bluuebunny/crossref_metadata_2025 huggingface dataset:
Elucidating the influence of linker histone variants on chromatosome dynamics and energetics
Authors: Woods Dustin C , Wereszczynski Jeff
Published: February 2020

Linker histones are epigenetic regulators that bind to nucleosomes and alter chromatin structures and dynamics. Biophysical studies have revealed two binding modes in the linker histone/nucleosome complex, the chromatosome, where the linker histone is either centered on or askew from the dyad axis. Each has been posited to have distinct effects on chromatin, however the molecular and thermodynamic mechanisms that drive them and their dependence on linker histone compositions remain poorly understood. We present molecular dynamics simulations of chromatosomes with the globular domain of two linker histone variants, generic H1 (genGH1) and H1.0 (GH1.0), to determine how their differences influence chromatosome structures, energetics and dynamics. Results show that both unbound linker histones adopt a single compact conformation. Upon binding, DNA flexibility is reduced, resulting in increased chromatosome compaction. While both variants enthalpically favor on-dyad binding, energetic benefits are significantly higher for GH1.0, suggesting that GH1.0 is more capable than genGH1 of overcoming the large entropic reduction required for on-dyad binding which helps rationalize experiments that have consistently demonstrated GH1.0 in on-dyad states but that show genGH1 in both locations. These simulations highlight the thermodynamic basis for different linker histone binding motifs, and details their physical and chemical effects on chromatosomes.
Recruitment and retention in clinical trials in chronic kidney disease: report from national workshops with patients, caregivers and health professionals
Authors: Natale Patrizia , Gutman Talia , Howell Martin , Dansie Kathryn , Hawley Carmel M , Cho Yeoungjee , Viecelli Andrea K , Craig Jonathan C , Jesudason Shilpanjali , Chapman Jeremy R , Johnson David W , Murphy Lisa , Reidlinger Donna , Crowe Sally , Duncanson Emily , Muthuramalingam Shyamsundar , Scholes-Robertson Nicole , Williamson Amber , McDonald Stephen , Wong Germaine , Teixeira-Pinto Armando , Strippoli Giovanni F M , Tong Allison
Published: February 2020

Background

Slow recruitment and poor retention jeopardize the reliability and statistical power of clinical trials, delaying access to effective interventions and increasing costs, as commonly observed in nephrology trials. Involving patients in trial design, recruitment and retention is infrequent but potentially transformational.

Methods

We conducted three workshops involving 105 patients/caregivers and 43 health professionals discussing patient recruitment and retention in clinical trials in chronic kidney disease.

Results

We identified four themes. ‘Navigating the unknown’—patients described being unaware of the research question, confused by technical terms, sceptical about findings and feared the risk of harm. ‘Wary of added burden’—patients voiced reluctance to attend additional appointments, were unsure of the commitment required or at times felt too unwell and without capacity to participate. ‘Disillusioned and disconnected’—some patients felt they were taken for granted, particularly if they did not receive trial results. Participants believed there was no culture of trial participation in kidney disease and an overall lack of awareness about opportunities to participate. To improve recruitment and retention, participants addressed ‘Building motivation and interest’.

Conclusions

Investigators should establish research consciousness from the time of diagnosis, consider optimal timing for approaching patients, provide comprehensive information in an accessible manner, emphasize current and future relevance to them and their illness, involve trusted clinicians in recruitment and minimize the burden of trial participation. Participation in clinical trials was seen as an opportunity for people to give back to the health system and for future people in their predicament.
Superiority of temozolomide over radiotherapy for elderly patients with RTK II methylation class, MGMT promoter methylated malignant astrocytoma
Authors: Wick Antje , Kessler Tobias , Platten Michael , Meisner Christoph , Bamberg Michael , Herrlinger Ulrich , Felsberg Jörg , Weyerbrock Astrid , Papsdorf Kirsten , Steinbach Joachim P , Sabel Michael , Vesper Jan , Debus Jürgen , Meixensberger Jürgen , Ketter Ralf , Hertler Caroline , Mayer-Steinacker Regine , Weisang Sarah , Bölting Hanna , Reuss David , Reifenberger Guido , Sahm Felix , von Deimling Andreas , Weller Michael , Wick Wolfgang
Published: February 2020

Background

O6-methylguanine DNA-methyl transferase (MGMT) promoter methylation status is predictive for alkylating chemotherapy, but there are non-benefiting subgroups.

Methods

This is the long-term update of NOA-08 (NCT01502241), which compared efficacy and safety of radiotherapy (RT, n = 176) and temozolomide (TMZ, n = 193) at 7/14 days in patients >65 years old with anaplastic astrocytoma or glioblastoma. DNA methylation patterns and copy number variations were assessed in the biomarker cohort of 104 patients and in an independent cohort of 188 patients treated with RT+TMZ-containing regimens in Heidelberg.

