cell lung cancer (SCLC) remain unknown. In our study, two SCLC cell lines (H1688 and H146) were used to investigate whether Gnt-V modulated the radiosensitivity and migration of SCLC cells through the epithelial-mesenchymal transition (EMT). The results showed that the expression of Gnt-V correlated with the N stage in patients with SCLC. Overexpression of Gnt-V led to a further increase in the relative viable cell number and survival fraction with a decrease in apoptosis rate and Bax/Bcl-2 ratio, when the cells were treated with irradiation. By contrast, knockdown of Gnt-V with irradiation resulted in a further decrease in the relative viable cell number and survival fraction but an increase in apoptosis rate and Bax/Bcl-2 ratio. Cells expressing high levels of Gnt-V increased migration whereas low levels of Gnt-V suppressed cell migration. Besides, the transient knockdown of ZEB2 led to an increase in radiosensitivity and an inhibition in the migration of SCLC cells. Furthermore, Gnt-V was negatively correlated with E-cadherin expression but positively correlated with N-cadherin, vimentin and ZEB2 expression. Finally, an in vivo study revealed that upregulation of Gnt-V caused tumour growth more quickly, as well as the expression of EMT-related markers (N-cadherin, vimentin and ZEB2). Taken together, the study suggested that an elevation of Gnt-V could lead to the radiosensitivity and migration of SCLC cells by inducing EMT, thereby highlighting Gnt-V as a potential therapeutic target for the prevention of EMT-associated tumour radioresistance and migration.

Huang|Chunyue|C| Huang|Miaojuan|M| Chen|Wenxia|W| Zhu|Weiliang|W| Meng|Hui|H| Guo|Linlang|L| Wei|Ting|T| Zhang|Jian|J|

N-acetylglucosaminyltransferase V
radiosensitivity
migration
small cell lung cancer
epithelial-mesenchymal transition


Jumpstart Mirror Trainer: A New Device for Teaching Mirror Skills to First-Year Dental Students.

Abstract: Learning indirect vision with a dental mirror is challenging and can be overwhelming for beginning dental students. The Jumpstart Mirror Trainer is a new device that allows students to become proficient with mirror use before the start of preclinic without requiring in-class practice sessions. The aim of this study, conducted in 2017, was to compare the effectiveness of the Jumpstart Mirror Trainer with the Mirroprep for teaching indirect motor skills. Forty-seven first-year dental students were randomized into three groups to use the Jumpstart Mirror Trainer, Mirroprep, or a control device for 15 minutes a day for ten days. To assess indirect motor skills improvement, students performed a maxillary cavity preparation before and after using their devices. A survey was used to assess students' comfort level with mirror skills and perceived helpfulness of the exercises. Forty students completed the study. The Jumpstart Mirror Trainer activities improved the students' scores significantly more than the Mirroprep activities (p=0.04) and the control device (p=0.006). Students in the Jumpstart Mirror Trainer group rated their device as being significantly more helpful than the control group rated its device in preparing them for the evaluation (p=0.001). There was no statistically significant difference in perceived helpfulness between the Mirroprep group and the control group (p=0.75). These results suggest that the Jumpstart Mirror Trainer may be able to improve students' indirect motor skills without requiring in-class practice sessions and to do so more effectively than other existing methods.

McClure|Alexander R|AR|
Roomian|Tamar C|TC|
Eisen|Steven E|SE|
Kugel|Gerard|G|
Amato|Robert B|RB|

D002983:Clinical Competence
D003737:Dental Cavity Preparation
D003762:Dental Instruments
D004497:Education, Dental
D004867:Equipment Design
D006801:Humans
D009048:Motor Skills
D016544:Patient Simulation
D013663:Teaching

Keywords: dental education
ergonomics
operative dentistry
patient simulation
psychomotor skills


Small RNA Profiling in Mycobacterium Provides Insights Into Stress Adaptability.

Abstract: Mycobacteria encounter a number of environmental changes during infection and respond using different mechanisms. Small RNA (sRNA) is a post-transcriptionally regulatory system for gene functions and has been investigated in many other bacteria. This study used Mycobacterium tuberculosis and Mycobacterium bovis Bacillus Calmette-Guérin (BCG) infection models and sequenced whole bacterial RNAs before and after host cell infection. A comparison of differentially expressed sRNAs using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) and target prediction was carried out. Six pathogenically relevant stress conditions, growth rate, and morphology were used to screen and identify sRNAs. From these data, a subset of sRNAs was differentially expressed in multiple infection groups and stress conditions. Many were found associated with lipid metabolism. Among them, ncBCG427 was significantly downregulated when BCG entered into macrophages and was associated with increased biofilm formation. The reduction of virulence possibility depends on regulating lipid metabolism.

Chen|Yingyu|Y| Zhai|Wenjun|W| Zhang|Kailun|K| Liu|Han|H| Zhu|Tingting|T| Su|Li|L| Bermudez|Luiz|L| Chen|Huanchun|H| Guo|Aizhen|A|

stress
mycobacteria
sRNA
Mycobacterium bovis
Mycobacterium bovis BCG


Urinalysis of MMX-mesalazine as a tool to monitor 5-ASA adherence in daily IBD practice.

Abstract: Adherence is pivotal but challenging in ulcerative colitis (UC) treatment. Many methods to assess adherence are subjective or have limitations. (Nac-)5-aminosalicylic acid (5-ASA) urinalysis by high-performance liquid chromatography (HPLC) seems feasible and reproducible in healthy volunteers. We performed a prospective study in adult quiescent UC patients to evaluate the feasibility of spot (Nac-)5-ASA urinalysis by HPLC to assess adherence in daily inflammatory bowel disease (IBD) care. Twenty-nine patients (51.7% male, mean age 52 ± 11 years) were included (median FU 9 months) and weekly spot urine samples were collected. We found large variation in spot (Nac-)5-ASA urinary excretion that was unrelated to brand, dosing schedule or dosage of 5-ASA. In conclusion, spot (Nac-)5-ASA urinalysis is not applicable to assess 5-ASA adherence in daily IBD care.

D002851:Chromatography, High Pressure Liquid

MMX-mesalazine
adherence
HPLC
inflammatory bowel disease
compliance


Characterization of the immune response in human paracoccidioidomycosis.

Abstract:
OBJECTIVES
Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the dimorphic fungus Paracoccidioides brasiliensis that presents two main clinical forms: the adult form (AF) and the juvenile form (JF); and an asymptomatic form denominated PCM-infection (PI). These forms of PCM are related to the immune response developed after infection, which has been associated with Th1 and Th2 responses. However, some PCM characteristics cannot be explained by this balance. In this study we aimed to complement the characterization of the immune response in PCM, including the newly described T cells subpopulations (Th17, Th9 and Th22).

METHODS
We analyzed the expression of cytokines and transcription factors characteristics of these different subpopulations of CD4(+) T cells in PBMCs from PCM patients and a PI group.

RESULTS
The results showed that the PI group presented a predominant Th1 response; that JF patients were characterized by a mixed Th2/Th9 response; and AF patients were characterized by a predominant Th17/Th22 response, as well as substantial participation of Th1 cells.

CONCLUSIONS
These results contribute to the existing knowledge on the immune responses associated with resistance or susceptibility to the P. brasiliensis infection, and thus could lead to the development of new strategies for patient management.

de Castro|Lívia Furquim|LF|
Ferreira|Maria Carolina|MC|
da Silva|Rosiane Maria|RM|
Blotta|Maria Heloisa de Souza Lima|MH|
Longhi|Larissa Nara Alegrini|LN|
Mamoni|Ronei Luciano|RL|

D000704:Analysis of Variance
D016022:Case-Control Studies
D015331:Cohort Studies
D016207:Cytokines
D006801:Humans
D010229:Paracoccidioidomycosis
D006377:T-Lymphocytes, Helper-Inducer
D018417:Th1 Cells
D058504:Th17 Cells
D018418:Th2 Cells


False-positive Aspergillus galactomannan immunoassays associated with intravenous human immunoglobulin administration.

Abstract:
OBJECTIVES
Evidence of false-positive galactomannan enzyme immunoassay (GM-EIA) results associated with intravenous immunoglobulin (IVIG) administration is scarce. Here, we aimed to determine the false-positive rate of GM-EIA after IVIG administration and to identify the related factors.

METHODS
Standard GM-EIA was performed using diluted and pure human IVIG samples with and without heat treatment. We also included adult patients who had at least one GM-EIA result within 1 week of IVIG administration for analysis. Those who had prior invasive aspergillosis within 1 year before IVIG therapy were excluded. The clinical characteristics and galactomannan index (GMI) kinetics between patients with false-positive and true-positive GMI were compared.

RESULTS
All diluted and pure IVIG samples tested positive for GM. Heat treatment resulted in the considerable elevation of GMI. Of 48 patients with positive GM-EIA results within 1 week of IVIG administration, 22 (45.8%) were considered to have false-positive antigenaemia (false-positive group, FPG). After the completion of IVIG administration, a decline in GMI was observed in all FPG patients but in only 18 out of 26 patients (69.2%) with true-positive results (true-positive group, TPG). By 7, 14, and 18 days of IVIG administration, GMI reverted to negative values in 7/15 (46.7%), 18/20 (90%) and 22/22 (100%) FPG patients, respectively, and 6/24 (25%), 14/24 (58.3%), and 16/26 (61.5%) of TPG patients, respectively. The TPG was more likely to have two or more consecutively positive GMIs after IVIG administration than the FPG (adjusted odds ratio, 9.01; 95% confidence interval, 1.99-40.9).

CONCLUSIONS
IVIG treatment may produce false-positive GM-EIA results. A positive GMI among patients receiving human IVIG should be interpreted with caution.

