bluuebunny/crossref_metadata_2025 huggingface dataset:
GIS-3D Platform to Help Decision Making for Energy Rehabilitation in Urban Environments
Authors: Izkara J L , Egusquiza A , Villanueva A
Published: June 2019

One of the main current challenges of European cities is to become energy self-sufficient entities. One of the vectors for this challenge is to improve the energy efficiency of the buildings and to promote the generation of renewable energies in the urban environment. The article describes a tool based on GIS-3D technologies to support the identification of the energy rehabilitation potential of neighbourhoods based on the introduction of renewable energies. The platform is based on a urban 3D model that collects the geometry of buildings, together with relevant information for the identification of rehabilitation opportunities (e.g. surfaces, heights, orientations and slopes). The project includes the generation of a cloud-based repository, which incorporates active and passive innovative solutions with metrics that allow the comparison of the solutions and the applicability of them to the real environment. The identification of rehabilitation opportunities combines information resulting from the diagnosis of the current energy performance of the district’s buildings with the potential for renewable generation in the area. A multicriteria analysis process facilitates the identification of the most appropriate rehabilitation solutions for the analysed environment based on different criteria as energy, cost or applicability. The result can be visualized through a web tool that combines 2D and 3D information, with comparative information in a quantitative and geo-referenced manner. The flexibility of the architecture allows the application of the same approach to different urban challenges as the application of energy conservation measures to protected historic urban areas.
Can Buildings Save and Improve Municipal Infrastructure?
Authors: Kujawski W
Published: June 2019

Architects, while creating the built environment, expand their knowledge by learning that buildings are more than places to live, work and play. Buildings can create a sense of community and add to the character of neighborhoods and cities. They can also support communities by either directly contributing to the infrastructure requirements or indirectly by reducing their demands and creating supply and treatment systems, thus increasing capacity in community energy, water treatment and stormwater systems for others. They can also reduce wastage by recapturing heat lost through inefficient systems, sewers, and by using municipal waste as a fuel source. Buildings can use a lot of energy delivered by conventional energy sources. The reduction potential for their high energy (and water) demand always represents an opportunity to decrease the potential impacts on municipal infrastructure. It is also a significant part of the challenge to reduce or cut emissions, mitigate the effects of climate change and save on resources. The paper explains how buildings can mitigate such impacts while also acting as contributors to the infrastructure. The examples demonstrate various urban and building related design concepts combined with some essential aspects of costs and savings incurring in sustainable buildings and communities. When buildings act as infrastructure they can benefit not just the developer, occupant or owner, they can also spread those benefits to the neighborhood and community and much further- to the entire planet.
Typology of Unclassified Buildings and Specifics of Input Parameters for Energy Audits in Latvia
Authors: Geikins A , Borodinecs A , Daksa G , Bogdanovics R , Zajecs D
Published: June 2019

The aim of the study is to analysis renovation solutions for unclassified buildings. According to Latvian law definition, unclassified buildings are prisons, security forces, police and fire services buildings including barracks, warehouse etc. Such buildings has completely different heat gains and heat losses balance and usage profile in comparison to traditional public and apartment buildings. Unclassified buildings could have higher internal heat and moisture loads, more strict requirements to dress code (CLO level), human metabolic equivalent and limited possibility for staff adaptation to IAQ parameters. The one of important factors is safety of energy supply and operation of HVAC systems. Although the energy security is a top priority for unclassified buildings, it should not be a barrier for implementation of renewable energy sources and innovative energy efficient retrofitting solutions in unclassified buildings.
Development of a Modular Retrofitting System for Residential Buildings and Experience from Pilot Installation
Authors: Hejtmánek P , Sojková K , Volf M , Lupíšek A
Published: June 2019

In order to significantly reduce energy consumption of its building stock, Europe has to focus on energy retrofitting of existing buildings. A usual building retrofitting process is very labour intensive and time consuming. It usually takes several weeks or even months to replace old windows by new, install new thermal insulation layers on the external walls and roofs of buildings and renew the heat distribution systems or to attach renewable energy sources on the building’s envelope. To make refurbishment more efficient and allow its scaling up, a European project Development and Advanced Prefabrication of Innovative, Multifunctional Building Envelope Elements for Modular Retrofitting and Connections (MORE-CONNECT) has been initiated under H2020 program. This project developed a system of prefabricated retrofitting modules, that enable to cut primary energy consumption of a typical residential building by 80 %, reduce on-site installation time bellow two weeks and improve the indoor environmental quality. At the same moment, the project aimed on implementation of systemic quality control over the whole design, pre-production, production and installation process in order to significantly reduce the number of warranty claims by the clients. The paper describes the design process of the modular retrofitting system and a pilot installation made on a mock-up building to test the concept, and presents the experience made.
Energy Renovation of Social Housing: Finding a Balance Between Increasing Insulation and Improving Heating System Efficiency
Authors: Van De Moortel E , Allacker K , De Troyer F , Stijnen L , Schoofs E
Published: June 2019