Results

In the full NOA-08 cohort, median overall survival (OS) was 8.2 [7.0–10.0] months for TMZ treatment versus 9.4 [8.1–10.4] months for RT; hazard ratio (HR) = 0.93 (95% CI: 0.76–1.15) of TMZ versus RT. Median event-free survival (EFS) [3.4 (3.2–4.1) months vs 4.6 (4.2–5.0) months] did not differ, with HR = 1.02 (0.83–1.25). Patients with MGMT methylated tumors had markedly longer OS and EFS when treated with TMZ (18.4 [13.9–24.4] mo and 8.5 [6.9–13.3] mo) versus RT (9.6 [6.4–13.7] mo and 4.8 [4.3–6.2] mo, HR 0.44 [0.27–0.70], P < 0.001 for OS and 0.46 [0.29–0.73], P = 0.001 for EFS). Patients with glioblastomas of the methylation classes receptor tyrosine kinase I (RTK I) and mesenchymal subgroups lacked a prognostic impact of MGMT in both cohorts.

Conclusion

MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ. It indicates favorable long-term outcome with initial TMZ monotherapy in patients with MGMT promoter-methylated tumors primarily in the RTK II subgroup.
Concussion Guidelines in National and International Professional and Elite Sports
Authors: Davis Gavin A , Makdissi Michael , Bloomfield Paul , Clifton Patrick , Cowie Charlotte , Echemendia Ruben , Falvey Eanna C , Fuller Gordon Ward , Green Gary Alan , Harcourt Peter , Hill Jerry , Leahy Kevin , Loosemore Mike P , McCrory Paul , McGoldrick Adrian , Meeuwisse Willem , Moran Kevin , Nagahiro Shinji , Orchard John W , Pugh Jennifer , Raftery Martin , Sills Allen K , Solomon Gary S , Valadka Alex B
Published: February 2020

The Berlin statement on sport-related concussion was published in 2017 using evidence-based recommendations. We aimed to examine (1) the implementation of, distribution and education based on the Berlin recommendations, and the development of sport-specific protocols/guidelines among professional and elite sports, (2) the implementation of guidelines at the community level, (3) translation of guidelines into different languages, and (4) research activities. Senior medical advisers and chief medical officers from Australian Football League, All Japan Judo Federation, British Horseracing Authority, Cricket Australia, Fédération Equestre Internationale, Football Association, Gaelic Athletic Association, International Boxing Association, Irish Horseracing Regulatory Board, Major League Baseball, National Football League, National Hockey League, National Rugby League, and World Rugby completed a questionnaire. The results demonstrated that all 14 sporting organizations have published concussion protocols/guidelines based on the Berlin recommendations, includingRecognize, Removal from play, Re-evaluation, Rest, Recovery, andReturn to play.There is variable inclusion ofProlonged symptoms. PreventionandRisk reductionandLong-term effectsare addressed in the guidelines, rules and regulations, and/or sport-specific research. There is variability in education programs, monitoring compliance with guidelines, and publication in other languages. All sporting bodies are actively involved in concussion research. We conclude that the Berlin recommendations have been included in concussion protocols/guidelines by all the sporting bodies, with consistency in the essential components of the recommendations, whilst also allowing for sport- and regional-specific variations. Education at the elite, community, and junior levels remains an ongoing challenge, and future iterations of guidelines may consider multiple language versions, and community- and junior-level guidelines.
Hydropower reservoirs on the upper Mekong River modify nutrient bioavailability downstream
Authors: Chen Qiuwen , Shi Wenqing , Huisman Jef , Maberly Stephen C , Zhang Jianyun , Yu Juhua , Chen Yuchen , Tonina Daniele , Yi Qitao
Published: February 2020

Hydropower development is the key strategy in many developing countries for energy supply, climate-change mitigation and economic development. However, it is commonly assumed that river dams retain nutrients and therefore reduce downstream primary productivity and fishery catches, compromising food security and causing trans-boundary disputes. Contrary to expectation, here we found that a cascade of reservoirs along the upper Mekong River increased downstream bioavailability of nitrogen and phosphorus. The dams caused phytoplankton density to increase with hydraulic residence time and stratification of the stagnant reservoirs caused hypoxia at depth. This allowed the release of bioavailable phosphorus from the sediment and an increase in dissolved inorganic nitrogen as well as a shift in nitrogen species from nitrate to ammonium, which were transported downstream by the discharge of water from the base of the dam. Our findings provide a new perspective on the environmental impacts of river dams on nutrient cycling and ecosystem functioning, with potential implications for sustainable development of hydropower worldwide.
Structural organization of dream experience during daytime sleep-onset rapid eye movement period sleep of patients with narcolepsy type 1
Authors: Cipolli Carlo , Pizza Fabio , Bellucci Claudia , Mazzetti Michela , Tuozzi Giovanni , Vandi Stefano , Plazzi Giuseppe
Published: February 2020

Study Objective

To assess the frequency of dream experience (DE) developed during naps at Multiple Sleep Latency Test (MSLT) by patients with narcolepsy type 1 (NT1) and establish, using story-grammar analysis, the structural organization of DEs developed during naps with sleep onset rapid eye movement (REM) period (SOREMP) sleep compared with their DEs during early- and late-night REM sleep.

Methods

Thirty drug-free cognitively intact adult NT1 patients were asked to report DE developed during each MSLT nap. Ten NT1 patients also spent voluntarily a supplementary night being awakened during the first-cycle and third-cycle REM sleep. Patients provided dream reports, white dreams, and no dreams, whose frequencies were matched in naps with SOREMP versus non-REM (NREM) sleep. All dream reports were then analyzed using story-grammar rules.