Liu|W-D|WD| Lin|S-W|SW| Shih|M-C|MC| Su|C-L|CL| Wang|Y-W|YW| Lin|S-C|SC| Lee|Y-F|YF| Huang|H-H|HH| Chou|W-C|WC| Wu|U-I|UI| Chen|Y-C|YC| Chang|S-C|SC|

False-positive
Aspergillus
Galactomannan
Human immunoglobulin
IVIG


The Contemporary Use of Radium-223 in Metastatic Castration-resistant Prostate Cancer.

Abstract: Radium-223 dichloride (radium-223) was approved for the treatment of patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases in the United States and Europe in 2013. This followed a reported overall survival benefit for patients treated with radium-223 and best standard of care (BSoC) when compared with placebo and BSoC in the ALpharadin in SYMptomatic Prostate CAncer (ALSYMPCA) trial. At that time, docetaxel was the standard first-line choice for patients with metastatic CRPC (mCRPC). Since then, the treatment landscape has changed dramatically with new hormonal agents (abiraterone and enzalutamide) considered to be the first-line choice for many patients. The optimal patient profile for radium-223 in the modern setting, and its best use either in sequence or in combination with other approved agents are unclear, with few definitive guidelines available. This article reports on the views of a group of urologists and medical oncologists experienced in treating patients with mCRPC with radium-223 in routine clinical practice. The aim is to provide an overview of the current use of radium-223 in the treatment of patients with mCRPC, and to discuss best practices for patient selection and on-treatment monitoring. Where agreement was reached, guidance on the optimal use of radium-223 is provided.

Heinrich|Daniel|D|
Bektic|Jasmin|J|
Bergman|Andries M|AM|
Caffo|Orazio|O|
Cathomas|Richard|R|
Chi|Kim N|KN|
Daugaard|Gedske|G|
Keizman|Daniel|D|
Kindblom|Jon|J|
Kramer|Gero|G|
Olmos|David|D|
Omlin|Aurelius|A|
Sridhar|Srikala S|SS|
Tucci|Marcello|M|
van Oort|Inge|I|
Nilsson|Sten|S|

Bone metastases
Patient selection
Targeted alpha therapy
Treatment monitoring
Treatment sequence


Synchronous leiomyosarcoma and fibroma in a single ovary: A case report and review of the literature.

Abstract: Primary ovarian leiomyosarcoma (POLMS) is a rare disease. To the best of our knowledge, only 72 cases, including the present case, have been reported in the English literature, while synchronous POLMS and fibroma in a single ovary have not previously been reported at all. In the present study, a 46-year-old premenopausal woman was diagnosed with a mass in the left ovary in 2005. A total of 5 years after the diagnosis of this mass, the patient was admitted to hospital exhibiting lower abdominal pain, and two masses were observed in the left ovary. An exploratory laparoscopy was performed. Frozen section analysis led to a diagnosis of fibroma. Furthermore, the observed second mass was hypothesized to be a malignant form of the original fibroma. A hysterectomy and bilateral salpingo-oophorectomy were performed. Pathological reports following surgery revealed concurrent stage Ic POLMS and fibroma in the left ovary. A total of 13 months after the initial surgery, recurrent leiomyosarcoma was detected. Although the patient underwent multiple cytoreductive surgeries and chemotherapy cycles, as well as interstitial brachytherapy and conventional therapy, a poor state of health ensued. Due to the rarity of POLMS, particularly in combination with ovarian fibroma, the current report presents a detailed overview of the literature and discusses a number of histogenetic and clinical issues.

He|Meng|M| Deng|Yan-Jie|YJ| Zhao|Dan-Yi|DY| Zhang|Yang|Y| Wu|Tao|T|

leiomyosarcoma
fibroma
ovary
histogenesis
synchronous tumors


Phototrophic Fe(II)-oxidation in the chemocline of a ferruginous meromictic lake.

Abstract: Precambrian Banded Iron Formation (BIF) deposition was conventionally attributed to the precipitation of iron-oxides resulting from the abiotic reaction of ferrous iron (Fe(II)) with photosynthetically produced oxygen. Earliest traces of oxygen date from 2.7 Ga, thus raising questions as to what may have caused BIF precipitation before oxygenic photosynthesis evolved. The discovery of anoxygenic phototrophic bacteria thriving through the oxidation of Fe(II) has provided support for a biological origin for some BIFs, but despite reports suggesting that anoxygenic phototrophs may oxidize Fe(II) in the environment, a model ecosystem of an ancient ocean where they are demonstrably active was lacking. Here we show that anoxygenic phototrophic bacteria contribute to Fe(II) oxidation in the water column of the ferruginous sulfate-poor, meromictic lake La Cruz (Spain). We observed in-situ photoferrotrophic activity through stimulation of phototrophic carbon uptake in the presence of Fe(II), and determined light-dependent Fe(II)-oxidation by the natural chemocline microbiota. Moreover, a photoferrotrophic bacterium most closely related to Chlorobium ferrooxidans was enriched from the ferruginous water column. Our study for the first time demonstrates a direct link between anoxygenic photoferrotrophy and the anoxic precipitation of Fe(III)-oxides in a ferruginous water column, providing a plausible mechanism for the bacterial origin of BIFs before the advent of free oxygen. However, photoferrotrophs represent only a minor fraction of the anoxygenic phototrophic community with the majority apparently thriving by sulfur cycling, despite the very low sulfur content in the ferruginous chemocline of Lake La Cruz.

Walter|Xavier A|XA|
Picazo|Antonio|A|
Miracle|Maria R|MR|
Vicente|Eduardo|E|
Camacho|Antonio|A|
Aragno|Michel|M|
Zopfi|Jakob|J|

banded iron formation
anoxygenic photosynthesis
cryptic sulfur cycling
early life evolution
geomicrobiology


Composition and Activity of the Non-canonical Gram-positive SecY2 Complex.

Abstract: The accessory Sec system in Streptococcus gordonii DL1 is a specialized export system that transports a large serine-rich repeat protein, Hsa, to the bacterial surface. The system is composed of core proteins SecA2 and SecY2 and accessory Sec proteins Asp1-Asp5. Similar to canonical SecYEG, SecY2 forms a channel for translocation of the Hsa adhesin across the cytoplasmic membrane. Accessory Sec proteins Asp4 and Asp5 have been suggested to work alongside SecY2 to form the translocon, similar to the associated SecY, SecE, and SecG of the canonical system (SecYEG). To test this theory, S. gordonii secY2, asp4, and asp5 were co-expressed in Escherichia coli The resultant complex was subsequently purified, and its composition was confirmed by mass spectrometry to be SecY2-Asp4-Asp5. Like SecYEG, the non-canonical complex activates the ATPase activity of the SecA motor (SecA2). This study also shows that Asp4 and Asp5 are necessary for optimal adhesion of S. gordonii to glycoproteins gp340 and fibronectin, known Hsa binding partners, as well as for early stage biofilm formation. This work opens new avenues for understanding the structure and function of the accessory Sec system.

Bandara|Mikaila|M|
Corey|Robin A|RA|
Martin|Remy|R|
Skehel|J Mark|JM|
Blocker|Ariel J|AJ|
Jenkinson|Howard F|HF|
Collinson|Ian|I|

D001426:Bacterial Proteins
D002135:Calcium-Binding Proteins
D004268:DNA-Binding Proteins
D006801:Humans
D011956:Receptors, Cell Surface
D000069816:SEC Translocation Channels
D054773:Streptococcus gordonii
D025521:Tumor Suppressor Proteins

SecY2
complex
accessory Sec system
Streptococcus gordonii
transport
membrane
translocon
ATPase
secretion


SWOT analysis and revelation in traditional Chinese medicine internationalization.

Abstract: Traditional Chinese medicine (TCM) is currently the best-preserved and most influential traditional medical system with the largest number of users worldwide. In recent years, the trend of TCM adoption has increased greatly, but the process of TCM internationalization has suffered from a series of setbacks for both internal and external reasons. Thus, the process of TCM internationalization faces formidable challenges, although it also has favourable opportunities. Using SWOT analysis, this paper investigates the strengths, weaknesses, opportunities and threats for TCM. These findings can serve as references for TCM enterprises with global ambitions.

Tang|Haitao|H| Huang|Wenlong|W| Ma|Jimei|J| Liu|Li|L|


High cognitive reserve in bipolar disorders as a moderator of neurocognitive impairment.

Abstract:
BACKGROUND
Cognitive reserve (CR) reflects the capacity of the brain to endure neuropathology, minimize clinical manifestations and successfully complete cognitive tasks. The present study aims to determine whether high CR may constitute a moderator of cognitive functioning in bipolar disorder (BD).

METHODS
102 patients with BD and 32 healthy controls were enrolled. All patients met DSM-IV criteria for I or II BD and were euthymic (YMRS≤6 and HDRS≤8) during a 6-month period. All participants were tested with a comprehensive neuropsychological battery, and a Cerebral Reserve Score (CRS) was estimated. Subjects with a CRS below the group median were classified as having low CR, whereas participants with a CRS above the median value were considered to have high CR.

RESULTS
Participants with BD with high CR displayed a better performance in measures of attention (digits forward: F=4.554, p=0.039); phonemic and semantic verbal fluency (FAS: F=9.328, p=0.004; and Animal Naming: F=8.532, p=0.006); and verbal memory (short cued recall of California Verbal Learning Test: F=4.236, p=0.046), after multivariable adjustment for potential confounders, including number of admissions and prior psychotic symptoms.

LIMITATIONS
The cross-sectional design of the study does not allow the establishment of causal inferences. Additionally, the small size of the sample may have limited some results.

CONCLUSIONS
High cognitive reserve may therefore be a valuable construct to explore for predicting neurocognitive performance in patients with BD regarding premorbid status.