As the budget of social housing companies is limited, reducing the energy use of their housing stock to be compliant with current standards and actions plans is an important challenge. Currently social housing companies in Flanders often prefer replacing the heating system to insulating the building envelope due to the lower investment cost and easy implementation. However, the investment in better heating systems has to be repeated several times during the service life of the building. This paper provides insights in the investment cost and life cycle cost of both renovation strategies. Moreover an environmental life cycle assessment provides insights in the environmental impact of the renovation strategies. The analysis reveals that it is recommended to replace heating boilers not earlier than at the end of their technical service life, both from an environmental and economic perspective. Sensitivity analyses show that changes in the estimated remaining building service life and increasing discount rate lead to changes in the life cycle costs but have no influence on the ranking of the renovation scenarios. Changes in the energy price, insulation level and original building type lead to changes in the costs and ranking of the renovation scenarios.
Acoustic Evaluation of the Air-Conditioning Unit in the Room
Authors: Králíček J , Kučera M
Published: June 2019

This paper deals with an acoustic simulation, evaluation and measurement of an indoor air-conditioning unit commonly used in hotel rooms. The unit is situated in the plaster board ceiling of a hotel room above the entrance of the hotel room. The first step was to create a model of the real indoor air-conditioning unit from the catalogue data of a manufacturer, then built the model for the simulation of the internal sound propagation in the hotel room. The second step was to mock-up the real hotel room. The goal of the paper is to compare the calculated data from the simulations with the measured data in-situ.
Assessment of the Indoor Environment for Education
Authors: Kraus M , Nováková P
Published: June 2019

Indoor environment quality (IEQ) and its effect on well-being, productivity and performance are phenomena. Achieving suitable and comfortable indoor environment is a key factor in the creation and operation of the buildings in terms of basic principles of the sustainable development. The poor indoor environment is associated with the Sick Building Syndrome (SBS). The occurrence of pollutants in the indoor environment brings health problems to occupants as well as affects their productivity and performance. The main aim of the contribution is the study of indoor environment for educational purposes. The ordinary university classrooms located on the outskirts of the city České Budějovice (Czechia) are analysed. The classrooms are places, where the students reading, calculating, writing, and solving the assigned tasks. Achieving and satisfying the comfort in the indoor environment for education purposes is necessary for these student’s activities. For example, insufficient air exchange and the CO2 concentration above of 1000 ppm, cause fatigue and decreased concentration. The assessment of physical-chemical parameters includes analysis of indoor air temperature [°C], relative humidity [%], Carbon Dioxide (CO2) concentration [ppm], and illumination intensity [lx] in the university classrooms. The high-quality sensor for measuring air flow, temperature, humidity, pressure, heat radiation, CO2 concentration and illumination intensity Testo 480 with globe probe, IAQ probe, light probe and comfort level probe is used for measurement. The work is supported by the grant Specific University Research SVV 201802 Address identification and analysis of the determinants of the Indoor Environment Quality (IEQ).
A Commercial Building Lighting Demand-Side Management through Passive Solar Design
Authors: Overen O K , Meyer E L , Makaka G
Published: June 2019

The commercial sector that comprises of schools, libraries, public and private offices is the third largest energy-consuming sector in South Africa. Lighting is a significant contributor to the overall energy consumption in this sector. The aim of this study is to analyse the indoor daylight illuminance of a passive solar office building and the potential demand-side management. A passive solar building in SolarWatt Park, Alice South Africa was used as a case study. The indoor illuminance that includes electric and day lightings were monitored by two sets of Li-210R photometric sensors. Four cool white fluorescent fittings with each containing two 58W lamps served as the electric lights of the office inner space. The average illuminance of the office space with all electric lights on and without daylight was found to be 460 lux. The indoor average daylighting illuminance was 910 and 170 lux on a typical clear sky and overcast days, respectively. A daily cumulative energy savings of 11.14 kWh on a clear sky day and 0.47 kWh on an overcast day was achieved, assuming the office inner space illuminance was maintained at 300 lux. The monetary savings due to the energy saved was estimated at 1285.36 USD per annum. Based on the findings of the study, daylighting through passive solar design reduces energy consumption without compromising the visual comfort of the occupants. Integration of passive solar design for daylighting with indoor daylight switch controller is recommended for optimum energy savings.
Building Integrated Photovoltaics (BIPV) in Line with Historic Buildings and Their Heritage Protection
Authors: Novak E , Vcelak J
Published: June 2019

Historic buildings are often classified as highly energy-intensive buildings with low energy efficiency. Thanks to their overall percentage share in the European real estate market, it is important to focus on these dwellings with an innovative approach and functional, sensitive aesthetic solutions, thus significantly reducing their energy intensity, increasing their energy efficiency and improving the indoor living conditions. At the same time, it will greatly increase the chance to meet the new energy and emission targets currently proposed by the European Commission.
Rethinking Public Buildings’ Functions: The Case for Participatory Design Methodology
Authors: Kandusová V , Vácha T
Published: June 2019