Results

DE was recalled in detail (dream report) by NT1 patients after 75% of naps with SOREMP sleep and after 25% of naps with NREM sleep. Dream reports were provided by 8 out of 10 NT1 patients after both awakenings from nighttime REM sleep. Story-grammar analysis of dream reports showed that SOREMP-DEs are organized as hierarchically ordered sequences of events (so-called dream-stories), which are longer and more complex in the first and fourth SOREMP naps and are comparable with nighttime REM-DEs.

Conclusions

The similar structural organization of SOREMP-DEs with nighttime REM-DEs indicates that their underlying cognitive processes are highly, albeit not uniformly, effective during daytime SOREMP sleep. Given the peculiar neurophysiology of SOREMP sleep, investigating SOREMP-DEs may cast further light on the relationships between the neurophysiological and psychological processes involved in REM-dreaming.
Starch characterization of commercial extruded dry pet foods
Authors: Corsato Alvarenga Isabella , Aldrich Charles G
Published: February 2020

Starches provide an effective energy source for dogs and cats and can affect health according to its inclusion and extent of digestion. The starch fraction that escapes small intestine (SI) digestion is called resistant starch (RS) and is desirable due to its prebiotic function. Starch is not an essential nutrient for dogs and cats and thus is not reported on commercial pet food labels. Hence, the objective of this work was to characterize starches in commercial pet foods. The top five pet food companies by sales were selected to represent U.S. pet foods, which were divided into four strata with a sampling frame of 654 foods: dog grain based (372 foods), dog grain free (71 foods), cat grain based (175 foods), and cat grain free (38 foods). Five random foods within each stratum were purchased (20 total). Starch analyses (total starch, resistant starch, and starch cook), as well as nutrient analyses were conducted on all foods. Total starch, RS, and starch cook means were compared using a two-group Z-test on dog vs. cat and grain-based (GB) vs. grain-free (GF) diets, and differences were considered significant at a P < 0.05. Total starch was higher (P < 0.05) in dog than cat food, and starch cook was greater (P < 0.05) in GF diets. A regression analysis showed that nitrogen-free extract was a good predictor of total starch. Resistant starch was low and not different among groups. A post hoc test showed that a total sample size of at least 28 diets per group would be required to detect differences in RS between GF and GB diets, if one exists.
‘Private Things Affect Other People’: Grange Hill’s Critique of British Sex Education Policy in the Age of AIDS
Authors: Elizabeth Hannah J
Published: February 2020

The article explores five key episodes of Grange Hill, which focused on HIV/AIDS and sex education in the context of the development of sex education policy under the Thatcher and Major governments and the British Broadcasting Corporation (BBC) children’s television provision. This addresses the BBC’s and the government’s conceptualization of childhood and specifically its intentions for, and assumptions about, the audience who watched Grange Hill in 1995. Having placed these key episodes in context, the article then reveals the didactic intent behind them, outlining their effects through a close textual analysis focused on the representation of sex education and HIV/AIDS stigma. The multiple narrative techniques deployed by Grange Hill’s creators receives particular scrutiny, allowing the article to expose how this storyline represented a culmination, response, and an intervention into the British politics of children’s AIDS education that preceded and surrounded it.
Proliferating Infantile Hemangioma Tissues and Primary Cell Lines Express Markers Associated with Endothelial-to-Mesenchymal Transition
Authors: Itinteang Tinte , Tan Cherise E. S. , van Schaijik Bede , Marsh Reginald W. , Davis Paul F. , Tan Swee T.
Published: February 2020

Background:

We have previously shown that the endothelium of the microvessels of infantile hemangioma (IH) exhibits a hemogenic endothelium phenotype and proposed its potential to give rise to mesenchymal stem cells, similar to the development of hematopoietic cells. This endothelial-to-mesenchymal transition (Endo-MT) process involves the acquisition of a migratory phenotype by the endothelial cells, similar to epithelial-to-mesenchymal transition that occurs during neural crest development. We hypothesized that proliferating IH expresses Endo-MT–associated proteins and investigated their expression at the mRNA, protein, and functional levels.

Methods:

Immunohistochemical staining of paraffin-embedded sections of proliferating IH samples from 10 patients was undertaken to investigate the expression of the Endo-MT proteins Twist1, Twist2, Snail1, and Slug. Transcriptional analysis was performed for the same markers on proliferating IH tissues and CD34+ and CD34− cells from proliferating IH-derived primary cell lines. Adipogenic and osteogenic differentiation plasticity was determined on the CD34-sorted fractions.

Results:

The endothelium of the microvessels and the cells within the interstitium of proliferating IH tissues expressed Twist1, Twist2, and Slug proteins. Twist1 was also expressed on the pericyte layer of the microvessels, whereas Snail1 was not expressed. Both CD34+ and CD34− populations from the IH-derived primary cell lines underwent adipogenic and osteogenic differentiation.