Grande|I|I|
Sanchez-Moreno|J|J|
Sole|B|B|
Jimenez|E|E|
Torrent|C|C|
Bonnin|C M|CM|
Varo|C|C|
Tabares-Seisdedos|R|R|
Balanzá-Martínez|V|V|
Valls|E|E|
Morilla|I|I|
Carvalho|A F|AF|
Ayuso-Mateos|J L|JL|
Vieta|E|E|
Martinez-Aran|A|A|

D039721:Diagnostic and Statistical Manual of Mental Disorders

Cognitive reserve
Bipolar disorder
Neurocognition
Cognitive heterogeneity


Development of mutagenicity during degradation of N-nitrosamines by advanced oxidation processes.

Abstract: Development of mutagenicity of five N-nitrosamines (N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodi-n-propylamine (NDPA), N-nitrosopyrrolidine (NPYR) and N-nitrosodiphenylamine (NDPhA)) was investigated during oxidative processes involving UV-photolysis, ozone and OH radicals. The mutagenicity was detected by the Ames test with 3 different strains, TA98, TAMix and YG7108, a strain which is sensitive for N-nitrosamines, in presence and absence of metabolic activation (S9). UV photolysis of mutagenic N-nitrosamines (NDMA, NDEA, NDPA and NPYR) leads to the removal of their specific mutagenic activity as detected in YG7108 in the presence of S9. A formation of mutagens during UV photolysis was detected only in case of NDPhA in the strain TA98. Oxidation products of NDMA, NDEA and NDPhA did not show any significant mutagenicity in the strains used, whereas oxidation of NDPA and NPYR by hydroxyl radicals seems to lead to the formation of direct mutagens (mutagenic in the absence of S9) in YG7108 and TAMix. Oxidation by hydroxyl radicals of N-nitrosamines with chains longer than ethyl can mimic metabolic activation of N-nitrosamines in vivo.

Mestankova|Hana|H|
Schirmer|Kristin|K|
Canonica|Silvio|S|
von Gunten|Urs|U|

Mutagenicity
N-nitrosamines
Ozone
Ames test
UV photolysis
Hydroxyl radicals


Renal safety outcomes of spironolactone in patients with resistant hypertension.

Abstract:
INTRODUCTION
Resistant hypertension (RH) is a significant health problem with complex management. The aim of this study was to evaluate the risks and benefits of adding spironolactone to treat RH.

MATERIAL AND METHODS
In total, 216 patients with RH in whom spironolactone (12.5-25mg daily) was added as an antihypertensive were evaluated. One-hundred and twenty-five (125) were analysed retrospectively and 91 prospectively. Blood pressure (BP) and laboratory parameters (serum creatinine [sCrea], estimated glomerular filtration rate [eGFR] and serum potassium [sK]) were analysed at baseline and at 3-6-12 months after introducing spironolactone.

RESULTS
A change of systolic/diastolic BP (mean±standard deviation) of -10.9±2.7/-4.3±1.6mmHg at 3 months and -13.6±2.8/-6.0±1.6mmHg at 12 months; p<0.001 was observed. These values were confirmed with ambulatory-BP monitoring at 12 months. At 3 months, an increase in sCrea of 0.10±0.04mg/dl, a decrease in eGFR of -5.4±1.9ml/min/1.73m2 and an increase in sK of 0.3±0.1mmol/l; p<0.001 was observed for all cases. These changes were maintained after 12 months. There were no significant differences in changes of BP, sCrea, eGFR and sK between 3 and 12 months. Results of the retrospective and prospective cohorts separately were superimposable. In the prospective cohort, spironolactone was withdrawn in 9 patients (9.9%) because of adverse effects.

CONCLUSIONS
After 3 months with spironolactone, a decrease in BP associated with a decrease in the eGFR and an increase in sCrea and sK was observed. These changes were maintained at 12 months. Spironolactone is an effective and safe treatment for RH in patients with baseline eGFR ≥30ml/min/1.73m2.

Galceran|Isabel|I| Vázquez|Susana|S| Durán|Xavier|X| Outón|Sara|S| Pascual|Julio|J| Oliveras|Anna|A|

Spironolactone
Resistant hypertension
Serum potassium
24-h ambulatory BP monitoring
Espironolactona
Función renal
Hipertensión arterial resistente
Office blood pressure
Potasio sérico
Presión arterial ambulatoria de 24h
Presión arterial clínica
Renal function


Localizing sites of disease in patients with rising serum prostate-specific antigen up to 1ng/ml following prostatectomy: How much information can conventional imaging provide?

Abstract:
PURPOSE
Accurate identification of the source of a detectable serum prostate-specific antigen (PSA) in the postprostatectomy setting is a major challenge among the urologic community. The aim of this study was to assess positivity rates of imaging examinations performed in patients with early PSA rise after prostatectomy and to summarize the management strategies adopted in this clinical scenario.

METHODS
Institutional Review Board-approved retrospective study of 142 postprostatectomy patients with PSA rise up to 1ng/ml who underwent evaluation with combination of multiparametric pelvic magnetic resonance imaging (MRI)±whole-body or bone MRI, bone scintigraphy, computed tomography (CT) chest-abdomen-pelvis, 18F-fludeoxyglucose-positron emission tomography (PET)/CT or 18F-sodium fluoride-PET/CT at a single tertiary cancer center. Imaging results were summarized per modality and compared with pathology findings.

RESULTS
Pelvic MRI was positive in 15/142 (11%) patients (14 patients with local recurrence in the surgical bed and 1 patient with pelvic osseous metastases). Of these 15, 10 patients underwent additional imaging examinations; none revealed positive findings. Of the 127 patients with negative pelvic MRI, 54 (43%) underwent additional imaging examinations; only 1/54 had positive findings (false-positive T8 lesion on bone scintigraphy and FDG-PET/CT; biopsy was negative for cancer). Overall, 12/16 patients with positive imaging findings and 75/126 (60%) patients with negative imaging received treatment (radiation, hormones or chemotherapy).

CONCLUSION
The conventional imaging identified sites of disease, almost always in the form of local recurrence, in a minority of patients with early PSA rise postprostatectomy.

Vargas|Hebert Alberto|HA|
Martin-Malburet|Alexandre G|AG|
Takeda|Toshikazu|T|
Corradi|Renato B|RB|
Eastham|James|J|
Wibmer|Andreas|A|
Sala|Evis|E|
Zelefsky|Michael J|MJ|
Weber|Wolfgang A|WA|
Hricak|Hedvig|H|

D000072078:Positron Emission Tomography Computed Tomography

MRI
CT
Recurrence
Bone scan
PET
Prostate cancer


Living Supramolecular Polymerization of DNA.

Abstract: Recently there have been notable synthetic successes in supramolecular polymerization. By contrast, it has long been known that DNA can undergo supramolecular polymerization (concatemerization). Concatemerization is a step-like polymerization and consequently suffers from broad molecular weight distributions and generally undesirable cyclization reactions. Here we demonstrate that another supramolecular polymerization of DNA, hybridization chain reaction (HCR), is in fact a living polymerization. After consumption of initial monomer, the polymerization can be continued with further addition of monomer, and the molecular weight can be varied by the ratio of monomer to initiator. In contrast to concatemerization, HCR produces polymers with narrow dispersity while avoiding cyclization. Identification of the living character of this supramolecular polymerization presents new opportunities in structural DNA nanotechnology and molecular biology.

D021141:Nucleic Acid Amplification Techniques

hybridization chain reaction
living polymerization
dispersity
concatemers
self-assembly


Sex chromosome evolution in snakes inferred from divergence patterns of two gametologous genes and chromosome distribution of sex chromosome-linked repetitive sequences.

Abstract:
BACKGROUND
The discovery of differentially organized sex chromosome systems suggests that heteromorphic sex chromosomes evolved from a pair of homologous chromosomes. Whereas karyotypes are highly conserved in alethinophidian snakes, the degeneration status of the W chromosomes varies among species. The Z and W chromosomes are morphologically homomorphic in henophidian species, whereas in snakes belonging to caenophidian families the W chromosomes are highly degenerated. Snakes therefore are excellent animal models in which to study sex chromosome evolution. Herein, we investigated the differentiation processes for snake sex chromosomes using both coding and repetitive sequences. We analyzed phylogenetic relationships of CTNNB1 and WAC genes, localized to the centromeric and telomeric regions, respectively, of the long arms on snake sex chromosomes, and chromosome distribution of sex chromosome-linked repetitive sequences in several henophidian and caenophidian species.

RESULTS
Partial or full-length coding sequences of CTNNB1 and WAC were identified for Z homologs of henophidian species from Tropidophiidae, Boidae, Cylindrophiidae, Xenopeltidae, and Pythonidae, and for Z and W homologs of caenophidian species from Acrochordidae, Viperidae, Elapidae, and Colubridae. Female-specific sequences for the two genes were not found in the henophidian (boid and pythonid) species examined. Phylogenetic trees constructed using each gene showed that the Z and W homologs of the caenophidian species cluster separately. The repetitive sequence isolated from the W chromosome heterochromatin of the colubrid Elaphe quadrivirgata and a microsatellite motif (AGAT)8 were strongly hybridized with W chromosomes of the viperid and colubrid species examined.

CONCLUSION
Our phylogenetic analyses suggest that the cessation of recombination between the Z and W homologs of CTNNB1 and WAC predated the diversification of the caenophidian families. As the repetitive sequences on the W chromosomes were shared among viperid and colubrid species, heterochromatinization of the proto-W chromosome appears to have occurred before the splitting of these two groups. These results collectively suggest that differentiation of the proto-Z and proto-W chromosomes extended to wide regions on the sex chromosomes in the common ancestor of caenophidian families during a relatively short period.