Municipalities often struggle with reconstructions and refurbishing of buildings in public ownership. This is not only because of limited expert capacities that municipalities struggle with (municipal architect position or urban planner position is vacant, or non-existent etc.) or lack of finances. There is an increasing need and demand from municipalities for redefining buildings’ original purpose and finding new, sustainable and innovate functions. They have to decide not only how to reconstruct, but how to rethink its original purpose. The case study from a city of Slaný shows how participatory design can serve the goal of finding new functions of a public building and effectively contribute to the planning phase of reconstruction projects. Sustainable urban development should react to people’s needs, new technologies and environmental challenges. Reconstruction projects should reflect innovations in both technologies and approaches and respond to newly emerged functions. The methodology demonstrated in the case study can serve as a tool for assessing preferences of citizens, needs of the municipality and bridge the gap between politicians, experts and citizens by supporting efficient communication and evidence-based decision making. Moreover, this case shows how to ensure social sustainability and project effectiveness by involving multidisciplinary teams, in this case architects, urban planners, sociologists, communications experts and environmental and engineering psychologists.
Almost Kenmotsu metric as a conformal Ricci soliton
Authors: Dey Dibakar , Majhi Pradip
Published: June 2019

In the present paper, we characterize

(
k
,
μ

)
′

(k,\mu )’

and generalized

(
k
,
μ

)
′

(k,\mu )’

-almost Kenmotsu manifolds admitting the conformal Ricci soliton. It is also shown that a

(
k
,
μ

)
′

(k,\mu )’

-almost Kenmotsu manifold

M

2
n
+
1

M^{2n+1}

does not admit conformal gradient Ricci soliton

(
g
,
V
,
λ
)

(g,V,\lambda )

with

V
V

collinear with the characteristic vector field

ξ
\xi

. Finally an illustrative example is presented.
An Examination of Flying Insects in Seven Hospitals in the United Kingdom and Carriage of Bacteria by True Flies (Diptera: Calliphoridae, Dolichopodidae, Fanniidae, Muscidae, Phoridae, Psychodidae, Sphaeroceridae)
Authors: Boiocchi Federica , Davies Matthew P , Hilton Anthony C
Published: June 2019

Insects are efficient vectors of bacteria and in the hospital environment may have a role in spreading nosocomial infections. This study sampled the flying insect populations of seven hospitals in the United Kingdom and characterized the associated culturome of Diptera, including the antibiotic resistance profile of bacterial isolates. Flying insects were collected in seven U.K. hospitals between the period March 2010 to August 2011. The bacteria carried by Diptera were isolated using culture-based techniques, identified and characterized by antimicrobial susceptibility testing. A total of 19,937 individual insects were collected with Diptera being the most abundant (73.6% of the total), followed by Hemiptera (13.9%), Hymenoptera (4.7%), Lepidoptera (2.9%), and Coleoptera (2%). From Diptera, 82 bacterial strains were identified. The majority of bacteria belonged to the Enterobacteriaceae (42%), followed by Bacillus spp. (24%) and Staphylococcus spp. (19%). Less abundant were bacteria of the genus Clostridium (6%), Streptococcus (5%), and Micrococcus (2%). A total of 68 bacterial strains were characterized for their antibiotic resistance profile; 52.9% demonstrated a resistant phenotype to at least one class of antibiotic. Staphylococcus spp. represented the highest proportion of resistant strains (83.3%), followed by Bacillus spp. (60%) and Enterobacteriaceae (31.3%). Diptera were the predominant flying insects present in the U.K. hospital environments sampled and found to harbor a variety of opportunistic human pathogens with associated antimicrobial resistance profiles. Given the ability of flies to act as mechanical vectors of bacteria, they present a potential to contribute to persistence and spread of antimicrobial-resistant pathogenic bacteria in the hospital environment.
Stability of an RNA•DNA–DNA triple helix depends on base triplet composition and length of the RNA third strand
Authors: Kunkler Charlotte N , Hulewicz Jacob P , Hickman Sarah C , Wang Matthew C , McCown Phillip J , Brown Jessica A
Published: June 2019

Recent studies suggest noncoding RNAs interact with genomic DNA, forming an RNA•DNA–DNA triple helix that regulates gene expression. However, base triplet composition of pyrimidine motif RNA•DNA–DNA triple helices is not well understood beyond the canonical U•A–T and C•G–C base triplets. Using native gel-shift assays, the relative stability of 16 different base triplets at a single position, Z•X–Y (where Z = C, U, A, G and X–Y = A–T, G–C, T–A, C–G), in an RNA•DNA–DNA triple helix was determined. The canonical U•A–T and C•G–C base triplets were the most stable, while three non-canonical base triplets completely disrupted triple-helix formation. We further show that our RNA•DNA–DNA triple helix can tolerate up to two consecutive non-canonical A•G–C base triplets. Additionally, the RNA third strand must be at least 19 nucleotides to form an RNA•DNA–DNA triple helix but increasing the length to 27 nucleotides does not increase stability. The relative stability of 16 different base triplets in DNA•DNA–DNA and RNA•RNA–RNA triple helices was distinctly different from those in RNA•DNA–DNA triple helices, showing that base triplet stability depends on strand composition being DNA and/or RNA. Multiple factors influence the stability of triple helices, emphasizing the importance of experimentally validating formation of computationally predicted triple helices.
An improved method for circular RNA purification using RNase R that efficiently removes linear RNAs containing G-quadruplexes or structured 3′ ends
Authors: Xiao Mei-Sheng , Wilusz Jeremy E
Published: June 2019