Conclusions:

The expression of Endo-MT–associated proteins Twist1, Twist2, and Slug by both the endothelium of the microvessels and cells within the interstitium, and Twist1 on the pericyte layer of the microvessels of proliferating IH, suggest the presence of a process similar to Endo-MT. This may enable a tightly controlled primitive endothelium of proliferating IH to acquire a migratory mesenchymal phenotype with the ability to migrate away, providing a plausible explanation for the development of a fibrofatty residuum observed during involution of IH.
Development and Psychometric Evaluation of a Fear of Dementia Scale for Community-Dwelling Older Adults
Authors: LEE Minkyung , JUNG Dukyoo
Published: February 2020

Background

Negative attitudes toward dementia may pose an obstacle to the early diagnosis and treatment of this syndrome. However, because no scale has been designed to measure fear of dementia, a reliable and valid instrument that is able to measure accurately the multifaceted attributes of fear of dementia must be developed.

Purpose

This study was designed to develop a scale to measure fear of dementia in community-dwelling older adults and to examine its validity and reliability.

Methods

A preliminary version of the measurement scale was developed using a literature review and conceptual framework. Expert analysis of content validity, item analysis based on classic test theory and item response theory, factor analysis, reliability analysis, criterion validity test, and a Rasch model analysis were performed for the psychometric evaluation. Data were analyzed using SPSS 22.0, AMOS 22.0, and WINSTEPS 3.92.1.

Results

The factor analysis revealed three dimensions, five factors, and 19 items that explain 78.44% of the total variance. The three dimensions are cognitive, social, and physical, and the five factors are (a) direct experience of precursor symptoms of dementia, (b) preliminary knowledge of dementia, (c) concerns about family burden, (d) shame, and (e) physical response.

Conclusions

The Fear of Dementia Scale for older adults was shown to be valid and reliable. Therefore, this scale may be used to accurately measure the fear of dementia in elderly individuals. Using this scale to identify the level of fear of dementia will facilitate the early diagnosis, treatment, and prevention of dementia.
Postrace Dry Needling Does Not Reduce Subsequent Soreness and Cramping—A Randomized Controlled Trial
Authors: Cushman Daniel M. , Cummings Keith , Skinner Lee , Holman Anna , Haight Peter , Brobeck Matthew , Teramoto Masaru , Tang Chi
Published: February 2020

Objective:

To identify whether a single session of postrace dry needling can decrease postrace soreness and quantity of postrace leg cramps in half-marathon and full-marathon runners.

Design:

Single-blind, prospective, randomized, controlled trial.

Setting:

Finish line of 2018 Salt Lake City Marathon & Half-Marathon.

Participants:

Runners aged 18 years or older who completed a marathon or half-marathon.

Interventions:

True or sham dry needling of the bilateral vastus medialis and soleus muscles within 1 hour of race completion by 2 experienced practitioners.

Main Outcome Measures:

The primary outcome measure was numeric pain rating improvements for soreness on days 1, 2, 3, and 7 compared to immediately postrace. Secondary outcome measures included number of postrace cramps and subjective improvement of soreness.

Results:

Sixty-two runners were included with 28 receiving true and 34 receiving sham dry needling. Objective pain scores showed an increase in pain of the soleus muscles at days 1 and 2 (P ≤ 0.003 and P ≤ 0.041, respectively) in the dry needling group. No differences were seen in postrace pain in the vastus medialis muscles (P > 0.05). No association was seen between treatment group and presence of postrace cramping at any time point (P > 0.05). Subjectively, there was a nonsignificant trend for those receiving dry needling to feel better than expected over time (P = 0.089), but no difference with cramping (P = 0.396).

Conclusions:

A single postrace dry needling session does not objectively improve pain scores or cramping compared to sham therapy.
Organizational Support for Nurse Practitioners in Primary Care and Workforce Outcomes
Authors: Poghosyan Lusine , Ghaffari Affan , Liu Jianfang , McHugh Matthew D.
Published: February 2020

Background

Lack of organizational support in healthcare settings has been linked to high levels of clinician stress, burnout, and job dissatisfaction. Little research exists on organizational support for nurse practitioners.

Objective

We investigated the relationship between organizational support and nurse practitioner outcomes, including job satisfaction, intent to leave, and quality of care.

Methods

A cross-sectional survey design was used to collect survey data from nurse practitioners (n = 398) in primary care practices in New York State in 2017. Nurse practitioners completed mail surveys with validated measures of organizational support, job satisfaction, intent to leave, and quality of care. Information on participant demographics and work characteristics was also collected. Multilevel regression models assessed the relationship between organizational-level organizational support and resources measure and job satisfaction, intent to leave, and quality of care.

Results

The organizational-level organizational support and resources measure had a mean of 3.31 on a 4-point scale. Twenty-five percent of the participants were either moderately dissatisfied or very dissatisfied with their jobs, and about 11% intended to leave their current jobs within 1 year. The average quality of care rated by participants was 8.51 out of 10—10 being the best quality of care. After adjusting for covariates, higher organizational-level organizational support and resources measure score was associated with higher job satisfaction category, lower odds of intent to leave, and higher quality of care.