Matsubara|Kazumi|K| Nishida|Chizuko|C| Matsuda|Yoichi|Y| Kumazawa|Yoshinori|Y|

Evolution
Snake
Gametolog
Repetitive sequences
W chromosome
Heterochromatin
Phylogeny
Z chromosome


Availability and quality assessment of online nutrition information materials for pelvic cancer patients in the UK.

Abstract:
OBJECTIVE
Written information can be an essential source of support in the promotion of lifestyle changes after a cancer diagnosis. This study aimed to identify and assess the quality of available online patient information materials (PIMs) in relation to diet and nutrition for patients with pelvic cancer.

METHODS
The online sources of the National Health Service, cancer centres and charitable organisations throughout the UK were searched. Content was assessed using an evidence-based checklist, and readability with two validated formulas. Consumer feedback was sought through patient and public involvement (PPI) groups.

RESULTS
Forty PIMs were identified; four were designed specifically for pelvic cancers (bladder, bowel, prostate) and 36 were generic (relevant for all cancers). Most PIMs had a good content score, with PIMs from charities scoring higher overall than PIMs from cancer centres [32 (4) vs. 23 (11), p < 0.001]. Seventy-three percent of PIMs had a readability score within acceptable levels (6th-8th grade; reading ability of 11-14 year-olds). PPI contributors found most PIMs useful and comprehensive but lacking specific information needed to meet individual needs.

CONCLUSION
There is limited availability of online PIMs for cancer survivors and even fewer tailored to pelvic cancers. Most materials have comprehensive content and acceptable readability. Some PIMs may require improvement.

D022126:Access to Information
D002173:Cancer Care Facilities
D002608:Charities
D015179:Colorectal Neoplasms
D032882:Comprehension
D054626:Consumer Health Information
D000072001:Diet, Healthy
D055317:Evidence-Based Practice
D005260:Female
D006801:Humans
D020407:Internet
D008297:Male
D044623:Nutrition Therapy
D010386:Pelvic Neoplasms
D011471:Prostatic Neoplasms
D013222:State Medicine
D006113:United Kingdom
D001749:Urinary Bladder Neoplasms

quality
nutrition
pelvic cancers
patient information
readability
public and patient involvement


Personalized genealogical history of UK individuals inferred from biobank-scale IBD segments.

Abstract:
BACKGROUND
The genealogical histories of individuals within populations are of interest to studies aiming both to uncover detailed pedigree information and overall quantitative population demographic histories. However, the analysis of quantitative details of individual genealogical histories has faced challenges from incomplete available pedigree records and an absence of objective and quantitative details in pedigree information. Although complete pedigree information for most individuals is difficult to track beyond a few generations, it is possible to describe a person's genealogical history using their genetic relatives revealed by identity by descent (IBD) segments-long genomic segments shared by two individuals within a population, which are identical due to inheritance from common ancestors. When modern biobanks collect genotype information for a significant fraction of a population, dense genetic connections of a person can be traced using such IBD segments, offering opportunities to characterize individuals in the context of the underlying populations. Here, we conducted an individual-centric analysis of IBD segments among the UK Biobank participants that represent 0.7% of the UK population.

RESULTS
We made a high-quality call set of IBD segments over 5 cM among all 500,000 UK Biobank participants. On average, one UK individual shares IBD segments with 14,000 UK Biobank participants, which we refer to as "relatives." Using these segments, approximately 80% of a person's genome can be imputed. We subsequently propose genealogical descriptors based on the genetic connections of relative cohorts of individuals sharing at least one IBD segment and show that such descriptors offer important information about one's genetic makeup, personal genealogical history, and social behavior. Through analysis of relative counts sharing segments at different lengths, we identified a group, potentially British Jews, who has a distinct pattern of familial expansion history. Finally, using the enrichment of relatives in one's neighborhood, we identified regional variations of personal preference favoring living closer to one's extended families.

CONCLUSIONS
Our analysis revealed genetic makeup, personal genealogical history, and social behaviors at the population scale, opening possibilities for further studies of individual's genetic connections in biobank data.

Naseri|Ardalan|A| Tang|Kecong|K| Geng|Xin|X| Shi|Junjie|J| Zhang|Jing|J| Shakya|Pramesh|P| Liu|Xiaoming|X| Zhang|Shaojie|S| Zhi|Degui|D|0000-0001-7754-1890

D018070:Biological Specimen Banks
D005789:Genealogy and Heraldry
D014644:Genetic Variation
D006801:Humans
D010375:Pedigree
D006113:United Kingdom

Genealogical history
Identity by descent
UK Biobank
RaPID


Rejection sensitivity and multiple group memberships: The moderating role of an oxytocin receptor gene polymorphism.

Abstract: Rejection sensitivity is a cognitive-affective processing disposition that has been linked to interpersonal difficulties. In this regard, the neuropeptide hormone, oxytocin, is thought to underlie social cognitions and behaviors that promote social affiliation. A single nucleotide polymorphism (SNP) on the oxytocin receptor gene (OXTR), in which guanine (G) is substituted for adenine (A), has been associated with less support-seeking behaviors. In the current study, among 376 undergraduate students, it was shown that the relationship between rejection sensitivity and depressive symptoms was mediated by multiple group memberships. Furthermore, the relation between rejection sensitivity and group memberships was only evident among individuals possessing the A allele on the OXTR gene. These findings further support the psychosocial deficits characteristic of individuals possessing the OXTR polymorphism, which in turn is linked to poor mood.

Woods|Robbie|R|
Bedard|Marc|M|
McQuaid|Robyn Jane|RJ|
Matheson|Kim|K|
Anisman|Hymie|H|

rejection sensitivity
group memberships
Oxytocin
depression


The Arabidopsis heat-intolerant 5 (hit5)/enhanced response to aba 1 (era1) mutant reveals the crucial role of protein farnesylation in plant responses to heat stress.

Abstract: Protein farnesylation is a post-translational modification known to regulate abscisic acid (ABA)-mediated drought tolerance in plants. However, it is unclear whether and to what extent protein farnesylation affects plant tolerance to high-temperature conditions. The Arabidopsis heat-intolerant 5 (hit5) mutant was isolated because it was thermosensitive to prolonged heat incubation at 37°C for 4 d but thermotolerant to sudden heat shock at 44°C for 40 min. Map-based cloning revealed that HIT5 encodes the β-subunit of the protein farnesyltransferase. hit5 was crossed with the aba-insensitive 3 (abi3) mutant, the aba-deficient 3 (aba3) mutant, and the heat shock protein 101 (hsp101) mutant, to characterize the HIT5-mediated heat stress response. hit5/abi3 and hit5/aba3 double mutants had the same temperature-dependent phenotypes as hit5. Additionally, exogenous supplementation of neither ABA nor the ABA synthesis inhibitor fluridone altered the temperature-dependent phenotypes of hit5. The hit5/hsp101 double mutant was still sensitive to prolonged heat incubation, yet its ability to tolerate sudden heat shock was lost. The results suggest that protein farnesylation either positively or negatively affects the ability of plants to survive heat stress, depending on the intensity and duration of high-temperature exposure, in an ABA-independent manner. HSP101 is involved in the hit5-derived heat shock tolerance phenotype.

Wu|Jia-Rong|JR| Wang|Lian-Chin|LC| Lin|Yu-Ru|YR| Weng|Chi-Pei|CP| Yeh|Ching-Hui|CH| Wu|Shaw-Jye|SJ|

D018506:Gene Expression Regulation, Plant

protein farnesylation
heat stress
HEAT-INTOLERANT 5 (HIT5)
heat shock protein 101 (HSP101)
Arabidopsis thaliana
ENHANCED RESPONSE TO ABA 1 (ERA1)
protein farnesyltransferase (PFT)


Efficient high light acclimation involves rapid processes at multiple mechanistic levels.

Abstract: Like no other chemical or physical parameter, the natural light environment of plants changes with high speed and jumps of enormous intensity. To cope with this variability, photosynthetic organisms have evolved sensing and response mechanisms that allow efficient acclimation. Most signals originate from the chloroplast itself. In addition to very fast photochemical regulation, intensive molecular communication is realized within the photosynthesizing cell, optimizing the acclimation process. Current research has opened up new perspectives on plausible but mostly unexpected complexity in signalling events, crosstalk, and process adjustments. Within seconds and minutes, redox states, levels of reactive oxygen species, metabolites, and hormones change and transmit information to the cytosol, modifying metabolic activity, gene expression, translation activity, and alternative splicing events. Signalling pathways on an intermediate time scale of several minutes to a few hours pave the way for long-term acclimation. Thereby, a new steady state of the transcriptome, proteome, and metabolism is realized within rather short time periods irrespective of the previous acclimation history to shade or sun conditions. This review provides a time line of events during six hours in the 'stressful' life of a plant.

light acclimation
metabolites
gene expression
Cell signalling
photosynthesis
redox regulation
translation.


Cholera Toxin Subunit B for Sensitive and Rapid Determination of Exosomes by Gel Filtration.

Abstract: We developed a sensitive fluorescence-based assay for determination of exosome concentration. In our assay, Cholera toxin subunit B (CTB) conjugated to a fluorescence probe and a gel filtration technique (size-exclusion chromatography) are used. Exosomal membranes are particularly enriched in raft-forming lipids (cholesterol, sphingolipids, and saturated phospholipids) and in GM1 ganglioside. CTB binds specifically and with high affinity to exosomal GM1 ganglioside residing in rafts only, and it has long been the probe of choice for membrane rafts. The CTB-gel filtration assay allows for detection of as little as 3 × 108 isolated exosomes/mL in a standard fluorometer, which has a sensitivity comparable to other methods using advanced instrumentation. The linear quantitation range for CTB-gel filtration assay extends over one order of magnitude in exosome concentration. Using 80 nM fluorescence-labeled CTB, we quantitated 3 × 108 to 6 × 109 exosomes/mL. The assay ranges exhibited linear fluorescence increases versus exosome concentration (r2 = 0.987). The assay was verified for exosomal liposomes. The assay is easy to use, rapid, and does not require any expensive or sophisticated instrumentation.

cholera toxin subunit B
exosomes
cholesterol
GM1 ganglioside
liposomes
gel chromatography


Atypical Somatic Symptoms in Adults With Prolonged Recovery From Mild Traumatic Brain Injury.