Thousands of eukaryotic protein-coding genes generate circular RNAs that have covalently linked ends and are resistant to degradation by exonucleases. To prove their circularity as well as biochemically enrich these transcripts, it has become standard in the field to use the 3′-5′ exonuclease RNase R. Here, we demonstrate that standard protocols involving RNase R can fail to digest >20% of all highly expressed linear RNAs, but these shortcomings can largely be overcome. RNAs with highly structured 3′ ends, including snRNAs and histone mRNAs, are naturally resistant to RNase R, but can be efficiently degraded once a poly(A) tail has been added to their ends. In addition, RNase R stalls in the body of many polyadenylated mRNAs, especially at G-rich sequences that have been previously annotated as G-quadruplex (G4) structures. Upon replacing K+ (which stabilizes G4s) with Li+ in the reaction buffer, we find that RNase R is now able to proceed through these sequences and fully degrade the mRNAs in their entirety. In total, our results provide important improvements to the current methods used to isolate circular RNAs as well as a way to reveal RNA structures that may naturally inhibit degradation by cellular exonucleases.
“It’s Probably Going to Be the Hardest Film to Make”
Authors: Kolker Robert P. , Abrams Nathan
Published: June 2019

Stanley Kubrick wanted to film Arthur Schnitzler’s Traumnovelle since the early 1950s. His interest lay in Schnitzler’s fascination with sexuality and domesticity. The intersection of Schnitzler’s writings with those of Sigmund Freud was of particular interest. Kubrick’s favorite director, Max Ophüls, had adapted some of Schnitzler’s plays, and this also attracted the author to Kubrick. Even though he kept putting off the making of the film, its ideas percolated into those films he did make, from Fear and Desire through The Shining. During this long period of gestation, Kubrick entertained many ideas for writers and stars. At one point, he wanted to make it as a comedy. Only after the failure to get his Holocaust film or his science fiction film, A.I.: Artificial Intelligence, made did he finally turn to directing Eyes Wide Shut.
Precision medicine for acute pancreatitis: current status and future opportunities
Authors: Mukherjee Rajarshi , Nunes Quentin , Huang Wei , Sutton Robert
Published: June 2019

Acute pancreatitis is a common inflammatory condition affecting the pancreas, predominantly caused by gallstones, alcohol excess, and hypertriglyceridaemia, with severe disease carrying up to 50% mortality. Despite significant research and preclinical promise, no targeted drug treatments exist for the disease and precision medicine approaches are lacking significantly, when compared to other health conditions. Advances in omics applications will facilitate improved preclinical models and target identification as well as biomarker discovery for refined trial design, focusing on risk stratification, subject selection, and outcome determination. Randomised treatment of Acute Pancreatitis with Infliximab: Double-blind, placebo-controlled, multi-centre trial (RAPID-I) is a pioneering trial, currently under way in acute pancreatitis, which may serve as an innovative model for the implementation of precision medicine strategies for acute pancreatitis in the future.
IL-18 as a biomarker linking systemic juvenile idiopathic arthritis and macrophage activation syndrome
Authors: Yasin Shima , Fall Ndate , Brown Rachel A , Henderlight Maggie , Canna Scott W , Girard-Guyonvarc’h Charlotte , Gabay Cem , Grom Alexei A , Schulert Grant S
Published: June 2019

Objectives

Systemic juvenile idiopathic arthritis (sJIA) is a childhood arthritis with features of autoinflammation and high risk of macrophage activation syndrome (MAS). IL-18 has been shown to have key roles in sJIA and MAS. We aimed to examine IL-18 levels in sJIA in relation to disease activity and history of MAS and other disease biomarkers namely S100 proteins and CXCL9.

Methods

Total IL-18, CXCL9 and S100 proteins levels were determined in 40 sJIA patients, and IL-18 levels were compared between patients with regards to disease activity, history of MAS, and other biomarkers.

Results

Total IL-18 levels were significantly higher in patients with active sJIA (median 16 499 pg/ml; interquartile range (IQR) 4816–61 839), and remained persistently elevated even in the majority of patients with inactive disease (1164 pg/ml; IQR 587–3444). Patients with history of MAS had significantly higher IL-18 levels (13 380 pg/ml; IQR 4212–62 628) as compared with those without MAS history (956.5 pg/ml; IQR 276.3–4262.5). Total IL-18 performed well with area under the curve of 0.8145 and 0.84 in predicting disease activity and history of MAS, respectively. We observed moderate correlation between IL-18 and CXCL9 (R = 0.56), S100A8/A9 (R = 0.47) and S100A12 (R = 0.46). The correlation was stronger for ferritin (R = 0.74) and overall for those with active disease.