Discussion

Nurse practitioners from primary care practices with higher levels of organizational support are more likely to be satisfied with their jobs, have less intent to leave their jobs, and report better quality of care. Thus, in order to promote nurse practitioner job satisfaction, retain them in clinical positions, and improve quality of care, administrators should take actions to promote organizational support for them. Our findings are consistent with existing literature regarding the relationship between organizational support and clinician outcomes.
A novel workflow for three-dimensional analysis of tumour cell migration
Authors: Ketchen Sophie , Rohwedder Arndt , Knipp Sabine , Esteves Filomena , Struve Nina , Peckham Michelle , Ladbury John E. , Curd Alistair , Short Susan C. , Brüning-Richardson Anke
Published: February 2020

The limitations of two-dimensional analysis in three-dimensional (3D) cellular imaging impair the accuracy of research findings in biological studies. Here, we report a novel 3D approach to acquisition, analysis and interpretation of tumour spheroid images. Our research interest in mesenchymal–amoeboid transition led to the development of a workflow incorporating the generation and analysis of 3D data with instant structured illumination microscopy and a new ImageJ plugin.
Retrocopying expands the functional repertoire of APOBEC3 antiviral proteins in primates
Authors: Yang Lei , Emerman Michael , Malik Harmit S. , McLaughlin Richard N.
Published: February 2020

Host-virus arms races are inherently asymmetric; viruses evolve much more rapidly than host genomes. Thus, there is high interest in discovering mechanisms by which host genomes keep pace with rapidly evolving viruses. One family of restriction factors, theAPOBEC3 (A3)cytidine deaminases, has undergone positive selection and expansion via segmental gene duplication and recombination. Here, we show that new copies ofA3genes have also been created in primates by reverse transcriptase-encoding elements like LINE-1 or endogenous retroviruses via a process termed retrocopying. First, we discovered that all simian primate genomes retain the remnants of an ancientA3retrocopy:A3I. Furthermore, we found that some New World monkeys encode up to ten additionalAPOBEC3G(A3G) retrocopies. Some of theseA3Gretrocopies are transcribed in a variety of tissues and able to restrict retroviruses. Our findings suggest that host genomes co-opt retroelement activity in the germline to create new host restriction factors as another means to keep pace with the rapid evolution of viruses.(163)
Spage2vec: Unsupervised detection of spatial gene expression constellations
Authors: Partel Gabriele , Wählby Carolina
Published: February 2020

Investigation of spatial cellular composition of tissue architectures revealed by multiplexed in situ RNA detection often rely on inaccurate cell segmentation or prior biological knowledge from complementary single cell sequencing experiments. Here we present spage2vec, an unsupervised segmentation free approach for decrypting the spatial transcriptomic heterogeneity of complex tissues at subcellular resolution. Spage2vec represents the spatial transcriptomic landscape of tissue samples as a spatial functional network and leverages a powerful machine learning graph representation technique to create a lower dimensional representation of local spatial gene expression. We apply spage2vec to mouse brain data from three different in situ transcriptomic assays, showing that learned representations encode meaningful biological spatial information of re-occuring gene constellations involved in cellular and subcellular processes.
Structure of hemed1-freecd1nitrite reductase NirS
Authors: Klünemann Thomas , Blankenfeldt Wulf
Published: February 2020

A key step in anaerobic nitrate respiration is the reduction of nitrite to nitric oxide, which is catalysed bycd1nitrite reductase NirS in e.g. the gram-negative opportunistic pathogenPseudomonas aeruginosa. Each subunit of this homodimeric enzyme consists of a cytochromecdomain and an eight-bladed β-propeller that binds the uncommon isobacteriochlorin hemed1as an essential part of its active site. Although NirS is mechanistically and structurally well studied, the focus of previous studies has been on the active, hemed1-bound form. The hemed1-free form of NirS reported here, representing a premature state of the reductase, adopts an open conformation with the cytochromecdomains moved away from each other with respect to the active enzyme. Further, movement of a loop around W498 seems to be related to a widening of the propeller, allowing easier access to the hemed1binding side. Finally, a possible link between the open conformation of NirS and flagella formation inP. aeruginosais discussed.

Synopsis

The crystal structure of hemed1-freecd1nitrite reductase NirS fromPseudomonas aeruginosahas been determined and provides insight into a premature form of the enzyme.
A genome assembly of the barley ‘transformation reference’ cultivar Golden Promise
Authors: Schreiber Miriam , Mascher Martin , Wright Jonathan , Padmarasu Sudharasan , Himmelbach Axel , Heavens Darren , Milne Linda , Clavijo Bernardo J. , Stein Nils , Waugh Robbie
Published: February 2020

Background

Barley (Hordeum vulgare) is one of the most important crops worldwide and is also considered a research model for the large-genome small grain temperate cereals. Despite genomic resources improving all the time, they are limited for thecv.Golden Promise, the most efficient genotype for genetic transformation.

Findings

We have developed a barleycv.Golden Promise reference assembly integrating Illumina paired-end reads, long mate-pair reads, Dovetail Chicago in vitro proximity ligation libraries and chromosome conformation capture sequencing (Hi-C) libraries into a contiguous reference assembly. The assembled genome of 7 chromosomes and 4.13Gb in size, has a super-scaffold N50 after Chicago libraries of 4.14Mb and contains only 2.2% gaps. Using BUSCO (benchmarking universal single copy orthologous genes) as evaluation the genome assembly contains 95.2% of complete and single copy genes from the plant database.