Abstract: Somatization may contribute to persistent symptoms after mild traumatic brain injury (mTBI). In two independently-recruited study samples, we characterized the extent to which symptoms atypical of mTBI but typical for patients suffering from somatization (e.g., gastrointestinal upset, musculoskeletal, and cardiorespiratory complaints) were present in adult patients with prolonged recovery following mTBI. The first sample was cross-sectional and consisted of mTBI patients recruited from the community who reported ongoing symptoms attributable to a previous mTBI (n = 16) along with a healthy control group (n = 15). The second sample consisted of patients with mTBI prospectively recruited from a Level 1 trauma center who had either good recovery (GOSE = 8; n = 32) or poor recovery (GOSE < 8; n = 29). In all participants, we evaluated atypical somatic symptoms using the Patient Health Questionnaire-15 and typical post-concussion symptoms with the Rivermead Post-Concussion Symptom Questionnaire. Participants with poor recovery from mTBI had significantly higher "atypical" somatic symptoms as compared to the healthy control group in Sample 1 (b = 4.308, p < 0.001) and to mTBI patients with good recovery in Sample 2 (b = 3.169, p < 0.001). As would be expected, participants with poor outcome in Sample 2 had a higher burden of typical rather than atypical symptoms [t (28) = 4.750, p < 0.001, d = 0.88]. However, participants with poor recovery still reported atypical somatic symptoms that were significantly higher (1.4 standard deviations, on average) than those with good recovery. Our results suggest that although "typical" post-concussion symptoms predominate after mTBI, a broad range of somatic symptoms also frequently accompanies mTBI, and that somatization may represent an important, modifiable factor in mTBI recovery.

Stubbs|Jacob L|JL|
Green|Katherine E|KE|
Silverberg|Noah D|ND|
Howard|Andrew|A|
Dhariwal|Amrit K|AK|
Brubacher|Jeffrey R|JR|
Garraway|Naisan|N|
Heran|Manraj K S|MKS|
Sekhon|Mypinder S|MS|
Aquino|Angela|A|
Purcell|Victoria|V|
Hutchison|James S|JS|
Torres|Ivan J|IJ|
Panenka|William J|WJ|

somatic symptoms
somatization
mild traumatic brain injury (mTBI)
concussion
post-concussion syndrome


Enhanced Electromagnetic Wave-Absorbing Performance of Magnetic Nanoparticles-Anchored 2D Ti3C2T MXene.

Abstract: Two-dimensional Ti3C2T MXene-based hybrids-anchored magnetic metal nanoparticles show a huge potential application as effective wave absorbers due to the synergistic electromagnetic (EM) loss effect. In this work, uniform and size-controllable nickel, cobalt, or nickel-cobalt alloy nanoparticles were in situ grown on the surface of MXene via a facile and moderate co-solvothermal method for the first time. As an example, a nickel nanoparticles-anchored MXene (Ni@MXene) hybrid was homodispersed into dielectric polyvinylidene fluoride to develop its EM wave-absorbing capacity to a great extent. As expected, the results showed strong reflection loss (RLmin = -52.6 dB at 8.4 GHz), broad effective absorption bandwidth (EAB = 3.7 GHz including 71% of X-band), low loading (10 wt % Ni@MXene), and thin thickness (3.0 mm). By adjusting the sample thickness, EAB can cover completely the whole X-band with a maximum of 6.1 GHz, showing a huge potential of Ni@MXene hybrid applying as aircraft stealth coating. The mechanism analyses revealed that the excellent impedance matching, magnetocoupling effect, conductance, magnetic loss, and multiple scatterings contribute to the splendid EM wave-absorbing performance of the Ni@MXene hybrid. Considering the excellent overall performance, the Ni@MXene hybrid was identified as a promising candidate for EM wave absorption.

magnetocoupling effect
2D Ti3C2Tx nanosheets
electromagnetic wave absorption
magnetic nanoparticles
synergistic loss effect


Evidence of a Conserved Molecular Response to Selection for Increased Brain Size in Primates.

Abstract: The adaptive significance of human brain evolution has been frequently studied through comparisons with other primates. However, the evolution of increased brain size is not restricted to the human lineage but is a general characteristic of primate evolution. Whether or not these independent episodes of increased brain size share a common genetic basis is unclear. We sequenced and de novo assembled the transcriptome from the neocortical tissue of the most highly encephalized nonhuman primate, the tufted capuchin monkey (Cebus apella). Using this novel data set, we conducted a genome-wide analysis of orthologous brain-expressed protein coding genes to identify evidence of conserved gene-phenotype associations and species-specific adaptations during three independent episodes of brain size increase. We identify a greater number of genes associated with either total brain mass or relative brain size across these six species than show species-specific accelerated rates of evolution in individual large-brained lineages. We test the robustness of these associations in an expanded data set of 13 species, through permutation tests and by analyzing how genome-wide patterns of substitution co-vary with brain size. Many of the genes targeted by selection during brain expansion have glutamatergic functions or roles in cell cycle dynamics. We also identify accelerated evolution in a number of individual capuchin genes whose human orthologs are associated with human neuropsychiatric disorders. These findings demonstrate the value of phenotypically informed genome analyses, and suggest at least some aspects of human brain evolution have occurred through conserved gene-phenotype associations. Understanding these commonalities is essential for distinguishing human-specific selection events from general trends in brain evolution.

Boddy|Amy M|AM|
Harrison|Peter W|PW|
Montgomery|Stephen H|SH|
Caravas|Jason A|JA|
Raghanti|Mary Ann|MA|
Phillips|Kimberley A|KA|
Mundy|Nicholas I|NI|
Wildman|Derek E|DE|

brain size
primate evolution
Cebus
adaptive evolution
comparative genomics
molecular evolution


Combined transcranial magnetic stimulation and brief cognitive behavioral therapy for suicide: study protocol for a randomized controlled trial in veterans.

Abstract:
BACKGROUND
At least 17 veterans die every day from suicide. Although existing treatments such as brief cognitive behavioral therapy (BCBT) have been found to reduce suicide attempts in military personnel, a number of patients go on to attempt suicide after completing therapy. Thus, finding ways to enhance treatment efficacy to reduce suicide is critical. Repetitive transcranial magnetic stimulation (TMS) is a noninvasive technique that can be used to stimulate brain regions that are impaired in suicidal patients, that has been successfully used to augment treatments for psychiatric disorders implicated in suicide. The goal of this study is to test whether augmenting BCBT with TMS in suicidal veterans reduces rates of suicidal ideation, attempts, and other deleterious treatment outcomes.

METHODS
One hundred thirty veterans with a suicide plan or suicidal behavior in the prior 2 weeks will be recruited from inpatient and outpatient settings at the Providence VA Medical Center in the USA. Veterans will be randomly assigned to receive 30 daily sessions of active or sham TMS in concert with a 12-week BCBT protocol in a parallel group design. Veterans will complete interviews and questionnaires related to psychiatric symptoms, suicidal ideation and behavior, treatment utilization, and functioning during a baseline assessment prior to treatment, at treatment endpoint, and 6- and 12-month follow-ups. Primary analyses will use mixed effect regressions to examine effects of treatment condition on suicidal behaviors, improvements in psychosocial functioning, and psychiatric hospitalization. Similar models as well as exploratory latent growth curve analyses will examine mediators and moderators of treatment effects.

DISCUSSION
This protocol provides a framework for designing multilayered treatment studies for suicide. When completed, this study will be the first clinical trial evaluating the efficacy of augmenting BCBT for suicide with TMS. The results of this trial will have implications for treatment of suicide ideation and behaviors and implementation of augmented treatment designs. If positive, results from this study can be rapidly implemented across the VA system and will have a direct and meaningful impact on veteran suicide.

TRIAL REGISTRATION
This study was registered prior to participant enrollment with ClinicalTrials.gov NCT03952468 . Registered on May 16, 2019.

TRIAL SPONSOR CONTACT
Robert O'Brien (VA Health Services R&D), robert.obrien7@va.gov.

D016032:Randomized Controlled Trials as Topic

Transcranial magnetic stimulation
Cognitive behavioral therapy
Suicide
Veterans
Neuroimaging


Olze et al. stages of radiographic visibility of root pulp and cameriere's third molar maturity index to estimate legal adult age in Hyderabad population.

Abstract:
Context
Predicting one's attainment of age of majority is a controversial issue and considered as important aspect in medicolegal cases. In India, individuals older than 18 years of age have full capacity regarding civil conduct and are tried as adults for criminal charges.

Aims and Objective
To compare the accuracy of Olze et al., stages of radiographic visibility of root pulp, and Cameriere's third molar maturity index (I 3M < 0.08) to estimate the age of majority.

Materials and Methods
A total of 615 digital orthopantomographs of children aged between 15 and 22 years. The lower left third molars were evaluated using ImageJ computer software. The effectiveness of both methods was evaluated using sensitivity, specificity, positive likelihood ratios (LR+), and LR negative (LR-).