Conclusion

Total IL-18 levels were elevated in the majority of sJIA patients regardless of clinical features, but were higher in patients with active disease and history of MAS. Change in IL-18 may reflect increased disease activity or development of MAS.
SOAPTyping: an open-source and cross-platform tool for Sanger sequence-based typing for HLA class I and II alleles
Authors: Zhang Yong , Chen Yongsheng , Xu Huixin , Fang Junbin , Zhao Zijian , Hu Weipeng , Yang Xiaoqin , Ye Jia , Cheng Yun , Wang Jiayin , Wang Jian , Yang Huanming , Yan Jing , Fang Lin
Published: June 2019

The human leukocyte antigen (HLA) gene family plays a key role in the immune response and thus is crucial in many biomedical and clinical settings. Utilizing Sanger sequencing - the gold standard technology for HLA typing – enables accurate identification of HLA alleles with high-resolution. However, there exists a current hurdle that only commercial software such as UType, SBT-Assign and SBTEngine, instead of any open source tools could be applied to perform HLA typing based on Sanger sequencing. To fill the gap, we developed a stand-alone, open-source and cross-platform software, known as SOAPTyping, for Sanger-based typing in HLA class I and II alleles.

Availability and implementation

SOAPTyping is implemented in C++ language and Qt framework, which is supported on Windows, Mac and Linux. Source code and detailed documentation are accessible via the project GitHub page: https://github.com/BGI-flexlab/SOAPTyping.

Contact

fangl@genomics.cn

Supplementary information

Supplementary data are available at Bioinformatics online.
A framework for annotation of antigen specificities in high-throughput T-cell repertoire sequencing studies
Authors: Pogorelyy Mikhail V , Shugay Mikhail
Published: June 2019

Recently developed molecular methods allow large-scale profiling of T-cell receptor (TCR) sequences that encode for antigen specificity and immunological memory of these cells. However, it is well known, that the even unperturbed TCR repertoire structure is extremely complex due to the high diversity of TCR rearrangements and multiple biases imprinted by VDJ rearrangement process. The latter gives rise to the phenomenon of “public” TCR clonotypes that can be shared across multiple individuals and non-trivial structure of the TCR similarity network. Here we outline a framework for TCR sequencing data analysis that can control for these biases in order to infer TCRs that are involved in response to antigens of interest. Using an example dataset of donors with known HLA haplotype and CMV status we demonstrate that by applying HLA restriction rules and matching against a database of TCRs with known antigen specificity it is possible to robustly detect motifs of an epitope-specific responses in individual repertoires. We also highlight potential shortcomings of TCR clustering methods and demonstrate that highly expanded TCRs should be individually assessed to get the full picture of antigen-specific response.
Biofilm formation displays intrinsic offensive and defensive features of Bacillus cereus
Authors: Joaquin Caro-Astorga , Elrike Frenzel , Richard Perkins James , de Vicente Antonio , Ranea Juan A.G. , Kuipers Oscar P. , Diego Romero
Published: June 2019

Background

Biofilm formation is a strategy of many bacterial species to adapt to a variety of stresses and has become a part of infections, contaminations or beneficial interactions. We previously observed that B. cereus ATCC 14579 (CECT148), formed a thick biomass of cells firmly adhered to abiotic surfaces.

Results

In this study, we combined two techniques, RNAseq and iTRAQ mass spectrometry, to demonstrate the profound physiological changes that permit Bacillus cereus to switch from a floating to a sessile lifestyle, to undergo further maturation of the biofilm, and to differentiate into offensive or defensive populations. The rearrangement of nucleotides, sugars, amino acids and energy metabolism lead to changes promoting reinforcement of the cell wall, activation of ROS detoxification strategies or secondary metabolite production, all oriented to defend biofilm cells from external aggressions. However, floating cells maintain a fermentative metabolic status along with a higher aggressiveness against hosts, evidenced by the production of toxins and other virulent factors.

Conclusions

We show that biofilm-associated cells seem to direct the energy to the individual and global defense against external aggressions and competitors. By contrary, floating cells are more aggressive against hosts. The maintenance of the two distinct subpopulations is an effective strategy to face changeable environmental conditions found in the life cycle of B. cereus.
Cutaneous Wounds in Mice Lacking Tumor Necrosis Factor-stimulated Gene-6 Exhibit Delayed Closure and an Abnormal Inflammatory Response
Authors: Shakya Sajina , Mack Judith A. , Alipour Minou , Maytin Edward V.
Published: June 2019

We investigated how loss of tumor necrosis factor-stimulated gene-6 (TSG-6) affects wound closure and skin inflammation. TSG-6 has several known biological functions including enzymatic transfer of heavy chain proteins (HC) from inter-α-trypsin inhibitor to hyaluronan (HA) to form HC-HA complexes. TSG-6 and HC-HA are constitutively expressed in normal skin and increase post-wounding, but are completely absent in TSG-6 null mice. Wound closure rates are significantly delayed in TSG-6 null mice relative to wildtype mice. Neutrophil recruitment is delayed in early wounds (12 h and Day 1), whereas late wounds (Day 7) show elevated neutrophil accumulation.In addition, the granulation phase is delayed, with persistent blood vessels and reduced dermal collagen at 10 days. The pro-inflammatory cytokine TNFα is elevated >3 fold in unwounded TSG-6 null skin, and increases further after wounding (from 12 h to 7 days) before returning to baseline by day 10. Other cytokines examined such as IL-6, IL-10, and MCP-1 showed no consistent differences. Importantly, reintroduction of TSG-6 into TSG-6 null wounds rescues both the delay in wound closure and the aberrant neutrophil phenotype. In summary, our study indicates that TSG-6 plays an important role in regulating wound closure and inflammation during cutaneous wound repair.
The genomic impact of European colonization of the Americas
Authors: Ongaro Linda , Scliar Marilia O. , Flores Rodrigo , Raveane Alessandro , Marnetto Davide , Sarno Stefania , Gnecchi-Ruscone Guido A. , Alarcon-Riquelme Marta , Patin Etienne , Wangkumhang Pongsakorn , Hellenthal Garrett , Gonzalez-Santos Miguel , King Roy J. , Kouvatsi Anastasia , Balanovsky Oleg , Balanovska Elena , Atramentova Lubov , Turdikulova Shahlo , Mastana Sarabjit , Marjanovic Damir , Kovacevic Lejla , Leskovac Andreja , Lima-Costa Maria F. , Pereira Alexandre C. , Barreto Mauricio L. , Horta Bernardo L. , Mabunda Nédio , May Celia A. , Moreno-Estrada Andres , Achilli Alessandro , Olivieri Anna , Semino Ornella , Tambets Kristiina , Kivisild Toomas , Luiselli Donata , Torroni Antonio , Capelli Cristian , Tarazona-Santos Eduardo , Metspalu Mait , Pagani Luca , Montinaro Francesco
Published: June 2019