Conclusions

A high-quality Golden Promise reference assembly will be useful and utilised by the whole barley research community but will prove particularly useful for CRISPR-Cas9 experiments.
Single-cell transcriptomic profile reveals macrophage heterogeneity in medulloblastoma and their treatment-dependent recruitment
Authors: Dang Mai T. , Gonzalez Michael , Gaonkar Krutika S. , Rathi Komal S. , Young Patricia , Arif Sherjeel , Zhai Li , Alam Md Zahidul , Devalaraja Samir , To Tsun Ki , Folkert Ian W. , Ramen Pichai , Rokita Jo Lynne , Martinez Daniel , Taroni Jaclyn N. , Shapiro Joshua , Greene Casey S. , Savonen Candace , Hakonarson Hakon , Curran Tom , Haldar Malay
Published: February 2020

The role of macrophages in medulloblastoma, the most common malignant pediatric brain tumor, is unclear. Using single-cell RNA sequencing in a mouse model of sonic hedgehog medulloblastoma and analysis of bulk RNA sequencing of human medulloblastoma, we investigated macrophage heterogeneity. Our findings reveal differential recruitment of macrophages with molecular-targeted versus radiation therapy and identify an immunosuppressive monocyte-derived macrophages following radiation treatment of mouse medulloblastoma, uncovering potential strategies for immunomodulation as adjunctive therapy.
Differential submergence tolerance between juvenile and adult Arabidopsis plants involves the ANAC017 transcription factor
Authors: Bui Liem T. , Shukla Vinay , Giorgi Federico M. , Trivellini Alice , Perata Pierdomenico , Licausi Francesco , Giuntoli Beatrice
Published: February 2020

Plants need to attune stress responses to the ongoing developmental programs to maximize their efficacy. For instance, successful submergence adaptation is often associated to a delicate poise between saving resources and their expenditure to activate measures that allow stress avoidance or attenuation. We observed a significant decrease in submergence tolerance associated with aging inArabidopsis thaliana, with a critical step between two and three weeks of post-germination development. This sensitization to flooding was concomitant with the transition from juvenility to adulthood. Transcriptomic analyses indicated that a group of genes related to ABA and oxidative stress response was more expressed in juvenile plants than in adult ones. These genes are induced by endomembrane tethered ANAC factors that were in turn activated by submergence-associated oxidative stress. A combination of molecular, biochemical and genetic analyses showed that these genes are located in genomic regions that move towards a heterochromatic state with adulthood, as marked by lysine 4 dimethylation of histone H3. We concluded that, while the mechanism of flooding stress perception and signal transduction were unaltered between juvenile and adult phases, the sensitivity that these mechanisms set into action is integrated, via epigenetic regulation, into the developmental programme of the plant.
Analysis of cardiac magnetic resonance imaging traits in 29,000 individuals reveals shared genetic basis with dilated cardiomyopathy
Authors: Pirruccello James P. , Bick Alexander , Wang Minxian , Chaffin Mark , Lubitz Steven A. , Ellinor Patrick T. , Khera Amit V , Kathiresan Sekar , Aragam Krishna G.
Published: February 2020

Dilated cardiomyopathy (DCM) is an important cause of heart failure and the leading indication for heart transplantation. Many rare genetic variants have been associated with DCM, but common variant studies of the disease have yielded few associated loci. As structural changes in the heart are a defining feature of DCM, we conducted a genome-wide association study (GWAS) of cardiac magnetic resonance imaging (MRI)-derived left ventricular measurements in 29,041 UK Biobank participants. 26 novel loci were associated with cardiac structure and function. These loci were found near 17 genes previously shown to cause Mendelian cardiomyopathies. A polygenic score of left ventricular end systolic volume was associated with incident DCM in previously disease-free individuals (hazard ratio = 1.54 per one standard deviation increase in the polygenic score, P = 2.1×10−16). Even among carriers of truncating mutations inTTN, the polygenic score influenced the size and function of the heart. These results further implicate common genetic polymorphisms in DCM pathogenesis.
Turning the screw: engineering extreme pH resistance inEscherichia colithrough combinatorial synthetic operons
Authors: de Siqueira Guilherme M. V. , Silva-Rocha Rafael , Guazzaroni María-Eugenia
Published: February 2020

Adoption of microorganisms as platforms for sustainable biobased production requires host cells to be able to withstand harsh industrial conditions, which are usually far from the ones where these organisms are naturally adapted to thrive. However, novel survival mechanisms unearthed by the study of microbiomes from extreme habitats may be exploited to enhance microbial robustness under the strict conditions needed for different applications. In this work, synthetic biology approaches were used to engineer enhanced acidic tolerance inEscherichia coliunder extreme conditions through the characterization of a library of twenty-seven unique operons composed of combinatorial assemblies of three novel genes from an extreme environment and three synthetic ribosome binding sites. The results here presented illustrate the efficacy of combining different metagenomic genes for tolerance in truly synthetic genetic operons, as expression of these gene clusters increased hundred-fold the survival percentage of cells exposed to an acidic shock in minimal media at pH 1.9 under aerobic conditions.
Formation of aggregates, icosahedral structures and percolation clusters of fullerenes in lipids bilayers: The key role of lipid saturation
Authors: Nisoh Nililla , Jarerattanachat Viwan , Karttunen Mikko , Wong-ekkabut Jirasak
Published: February 2020