Results
For I 3M < 0.08, the sensitivity, specificity, LR+, LR- were 0.76, 0.72, 2.79, 0.32 and 0.67, 0.76, 2.83, 0.43 in males and females respectively. For Stage 0, the sensitivity, specificity, LR+, LR- were 0.68, 0.86, 5.18, 0.36 and 0.72, 0.91, 8.63, 0.31, respectively.

Conclusion
Stage 0 of Olze's radiographic root pulp visibility showed to be more accurate than cutoff value of I 3M< 0.08 in discriminating adults and minors of Hyderabad sample when a test of high sensitivity and specificity is required.

Kumar|G Kiran|GK|
Kumar|D R Shravan|DRS|
Kulkarni|Ganesh|G|
Balla|Sudheer B|SB|
Shyam|N D V N|NDVN|
Naishadham|Yashovardhan|Y|

third molar maturity index
Hyderabad
Age of majority
orthopantomograph
radiographic root pulp visibility


Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration.

Abstract: Research on astronaut health and model organisms have revealed six features of spaceflight biology that guide our current understanding of fundamental molecular changes that occur during space travel. The features include oxidative stress, DNA damage, mitochondrial dysregulation, epigenetic changes (including gene regulation), telomere length alterations, and microbiome shifts. Here we review the known hazards of human spaceflight, how spaceflight affects living systems through these six fundamental features, and the associated health risks of space exploration. We also discuss the essential issues related to the health and safety of astronauts involved in future missions, especially planned long-duration and Martian missions.

Afshinnekoo|Ebrahim|E|
Scott|Ryan T|RT|
MacKay|Matthew J|MJ|
Pariset|Eloise|E|
Cekanaviciute|Egle|E|
Barker|Richard|R|
Gilroy|Simon|S|
Hassane|Duane|D|
Smith|Scott M|SM|
Zwart|Sara R|SR|
Nelman-Gonzalez|Mayra|M|
Crucian|Brian E|BE|
Ponomarev|Sergey A|SA|
Orlov|Oleg I|OI|
Shiba|Dai|D|
Muratani|Masafumi|M|
Yamamoto|Masayuki|M|
Richards|Stephanie E|SE|
Vaishampayan|Parag A|PA|
Meydan|Cem|C|
Foox|Jonathan|J|
Myrrhe|Jacqueline|J|
Istasse|Eric|E|
Singh|Nitin|N|
Venkateswaran|Kasthuri|K|
Keune|Jessica A|JA|
Ray|Hami E|HE|
Basner|Mathias|M|
Miller|Jack|J|
Vitaterna|Martha Hotz|MH|
Taylor|Deanne M|DM|
Wallace|Douglas|D|
Rubins|Kathleen|K|
Bailey|Susan M|SM|
Grabham|Peter|P|
Costes|Sylvain V|SV|
Mason|Christopher E|CE|
Beheshti|Afshin|A|

spaceflight
oxidative stress
DNA damage
epigenetic
telomere
microbiome
aerospace medicine
mitochondria
multi-omics
space biology


Genomics, phylogeny and in silico analysis of mitochondrial glutathione S-transferase-kappa from the camel Camelus dromedarius.

Abstract: The domesticated one-humped camel, Camelus dromedarius, is one of the most important animals in the Arabian Peninsula. For most of its life, this species is exposed to both intrinsic and extrinsic genotoxic factors that cause gross DNA alterations in many organisms. GST enzymes constitute an important supergene family involved in protection against the deleterious effects of oxidative stress and xenobiotics. Cloning the camel mitochondrial GST kappa (GSTK) gene and comparing its structural similarities with different species may aid in understanding its evolutionary relics. We cloned the camel GSTK using RT-PCR. This yielded an open reading frame of 678 nucleotides, encoding a protein of 226 amino acid residues. In a comparative analysis, the cloned GSTK was used to screen orthologues from different organisms. Phylogenetic analysis demonstrated that the camel GSTK apparently evolved from an ancestral GSTK gene that predated the appearance of vertebrates, and it grouped with pig, cattle, dog, horse, human and monkey GSTKs. The calculated molecular weight of the translated ORF was 25.52 kDa and the isoelectric point was 8.4. The deduced cGSTK sequence exhibited high identity with many mammals, such as Bactrian camel (99.55%), pig, cattle and human (>74%), and lower identity with other unrelated organisms, such as frog (Xenopus tropicalis, 61%), chicken (Gallus gallus, 57%), salmon (Salmo salar, 49%), sponge (Amphimedon queenslandica, 46%), tick (Amblyomma maculatum, 45%) and roundworm (Caenorhabditis elegans, 33%). A 3D structure was built based on the crystal structure of the human and rat enzymes. The levels of cGSTK expression in five camel tissues were examined via real-time PCR. The highest level of cGSTK transcripts was found in the camel liver, followed by the testis, spleen, kidney and lung.

Ataya|Farid S|FS|
Al-Jafari|Abdul Aziz|AA|
Daoud|Mohamed S|MS|
Al-Hazzani|Amal Abdulaziz|AA|
Shehata|Afaf Ibrahim|AI|
Saeed|Hesham M|HM|
Fouad|Dalia|D|

One-humped camel
Cloning
GST-kappa
Phylogenetic tree
Structure modelling
qPCR


Stump classification was correlated with retear in the suture-bridge and double-row repair techniques for arthroscopic rotator cuff repair.

Abstract:
PURPOSE
The Stump classification is significantly correlated with a retear after arthroscopic rotator cuff repair. However, no study has evaluated whether or not the stump classification is correlated with retear in the suture-bridge or double-row repair techniques. The aim of this study was to evaluate the relationship between a retear and the stump classification in the suture-bridge and double-row repair techniques.

METHODS
Among 389 patients who underwent arthroscopic repairs of full-thickness rotator cuff tears using suture-bridge or double-row repair techniques, 326 patients (median age 67.0 years; range 25-85) were included. There were 51 small, 172 medium, 83 large, and 20 massive tears. Two hundred forty patients were treated with the suture-bridge technique, and 86 patients were treated with the double-row technique. The following variables were analyzed: age, sex, the Cofield classification, anteroposterior and mediolateral tear size on preoperative MRI, global fatty degeneration index, and the stump classification. Cuff integrity was evaluated on magnetic resonance imaging at 6 months after surgery. The patients were divided into the intact and retear groups and the relationship between the variables and retear was evaluated by multivariate logistic regression analysis.

RESULTS
The overall retear rate was 10.1%. In the multivariate logistic regression analysis, the independent predictors of a retear were the stump classification type 3 (Odds ratio: 4.71, p = 0.0246), global fatty degeneration index (Odds ratio: 3.87, p = 0.0030), and anteroposterior tear size (Odds ratio: 1.07, p = 0.0077) in the suture bridge technique. In the double-row technique, the independent predictors of retear were stump classification type 3 (Odds ratio: 7.82, p = 0.0348), and age (Odds ratio: 1.22, p = 0.0163).

CONCLUSION
The stump classification was significantly correlated with retear in the suture-bridge and double-row repair technique. Stump classification type 3 was indicated to be an important risk factor for predicting retear.

LEVEL OF EVIDENCE
III.

Stump classification
Retear
Risk factor
Arthroscopic rotator cuff tear


Towards semantic fMRI neurofeedback: navigating among mental states using real-time representational similarity analysis.

Abstract: Objective. Real-time functional magnetic resonance imaging neurofeedback (rt-fMRI-NF) is a non-invasive MRI procedure allowing examined participants to learn to self-regulate brain activity by performing mental tasks. A novel two-step rt-fMRI-NF procedure is proposed whereby the feedback display is updated in real-time based on high-level representations of experimental stimuli (e.g. objects to imagine) via real-time representational similarity analysis of multi-voxel patterns of brain activity.Approach. In a localizer session, the stimuli become associated with anchored points on a two-dimensional representational space where distances approximate between-pattern (dis)similarities. In the NF session, participants modulate their brain response, displayed as a movable point, to engage in a specific neural representation. The developed method pipeline is verified in a proof-of-concept rt-fMRI-NF study at 7 T involving a single healthy participant imagining concrete objects. Based on this data and artificial data sets with similar (simulated) spatio-temporal structure and variable (injected) signal and noise, the dependence on noise is systematically assessed.Main results. The participant in the proof-of-concept study exhibited robust activation patterns in the localizer session and managed to control the neural representation of a stimulus towards the selected target in the NF session. The offline analyses validated the rt-fMRI-NF results, showing that the rapid convergence to the target representation is noise-dependent.Significance. Our proof-of-concept study introduces a new NF method allowing the participant to navigate among different mental states. Compared to traditional NF designs (e.g. using a thermometer display to set the level of the neural signal), the proposed approach provides content-specific feedback to the participant and extra degrees of freedom to the experimenter enabling real-time control of the neural activity towards a target brain state without suggesting a specific mental strategy to the subject.

Russo|Andrea G|AG|0000-0002-2793-4212
Lührs|Michael|M|
Di Salle|Francesco|F|
Esposito|Fabrizio|F|0000-0002-5099-9786
Goebel|Rainer|R|

neurofeedback
representational similarity
real-time fMRI
semantic representation


Pseudocirrhosis after chemotherapy in breast cancer, case reports.

Abstract: Pseudocirrhosis is a rare hepatic complication of chemotherapy, which is morphological changes in hepatic contour that closely mimic cirrhosis. Like in classic cirrhosis, portal hypertension is common in patients with this condition. The mechanism of pseudocirrhosis is unknown to date. We report three cases of pseudocirrhosis arising in the setting of regression of breast cancer liver metastases. All the cases underwent systemic chemotherapy, and all had remarkable responses. Their hormone receptor statuses were all positive and Her2/neu statuses were all negative. They were all treated with cytotoxic chemotherapeutic agent and also hormone therapy. This report suggests clinicians should have pseudocirrhosis in mind when hormone therapy and cytotoxic chemotherapy are jointly administered.