The human genetic diversity of the Americas has been shaped by several events of gene flow that have continued since the Colonial Era and the Atlantic slave trade. Moreover, multiple waves of migration followed by local admixture occurred in the last two centuries, the impact of which has been largely unexplored.

Here we compiled a genome-wide dataset of ∼12,000 individuals from twelve American countries and ∼6,000 individuals from worldwide populations and applied haplotype-based methods to investigate how historical movements from outside the New World affected i) the genetic structure, ii) the admixture profile, iii) the demographic history and iv) sex-biased gene-flow dynamics, of the Americas.

We revealed a high degree of complexity underlying the genetic contribution of European and African populations in North and South America, from both geographic and temporal perspectives, identifying previously unreported sources related to Italy, the Middle East and to specific regions of Africa.
SKELETAL MyBP-C ISOFORMS TUNE THE MOLECULAR CONTRACTILITY OF DIVERGENT SKELETAL MUSCLE SYSTEMS
Authors: Li Amy , Nelson Shane , Rahmanseresht Sheema , Braet Filip , Cornachione Anabelle S. , Previs Samantha Beck , O’Leary Thomas S. , McNamara James W. , Rassier Dilson E. , Sadayappan Sakthivel , Previs Michael J. , Warshaw David M.
Published: June 2019

Skeletal muscle myosin-binding protein C (MyBP-C) is a myosin thick filament-associated protein; localized through its C terminus to distinct regions (C-zones) of the sarcomere. MyBP-C modulates muscle contractility, presumably through its N terminus extending from the thick filament and interacting with either the myosin head region and/or the actin thin filament. Two isoforms of MyBP-C (fast- and slow-type) are expressed in a muscle-type specific manner. Are the expression, localization, and Ca2+-dependent modulatory capacities of these isoforms different in fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles derived from Sprague-Dawley rats? By mass spectrometry, four MyBP-C isoforms (one fast-type MyBP-C and three N-terminally spliced slow-type MyBP-C) were expressed in EDL but only the three slow-type MyBP-C isoforms in SOL. Using EDL and SOL native thick filaments in which the MyBP-C stoichiometry and localization are preserved, native thin filament sliding over these thick filaments showed that only in the C-zone, MyBP-C Ca2+-sensitizes the thin filament and slows thin filament velocity. These modulatory properties depended on MyBP-C’s N-terminus, as N-terminal proteolysis attenuated MyBP-C’s functional capacities. To determine each MyBP-C isoform’s contribution to thin filament Ca2+-sensitization and slowing in the C-zone, we used a combination ofin vitromotility assays using expressed recombinant N-terminal fragments andin silicomechanistic modeling. Our results suggest that each skeletal MyBP-C isoform’s N terminus is functionally distinct and has modulatory capacities that depend on the muscle-type in which they are expressed, providing the potential for molecular tuning of skeletal muscle performance through differential MyBP-C expression.

SIGNIFICANCE

Myosin-binding protein C (MyBP-C) is a critical component of the skeletal muscle sarcomere, muscle’s smallest contractile unit. MyBP-C’s importance is evident by genetic mutations leading to human myopathies, such as distal arthrogryposis (i.e. club foot). However, the molecular basis of MyBP-C’s functional impact on skeletal muscle contractility is far from certain. Complicating matters further is the expression of fast- and slow-type MyBP-C isoforms that depend on whether the muscle is fast- or slow-twitch. Using multi-scale proteomic, biophysical and mathematical modeling approaches, we define the expression, localization, and modulatory capacities of these distinct skeletal MyBP-C isoforms in rat skeletal muscles. Each MyBP-C isoform appears to modulate muscle contractility differentially; providing the capacity to fine-tune muscle’s mechanical performance as physiological demands arise.
Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain
Authors: Mann Mandeep K. , Franzoni Ivan , de Freitas Renato Ferreira , Tempel Wolfram , Houliston Scott , Arrowsmith Cheryl H. , Harding Rachel J. , Schapira Matthieu
Published: June 2019