Carbon nanoparticles (CNPs) are attractive materials for a great number of applications but there are serious concerns regarding their influence on health and environment. Here, our focus is on the behavior of fullerenes in lipid bilayers with varying lipid saturations, chain lengths and fullerene concentrations using coarse-grained molecular dynamics (CG-MD) simulations. Our findings show that the lipid saturation level is a key factor in determining how fullerenes behave and where the fullerenes are located inside a lipid bilayer. In saturated and monounsaturated bilayers fullerenes aggregated and formed clusters with some of them showing icosahedral structures. In polyunsaturated lipid bilayers, no such structures were observed: In polyunsaturated lipid bilayers at high fullerene concentrations, connected percolation-like networks of fullerenes spanning the whole lateral area emerged at the bilayer center. In other systems only separate isolated aggregates were observed. The effects of fullerenes on lipid bilayers depend strongly on fullerene aggregation. When fullerenes aggregate, their interactions with the lipid tails change.
Stress-Dependent Conformational Changes of Artemin: Effects of Heat and Oxidant
Authors: Takalloo Z. , Ardakani Z. Afshar , Maroufi B. , Shahangian S. Shirin , Sajedi R. H.
Published: February 2020

Artemin is an abundant thermostable protein inArtemiaembryos and considered as a highly efficient molecular chaperone against extreme environmental stress conditions. The dynamic conformational properties of artemin appear to play a critical role in its biological activities. In this study, we have investigated the conformational transitions and functional changes of artemin under heat and oxidative stress to find some evidence of the relationship between the structure and function of artemin. The tertiary and quaternary structures of artemin have been evaluated by fluorescence measurements, protein cross-linking analysis, and dynamic light scattering. Based on the structural analysis, artemin showed irreversible substantial conformational lability in response to heat and oxidant which mainly mediated through the hydrophobic interactions and dimerization of the chaperone. In addition, the chaperone-like activity of the heated and oxidized artemin was examined using lysozyme refolding assay and the experiments showed that although both factors, i.e. heat and oxidant, at specific levels improved artemin potency, simultaneous incubation with both stressors significantly triggered the activation of artemin. Moreover, the heat-induced dimerization of artemin was found to be the most critical factor for its activation. It was suggested that oxidation presumably acts through stabilizing the dimer structures of artemin through formation of disulfide bridges between the subunits and strengthens its chaperoning efficacy. Accordingly, it was proposed that artemin probably exists in a monomer–oligomer equilibrium inArtemiacysts and environmental stresses and intracellular portion of protein substrates may shift the equilibrium towards the active dimer forms of the chaperone.

STATEMENT OF SIGNIFICANCE

There are a number of reports in which the chaperone-like activity of artemin, as a stress protein, has been confirmedin vivoandin vitro.Nonetheless, the details of structural changes of the protein have not been fully discovered yet. In the present work, we focused on conformational properties of artemin fromA. urmianaupon exposing to heat and oxidation, by using various structural and functional analysis in order to predict the mechanisms of artemin’s activation. Notably, this is the first document on reporting the structural transitions of the chaperone in stress conditions.
Reduced dopamine signaling impacts pyramidal neuron excitability in mouse motor cortex
Authors: Swanson Olivia K. , Semaan Rosa , Maffei Arianna
Published: February 2020

Dopaminergic modulation is essential for the control of voluntary movement, however the role of dopamine in regulating the neural excitability of the primary motor cortex (M1) is not well understood. Here, we investigated two modes by which dopamine influences the input/output function of M1 neurons. To test the direct regulation of M1 neurons by dopamine, we performed whole-cell recordings of excitatory neurons and measured excitability before and after local, acute dopamine receptor blockade. We then determined if chronic depletion of dopaminergic input to the entire motor circuit, through a mouse model of Parkinson’s Disease, was sufficient to shift M1 neuron excitability. We show that D1 and D2 receptor (D1R, D2R) antagonism altered subthreshold and suprathreshold properties of M1 pyramidal neurons in a layer-specific fashion. The effects of D1R antagonism were primarily driven by changes to intrinsic properties, while the excitability shifts following D2R antagonism relied on synaptic transmission.

In contrast, chronic depletion of dopamine to the motor circuit with 6-hydroxydopamine (6OHDA) induced layer-specific synaptic transmission-dependent shifts in M1 neuron excitability that only partially overlapped with the effects of acute D1R antagonism. These results suggest that while acute and chronic changes in dopamine modulate the input/output function of M1 neurons, the mechanisms engaged are distinct depending on the duration and location of the manipulation. Our study highlights dopamine’s broad influence on M1 excitability by demonstrating the consequences of local and global dopamine depletion on neuronal input/output function.