Aoyagi|Tomoyoshi|T| Takabe|Kazuaki|K| Tamanuki|Tamaki|T| Matsubara|Hisahiro|H| Matsuzaki|Hiroshi|H|

D000971:Antineoplastic Combined Chemotherapy Protocols

D056486:Chemical and Drug Induced Liver Injury

Pseudocirrhosis
Chemotherapy
Breast cancer
Hepatic metastasis


Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice.

Abstract: Muscular dystrophy-dystroglycanopathies (MDDGs) resulting from fukutin-related protein (FKRP) gene mutations are rare disorders that result in a wide spectrum of clinical severity based on the age of onset, the degree of myogenic atrophy, and/or neurologic involvement. There is no cure for any of the FKRP-related disorders, and few options are available for symptom management. Herein, we examine the longitudinal effects of a dose-escalation study to evaluate the safety and therapeutic potential of FKRP gene-replacement therapy in a p.P448L (FKRPP448L) mouse model of MDDG. A recombinant adeno-associated virus (AAV) serotype 9 vector expressing human FKRP (AAV9-FKRP) was systemically administered to FKRPP448L mice at 5 weeks of age, when early onset of the disease is evidenced. A comprehensive analysis of protein and gene expression, histopathology, skeletal muscle function, and cardiorespiratory function was performed over short (9-week) and/or long-term (52-week) study periods. Additional studies assessed the impact of FKRP gene-replacement therapy on lifespan at an advanced stage of disease progression. Results indicate that treatment intervention can restore the biochemical defects in a dose-dependent manner, with potential for improvement in the trajectory of disease progression and extension of the expected lifespan. This study supports the initiation of early-stage clinical trials for FKRP-related disorders.

Vannoy|Charles Harvey|CH|
Leroy|Victoria|V|
Lu|Qi Long|QL|

muscular dystrophy-dystroglycanopathy
fukutin-related protein
gene therapy


Population structure of root nodulating Rhizobium leguminosarum in Vicia cracca populations at local to regional geographic scales.

Abstract: The genetic diversity and population structure of about 350 Rhizobium leguminosarum biovar viciae isolates from Vicia cracca were analysed. A hierarchical sampling design was used covering three regions, one region in Belgium and two in France, in which multiple local V. cracca populations were sampled. Rhizobium isolates were genotyped using RAPD and by sequencing two chromosomal housekeeping genes (glnII and recA) and one plasmid-borne gene (nodC). Twenty-six nodC types and sixty-seven chromosomal types were identified, many of which appeared to be regional or local endemics. We found strong genetic differentiation both among V. cracca populations that are separated by only a few kilometres, and among regions that are 50 to 350km apart. Despite significant plasmid exchange, chromosomal and nod types were similarly structured among host populations and regions. We found two lineages of which one prevailed in the Belgian region while the other dominated the French regions. Although a significant correlation between genetic differentiation and geographic distance was found, it is deemed more likely that the observed biogeographic patterns are rather due to coevolutionary interactions and environmental pressures. Furthermore, the impact of recombination on the chromosomal differentiation was found to be considerable.

Van Cauwenberghe|Jannick|J|
Verstraete|Brecht|B|
Lemaire|Benny|B|
Lievens|Bart|B|
Michiels|Jan|J|
Honnay|Olivier|O|

Vicia cracca
Rhizobium leguminosarum biovar viciae
Hierarchical sampling
Genetic differentiation
Recombination
Population genetic structure


Corticosteroids for the management of immune-related adverse events in patients receiving checkpoint inhibitors.

Abstract:
INTRODUCTION
Due to enhanced T-cell activity, immune checkpoint inhibitors cause immune-related adverse effects. Corticosteroids are the mainstay of immune-related adverse effect management but the optimal strategy has not been determined, putting patients at risk for steroid-related adverse effects and potentially decreased efficacy of immunotherapy. This study aims to characterize the use of corticosteroids for the management of immune-related adverse effect.

METHODS AND MATERIALS
A retrospective, single-center evaluation of patients receiving checkpoint inhibitors was conducted. The primary objective was to evaluate corticosteroid use for immune-related adverse effects, including starting dose, taper strategy, total duration, and resumption of immunotherapy. Secondary objective was to describe the incidence and significance of hyperglycemia.

RESULTS
One hundred and three patients met inclusion criteria and experienced 123 immune-related adverse effects. Prednisone was used most commonly (67%) at an average starting dose of 0.88 mg/kg (range 0.07-17.0). On average, steroid tapers began 9.2 days after initiation (range 0-89) and were continued for a total of 84.2 days (range 3-693). In 21.1% of cases, checkpoint inhibitor therapy was not delayed and 68.6% resumed checkpoint inhibitors, while the patient was taking steroids (30.4 mg prednisone on average, range 5-80). On average, checkpoint inhibitor therapy was resumed 18.6 days after detection of immune-related adverse effect (range 0-150). Clinically relevant hyperglycemia occurred in 8.9%.

CONCLUSION
Utilization of steroids for immune-related adverse effect at our institution is highly variable. The majority of patients received prolonged courses of steroids and resumed checkpoint inhibitor therapy with concomitant steroids above recommended doses. Additional monitoring for hyperglycemia and other steroid associated adverse effects should be considered.

Williams|Kiersten J|KJ|
Grauer|Dennis W|DW|
Henry|David W|DW|
Rockey|Michelle L|ML|

corticosteroids
Checkpoint inhibitors
immune-related adverse effect
immune mediated side effects
steroid toxicity


A graph-based approach for proteoform identification and quantification using top-down homogeneous multiplexed tandem mass spectra.

Abstract:
BACKGROUND
Top-down homogeneous multiplexed tandem mass (HomMTM) spectra are generated from modified proteoforms of the same protein with different post-translational modification patterns. They are frequently observed in the analysis of ultramodified proteins, some proteoforms of which have similar molecular weights and cannot be well separated by liquid chromatography in mass spectrometry analysis.

RESULTS
We formulate the top-down HomMTM spectral identification problem as the minimum error k-splittable flow problem on graphs and propose a graph-based algorithm for the identification and quantification of proteoforms using top-down HomMTM spectra.

CONCLUSIONS
Experiments on a top-down mass spectrometry data set of the histone H4 protein showed that the proposed method identified many proteoform pairs that better explain the query spectra than single proteoforms.

Top-down
Mass spectrometry
Graph algorithms
Multiplexed mass spectra


A universal allosteric mechanism for G protein activation.

Abstract: G proteins play a central role in signal transduction and pharmacology. Signaling is initiated by cell-surface receptors, which promote guanosine triphosphate (GTP) binding and dissociation of Gα from the Gβγ subunits. Structural studies have revealed the molecular basis of subunit association with receptors, RGS proteins, and downstream effectors. In contrast, the mechanism of subunit dissociation is poorly understood. We use cell signaling assays, molecular dynamics (MD) simulations, and biochemistry and structural analyses to identify a conserved network of amino acids that dictates subunit release. In the presence of the terminal phosphate of GTP, a glycine forms a polar network with an arginine and glutamate, putting torsional strain on the subunit binding interface. This "G-R-E motif" secures GTP and, through an allosteric link, discharges the Gβγ dimer. Replacement of network residues prevents subunit dissociation regardless of agonist or GTP binding. These findings reveal the molecular basis of the final committed step of G protein activation.

Knight|Kevin M|KM|
Ghosh|Soumadwip|S|
Campbell|Sharon L|SL|
Lefevre|Tyler J|TJ|
Olsen|Reid H J|RHJ|
Smrcka|Alan V|AV|
Valentin|Natalie H|NH|
Yin|Guowei|G|
Vaidehi|Nagarajan|N|
Dohlman|Henrik G|HG|

bioluminescence resonance energy transfer


Localized surface plasmon resonance induced assembly of bimetal nanochains.

Abstract: Bimetal nanochains (NCs) are attracting increasing attention in the fields of catalysis and electrocatalysis due to the synergistic effects in electronic and optical properties, but the fabrication of bimetal NCs remains challenging. Here, we report a general strategy named "nucleation in the irradiation then growth in the dark" for the preparation of Au/M (second metal) NCs. In the irradiation stage, the localized surface plasmon resonance (LSPR) effect of Au NPs is excited to overcome the nucleation energy barrier for the deposition of second metals (Pt, Ag and Pd). In the followed dark process, the preferential growth of second metals on the existed nucleus leads to the formation of nanochain rather than the core/shell nanostructure. In the model reaction of electrocatalytic hydrogen evolution, the optimized Au/Pt NCs showed much better performance compared with the commercial Pt/C.

Li|Ting|T| Jiang|Wentao|W| Liu|Yidan|Y| Jia|Rongrong|R| Shi|Liyi|L| Huang|Lei|L|

Electrochemical
Hydrogen evolution reaction
Photodeposition
Self-assembly


C/EBP-Induced Transdifferentiation Reveals Granulocyte-Macrophage Precursor-like Plasticity of B Cells.

Abstract: The lymphoid-myeloid transdifferentiation potentials of members of the C/EBP family (C/EBPα, β, δ, and ε) were compared in v-Abl-immortalized primary B cells. Conversion of B cells to macrophages was readily induced by the ectopic expression of any C/EBP, and enhanced by endogenous C/EBPα and β activation. High transgene expression of C/EBPβ or C/EBPε, but not of C/EBPα or C/EBPδ, also induced the formation of granulocytes. Granulocytes and macrophages emerged in a mutually exclusive manner. C/EBPβ-expressing B cells produced granulocyte-macrophage progenitor (GMP)-like progenitors when subjected to selective pressure to eliminate lymphoid cells. The GMP-like progenitors remained self-renewing and cytokine-independent, and continuously produced macrophages and granulocytes. In addition to their suitability to study myelomonocytic lineage bifurcation, lineage-switched GMP-like progenitors could reflect the features of the lympho-myeloid lineage switch observed in leukemic progression.