USP5 disassembles unanchored polyubiquitin chains to recycle free mono-ubiquitin, and is one of twelve ubiquitin-specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and other ubiquitin signalling pathways in health and disease.
Degradation of Polycomb Repressive Complex 2 with an EED-targeted Bivalent Chemical Degrader
Authors: Potjewyd Frances , Turner Anne-Marie W. , Beri Joshua , Rectenwald Justin M. , Norris-Drouin Jacqueline L. , Cholensky Stephanie H. , Margolis David M. , Pearce Kenneth H. , Herring Laura E. , James Lindsey I.
Published: June 2019

Protein degradation via the use of bivalent chemical degraders provides an alternative strategy to block protein function and assess the biological roles of putative drug targets. This approach capitalizes on the advantages of small molecule inhibitors while moving beyond the restrictions of traditional pharmacology. Herein we report a first-in-class chemical degrader (UNC6852) that targets Polycomb Repressive Complex 2 (PRC2). UNC6852 contains an EED226 derived ligand and a ligand for VHL which bind to the WD40 aromatic cage of EED and CRL2VHL, respectively, to induce proteasomal degradation of PRC2 components, EED, EZH2, and SUZ12. Degradation of PRC2 with UNC6852 blocks the histone methyltransferase activity of EZH2, decreasing H3K27me3 levels in HeLa cells and diffuse large B-cell lymphoma (DLBCL) cells containing an EZH2Y641N gain-of-function mutation. UNC6852 degrades both wild type EZH2 and EZH2Y641N, and additionally displays anti-proliferative effects in this cancer model system.

Abstract Figure
In-situ Real-time Field Imaging and Monitoring of Leaf Stomata by High-resolution Portable Microscope
Authors: Purwar Prashant , Lee Junghoon
Published: June 2019

Stomata, functionally specialized micrometer-sized pores on the epidermis of leaves (mainly on the lower epidermis), control the flow of gases and water between the interior of the plant and atmosphere. Real-time monitoring of stomatal dynamics can be used for predicting the plant hydraulics, photosensitivity, and gas exchanges effectively. To date, several techniques offer the direct or indirect measurement of stomatal dynamics, yet none offer real-time, long-term persistent measurement of multiple stomal apertures simultaneously of an intact leaf in a field under natural conditions. Here, we report a high-resolution portable microscope-based technique for in situ real-time field imaging and monitoring of stomata. Our technique is capable of analyzing and quantifying the multiple lower epidermis stomal pore dynamics simultaneously and does not require any physical or chemical manipulation of a leaf. An upward facing objective lens in our portable microscope allows the imaging of lower epidermis stomatal opening of a leaf while upper epidermis being exposed to the natural environment. Small depth of field (~ 1.3 μm) of a high-magnifying objection lens assists in focusing the stomatal plane in highly non-planar tomato leaf having a high density of trichome (hair-like structures). For long-term monitoring, the leaf is fixed mechanically by a novel designed leaf holder providing freedom to expose the upper epidermis to the sunlight and lower epidermis to the wind simultaneously. In our study, a direct relation between the stomatal opening and the intensity of sunlight illuminating on the upper epidermis has been observed in real-time. In addition, real-time porosity of leaf (ratio between the areas of stomatal opening to the area of a leaf) and stomatal aspect ratio (ratio between the major axis and minor axis of stomatal opening) along with stomatal density have been quantified.
Analysis of the three dimensional structure of the kidney glomerulus capillary network
Authors: Terasaki Mark , Brunson Jason Cory , Sardi Justin
Published: June 2019

The capillary network of the kidney glomerulus filters small molecules from the blood. The glomerular 3D structure should help to understand its function, but it is poorly characterized. We therefore devised a new approach in which an automated tape collecting microtome(ATUM) was used to collect 0.5 micron thick serial sections from fixed mouse kidneys. The sections were imaged by scanning electron microscopy at ∼50 nm / pixel resolution. With this approach, 12 glomeruli were reconstructed at an x-y-z resolution ∼10x higher than that of paraffin sections. We found a no-cross zone between afferent and efferent branches on the vascular pole side; connections here could allow blood to exit without being adequately filtered. Network analysis indicates that the glomerular network does not form by repetitive longitudinal splitting of capillaries. It also suggests that capillaries vary their diameter to make flow more efficient. The shortest path (minimum number of branches to travel from afferent to efferent arterioles) is relatively independent of glomerular size and is present primarily on the vascular pole size. This suggests that the shortest path is established on the vascular pole side, after which new branches and longer paths form on the urinary pole side. Thus the 3D structure of the glomerular capillary network provides useful information with which to understand glomerular function. Other tissue structures in the body may benefit from this new three dimensional approach.
Cyclophilin A Prevents HIV-1 Restriction in Lymphocytes by Blocking Human TRIM5α Binding to the viral Core
Authors: Selyutina Anastasia , Persaud Mirjana , Bulnes-Ramos Angel , Buffone Cindy , Martinez-Lopez Alicia , Scoca Viviana , Di Nunzio Francesca , Hiatt Joseph , Krogan Nevan J. , Hultquist Judd F. , Diaz-Griffero Felipe
Published: June 2019