Significance statement

Dopaminergic signaling is crucial for the control of voluntary movement, and loss of dopaminergic transmission in the motor circuit is thought to underlie motor symptoms in those with Parkinson’s Disease (PD). Studies in animal models of PD highlight changes in M1 activity following dopamine depletion, however the mechanisms underlying this phenomenon remain poorly understood. Here we show that diminished dopamine signaling significantly alters the excitability and input/output function of M1 pyramidal neurons. The effects differed depending on the mode and location – local versus across the motor pathway – of the dopamine manipulation. Our results demonstrate how loss of dopamine can engage complex mechanisms to alter M1 neurons activity.
Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model
Authors: Donnard Elisa , Shu Huan , Garber Manuel
Published: February 2020

Despite advances in understanding the pathophysiology of Fragile X syndrome (FXS), its molecular bases are still poorly understood. Whole brain tissue expression profiles have proved surprisingly uninformative. We applied single cell RNA sequencing to profile a FXS mouse model. We found that FXS results in a highly cell type specific effect and it is strongest among different neuronal types. We detected a downregulation of mRNAs bound by FMRP and this effect is prominent in neurons. Metabolic pathways including translation are significantly upregulated across all cell types with the notable exception of excitatory neurons. These effects point to a potential difference in the activity of mTOR pathways, and together with other dysregulated pathways suggest an excitatory-inhibitory imbalance in the FXS cortex which is exacerbated by astrocytes. Our data demonstrate the cell-type specific complexity of FXS and provide a resource for interrogating the biological basis of this disorder.
Characterising the mechanism of action of an ancient antimicrobial, honey, using modern transcriptomics
Authors: Bouzo Daniel , Cokcetin Nural N. , Li Liping , Ballerin Giulia , Bottomley Amy L. , Lazenby James , Whitchurch Cynthia B. , Paulsen Ian T. , Hassan Karl A. , Harry Elizabeth J.
Published: February 2020

Manuka honey has broad-spectrum antimicrobial activity and unlike traditional antibiotics, resistance to its killing effects has not been reported. However, its mechanism of action remains unclear. Here we investigated the mechanism of action of manuka honey and its key antibacterial components using a transcriptomic approach in a model organism,Pseudomonas aeruginosa.We show that no single component of honey can account for its total antimicrobial action, and that honey affects the expression of genes in the SOS response, oxidative damage and quorum sensing. Manuka honey uniquely affects genes involved in the explosive cell lysis process and in maintaining the electron transport chain, causing protons to leak across membranes and collapsing the proton motive force; and induces membrane depolarisation and permeabilisation inP. aeruginosa. These data indicate that the activity of manuka honey comes from multiple mechanisms of action that do not engender bacterial resistance.

Importance

The threat of antimicrobial resistance to human health has prompted interest in complex, natural products with antimicrobial activity. Honey has been an effective topical wound treatment throughout history, predominantly due to its broad-spectrum antimicrobial activity. Unlike traditional antibiotics, honey-resistant bacteria have not been reported, however, honey remains underutilised in the clinic in part due to a lack of understanding of its mechanism of action. Here we demonstrate that honey affects multiple processes in bacteria, and this is not explained by its major antibacterial components. Honey also uniquely affects bacterial membranes and this can be exploited for combination therapy with antibiotics that are otherwise ineffective on their own. We argue that honey should be included as part of the current array of wound treatments due to its effective antibacterial activity that does not promote resistance in bacteria.
Understanding the present status and forecasting of COVID―19 in Wuhan
Authors: Tomie Toshihisa
Published: February 2020

The present status of COVID―19 is analyzed and the end of the disease is forecasted. The peak of the epidemic is different in three regions, Wuhan, Hubei province except Wuhan, and mainland China except Hubei. In two regions except Wuhan, the peak of the epidemic passed ten days ago. If the trend until February 11 does not change, the disease may end by the end of February. In Wuhan, the epidemic reached a peak but the reported number of newly infected patients fluctuates largely. We need to know the reason for the big fluctuation to forecast the end of the disease.
Evaluating quality improvement at scale: routine reporting for executive board governance in a UK National Health Service organisation
Authors: Chua Kia-Chong , Henderson Claire , Grey Barbara , Holland Michael , Sevdalis Nick
Published: February 2020

Purpose

Quality improvement (QI) in healthcare is a cultural transformation process that requires long-term commitment from the executive board. As such, an overview of QI applications and their impact needs to be made routinely visible. We explored how routine reporting could be developed for QI governance.

Design

We developed a retrospective evaluation of QI projects in an NHS healthcare organisation. The evaluation was conducted as an online survey so that the data accrual process resembled routine reporting to help identify implementation challenges. A purposive sample of QI projects was identified to maximise contrast between projects that were or were not successful as determined by the resident QI team. To hone strategic focus in what should be reported, we also compared factors that might affect project outcomes.

Findings

Out of 52 QI projects, 10 led to a change in routine practice (‘adoption’). Details of project outcomes were limited. Project team outcomes, indicative of capacity building, were not systematically documented. Service user involvement, quality of measurement plan, fidelity of plan-do-study-act (PDSA) cycles had a major impact on adoption. We discussed how routine visibility of these factors may aid QI governance.

Originality

Designing a routine reporting framework is an iterative process involving continual dialogue with frontline staff and improvement specialists to navigate data accrual demands. We demonstrated how a retrospective evaluation, as in this study, can yield empirical insights to support dialogue around QI governance, thereby honing the implementation science of QI in a healthcare organisation.