Cirovic|Branko|B| Schönheit|Jörg|J| Kowenz-Leutz|Elisabeth|E| Ivanovska|Jelena|J| Klement|Christine|C| Pronina|Nina|N| Bégay|Valérie|V| Leutz|Achim|A|

progenitor
lineage switch
differentiation
hematopoiesis
leukemia
stem cell


No impact of resistance-associated substitutions on the efficacy of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in HCV DAA-experienced patients.

Abstract:
BACKGROUND & AIMS
In phase III studies, the fixed dose combination of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) administered for 12 weeks led to a sustained virologic response at 12 weeks (SVR12) in 96% of NS5A inhibitor-experienced patients, and an SVR12 rate of 98% in DAA-experienced patients who had not previously received an NS5A inhibitor. Herein, we evaluate the relationship between the presence of detectable resistance-associated substitutions (RASs) at baseline and treatment outcome, and whether RASs were selected for in cases of virologic failure.

METHODS
NS3, NS5A, and NS5B deep sequencing analyses were performed at baseline for all patients and at the time of virologic failure. Results are reported using a 15% cut-off.

RESULTS
A total of 82.7% of NS5A inhibitor-experienced patients (205/248) had baseline NS3 and/or NS5A RASs; 79% had baseline NS5A RASs. SVR12 rates were similar in patients with or without NS3 and/or NS5A RASs, and with or without VOX- or VEL-specific RASs. RASs at NS5A position Y93 were present in 37.3% of patients and 95% achieved SVR12. All patients with ≥2 NS5A RASs achieved SVR12. Baseline NS3 and/or NS5A RASs were present in 46.6% (83/178) of non-NS5A inhibitor DAA-experienced patients, all of whom achieved SVR12. All patients with baseline NS5B nucleoside inhibitor RASs, including two patients with S282T, achieved SVR12. Treatment-selected resistance was seen in one of seven patients who relapsed.

CONCLUSIONS
Baseline RASs had no impact on virologic response in DAA-experienced patients following treatment with SOF/VEL/VOX for 12 weeks. Selection of viral resistance with virologic relapse was uncommon.

LAY SUMMARY
In phase III studies, 12 weeks of treatment with the combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) cured 97% of patients with hepatitis C virus who failed prior treatment with direct-acting antiviral drugs. Herein, we show that the presence of pretreatment drug resistance did not affect treatment outcome in these patients who had previously received direct-acting antivirals. We also showed that new drug resistance was rare in patients who failed treatment with SOF/VEL/VOX for 12 weeks. This has important implications for the selection of best retreatment strategies for these patients.

Sarrazin|Christoph|C|
Cooper|Curtis L|CL|
Manns|Michael P|MP|
Reddy|K Rajender|KR|
Kowdley|Kris V|KV|
Roberts|Stuart K|SK|
Dvory-Sobol|Hadas|H|
Svarovskia|Evguenia|E|
Martin|Ross|R|
Camus|Gregory|G|
Doehle|Brian P|BP|
Stamm|Luisa M|LM|
Hyland|Robert H|RH|
Brainard|Diana M|DM|
Mo|Hongmei|H|
Gordon|Stuart C|SC|
Bourliere|Marc|M|
Zeuzem|Stefan|S|
Flamm|Steven L|SL|

D006576:Heterocyclic Compounds, 4 or More Rings

Resistance-associated substitutions
SOF
VEL
VOX
NS5A
Direct-acting antivirals
Pan-genotypic


Serum Markers of Refractoriness and Enteropathy-Associated T-Cell Lymphoma in Coeliac Disease.

Abstract: The persistence or recurrence of symptoms in patients with coeliac disease (CD), despite a gluten-free diet (GFD), must prompt further work-up for excluding refractory CD (RCD). The aim of this study was to assess the accuracy of serum markers in predicting refractoriness in CD patients. This study included 72 patients affected by CD followed-up at our center, namely 49 uncomplicated CD before and after GFD and 23 RCD. Serum levels of chromogranin A (CgA) and β2-microglobuline were measured at baseline and at follow-up (median time of 13 months) in each group of patients. Cut-off points for each marker were estimated to differentiate RCD from uncomplicated CD patients. Serum levels of CgA and β2-microglobuline were significantly higher in patients with RCD compared to uncomplicated CD (p < 0.001), both at baseline and at follow-up, with no significant difference between RCD type 1 and type 2. The estimated cut-off point for CgA was 90.2 ng/mL (sensitivity 83%, specificity 100%), while for β2-microglobuline it was 696 mcg/L (sensitivity 100%, specificity of 100%). To conclude, CgA and β2-microglobuline could be useful serological markers of refractoriness in CD, with the ability to discriminate those patients who should undergo upper gastrointestinal endoscopy for making a definite diagnosis.

serum markers
chromogranin A
β2-microglobuline
refractory coeliac disease


Loss of fundus view as an indication for secondary enucleation in retinoblastoma.

Abstract: In this retrospective study, we evaluated loss of fundus view as an indication for secondary enucleation and associated histopathologic findings. Of 64 secondarily enucleated eyes, 24 were enucleated for loss of fundus view. Average time from loss of fundus view to enucleation was 4.7 months. Of these eyes, 22 had viable tumor cells on histopathology, but none had high-risk features. Loss of fundus view was a common indication for secondary enucleation after chemoreduction. Given the high prevalence of viable histopathologic tumor cells, enucleation for loss of fundus view should not be significantly delayed to decrease risk of high-risk tumor progression.

Berry|Jesse L|JL|0000-0002-8907-9100
Kogachi|Kaitlin|K|
Jubran|Rima|R|
Kim|Jonathan W|JW|

loss of fundus view
secondary enucleation
retinoblastoma
high-risk histopathology


Efficacy of the World Health Organization analgesic ladder in the paclitaxel-induced pain syndrome in rats.

Abstract: Paclitaxel use in cancer treatment is limited by a painful syndrome that has no effective treatment. Despite new therapies, drugs of the World Health Organization (WHO) analgesic ladder remain a useful therapeutic tool for cancer pain relief. Since cancer pain is caused by both tumor and chemotherapy, we assessed the efficacy of drugs from the WHO analgesic ladder for cancer pain relief in a paclitaxel-induced pain syndrome (P-IPS) model. P-IPS was induced in rats by one or four injections of paclitaxel on alternate days. The acute and chronic phases were assessed 24 h and 15 days after the first paclitaxel injection, respectively. The mechanical allodynia was evaluated after (step 1 of the ladder) paracetamol, (step 2) codeine alone or plus paracetamol and (step 3) morphine treatment in the acute or chronic phase of P-IPS. Paracetamol, codeine and morphine were equally efficacious in reducing the acute phase of the P-IPS. Codeine plus paracetamol had similar efficacy and potency when administered together in the acute phase of the P-IPS, but produced a longer-lasting effect than when separately managed. Moreover, paracetamol, codeine and morphine partially reduced the chronic phase of P-IPS, losing their efficacy and, in the case of codeine, potency when compared to the acute phase. However, paracetamol plus codeine increased the potency and efficacy of the codeine when compared to codeine administered alone in the chronic phase of P-IPS, producing a long-lasting anti-allodynic effect. Together, analgesics of WHO analgesic ladder reduce both acute and chronic phases of P-IPS, with codeine plus paracetamol presenting more potent, efficacious and long-lasting effect. Thus, in addition to tumor pain, drugs of WHO analgesics ladder could also be useful to treat P-IPS.

Pinheiro|Kelly de Vargas|KV|
Brusco|Indiara|I|
Hausen|Bruna Dos Santos|BDS|
Moresco|Rafael Noal|RN|
Rigo|Flávia K|FK|
Oliveira|Sara Marchesan|SM|
Ferreira|Juliano|J|

Chemotherapy Allodynia Neoplasms Nsaids Opioids


Most non-canonical proteins uniquely populate the proteome or immunopeptidome.

Abstract: Combining RNA sequencing, ribosome profiling, and mass spectrometry, we elucidate the contribution of non-canonical translation to the proteome and major histocompatibility complex (MHC) class I immunopeptidome. Remarkably, of 14,498 proteins identified in three human B cell lymphomas, 2,503 are non-canonical proteins. Of these, 28% are novel isoforms and 72% are cryptic proteins encoded by ostensibly non-coding regions (60%) or frameshifted canonical genes (12%). Cryptic proteins are translated as efficiently as canonical proteins, have more predicted disordered residues and lower stability, and critically generate MHC-I peptides 5-fold more efficiently per translation event. Translating 5' "untranslated" regions hinders downstream translation of genes involved in transcription, translation, and antiviral responses. Novel protein isoforms show strong enrichment for signaling pathways deregulated in cancer. Only a small fraction of cryptic proteins detected in the proteome contribute to the MHC-I immunopeptidome, demonstrating the high preferential access of cryptic defective ribosomal products to the class I pathway.

Ruiz Cuevas|Maria Virginia|MV|
Hardy|Marie-Pierre|MP|
Hollý|Jaroslav|J|
Bonneil|Éric|É|
Durette|Chantal|C|
Courcelles|Mathieu|M|
Lanoix|Joël|J|
Côté|Caroline|C|
Staudt|Louis M|LM|
Lemieux|Sébastien|S|
Thibault|Pierre|P|
Perreault|Claude|C|
Yewdell|Jonathan W|JW|

ribosome profiling
mass spectrometry
non-canonical translation
major histocompatibility complex
peptides
protein isoforms
defective ribosomal products
computational biology
proteomic methods