Disruption of cyclophilin A (CypA)-capsid interactions affects HIV-1 replication in human lymphocytes. To understand the mechanism, we used Jurkat cells, human PBMCs, and human CD4+T cells. Our results showed that the inhibition of HIV-1 infection caused by disrupting CypA-capsid interactions is dependent on human TRIM5α (TRIM5αhu), suggesting that TRIM5αhurestricts HIV-1. Accordingly, we found that TRIM5αhubinds to the HIV-1 core. Disruption of CypA-capsid interactions failed to affect HIV-1-A92E infection, correlating with the loss of TRIM5αhubinding to HIV-1-A92E cores. Disruption of CypA-capsid interactions in PBMCs and CD4+T cells had a greater inhibitory effect on HIV-1 when compared to Jurkat cells. HIV-1-A92E infection of PBMCs and CD4+T cells was unaffected by disruption of CypA-capsid interactions. Consistent with TRIM5α restriction, disruption of CypA-capsid interactions in CD4+T cells inhibited reverse transcription. Overall, our results showed that CypA binding to the core protects HIV-1 from TRIM5αhurestriction.
Themetagenomics: Exploring Thematic Structure and Predicted Functionality of 16s rRNA Amplicon Data
Authors: Woloszynek Stephen , Mell Joshua Chang , Zhao Zhengqiao , Simpson Gideon , O’Connor Michael P. , Rosen Gail L.
Published: June 2019

Analysis of microbiome data involves identifying co-occurring groups of taxa associated with sample features of interest (e.g., disease state). Elucidating such relations is often difficult as microbiome data are compositional, sparse, and have high dimensionality. Also, the configuration of co-occurring taxa may represent overlapping subcommunities that contribute to sample characteristics such as host status. Preserving the configuration of co-occurring microbes rather than detecting specific indicator species is more likely to facilitate biologically meaningful interpretations. Additionally, analyses that use taxonomic relative abundances to predict the abundances of different gene functions aggregate predicted functional profiles across taxa. This precludes straightforward identification of predicted functional components associated with subsets of co-occurring taxa. We provide an approach to explore co-occurring taxa using “topics” generated via a topic model and link these topics to specific sample features (e.g., disease state). Rather than inferring predicted functional content based on overall taxonomic relative abundances, we instead focus on inference of functional content within topics, which we parse by estimating interactions between topics and pathways through a multilevel, fully Bayesian regression model. We apply our methods to three publicly available 16S amplicon sequencing datasets: an inflammatory bowel disease dataset from Gevers et al., an oral cancer dataset from Schmidt et al., and a time-series dataset from David et al. Using our topic model approach to uncover latent structure in 16S rRNA amplicon surveys, investigators can (1) capture groups of co-occurring taxa termed topics; (2) uncover within-topic functional potential; (3) link taxa co-occurrence, gene function, and environmental/host features; and (4) explore the way in which sets of co-occurring taxa behave and evolve over time. These methods have been implemented in a freely available R package: https://github.com/EESI/themetagenomics.
On the development of sleep states in the first weeks of life
Authors: Wielek Tomasz , Del Giudice Renata , Lang Adelheid , Wislowska Malgorzata , Ott Peter , Schabus Manuel
Published: June 2019

Human newborns spend up to 18 hours sleeping. The organization of their sleep differs immensely from adult sleep, and its quick maturation and fundamental changes correspond to the rapid cortical development at this age. Manual sleep classification is specifically challenging in this population given major body movements and frequent shifts between vigilance states; in addition various staging criteria co-exist. In the present study we utilized a machine learning approach and investigated how EEG complexity and sleep stages evolve during the very first weeks of life. We analyzed 42 full-term infants which were recorded twice (at week two and five after birth) with full polysomnography. For sleep classification EEG signal complexity was estimated using multi-scale permutation entropy and fed into a machine learning classifier. Interestingly the baby’s brain signal complexity (and spectral power) revealed huge developmental changes in sleep in the first 5 weeks of life, and were restricted to NREM (“quiet”) and REM (“active sleep”) states with little to no changes in state wake. Data demonstrate that our classifier performs well over chance (i.e., >33% for 3-class classification) and reaches almost human scoring accuracy (60% at week-2, 73% at week-5). Altogether, these results demonstrate that characteristics of newborn sleep develop rapidly in the first weeks of life and can be efficiently identified by means of machine learning techniques.

Author summary

The organization of newborn sleep differs from adult sleep, and its ongoing maturation over time corresponds with cortical development. However, sleep scoring in this population is challenging given frequent artifacts in polysomnography (PSG) and absence of established staging criteria which results in low inter-scorer reliability. To investigate changes in the early brain activity, we analyzed large sample of newborn data at week 2 and 5 after birth. First we evaluated sleep that was previously scored visually, in terms of both entropy and oscillatory power. Next we accessed the performance of automatic sleep scoring based on machine learning compared with conventional, manual scoring. We observed clear developmental changes on the brain-level in the first 5 weeks of life in human newborns. These changes were limited to “quiet” NREM and “active” REM sleep. Also our classifier data demonstrated that we can classify well above chance and similar to human scorers using multi-scale permutation entropy (and just 6 EEG and 5 physiological channels).