bluuebunny/crossref_metadata_2025 huggingface dataset:
Patienteninformation – Übungen gegen den Handynacken
Authors: Eva-Maria Bläsi
Published: October 2018

Verspannungen vorbeugen Beim Gebrauch des Smartphones oder Tablets hält man den Kopf meist gebeugt. Diese Haltung kann die Halswirbelsäule überlasten und zu Muskelverspannungen und Schmerzen führen. Mit ein paar einfachen Übungen kräftigen Sie Ihre Muskulatur und geben Verspannungen keine Chance.
Practical Negotiation for Medical Professionals
Authors: Eisemann Bradley , Wagner Ryan , Reece Edward
Published: October 2018

Despite incredible advances in medical innovation and education, many students finish medical school, and physicians finish residency, without sound business acumen regarding the financial realities of the modern profession. The curriculum in medical schools and residency programs too often neglects teaching the business of medicine. This overview addresses how physicians can utilize effective negotiation strategies to help develop a medical practice or add value to an existing practice or institution. The authors applied the six foundations of effective negotiating, detailed by Richard Shell in his Bargaining for Advantage, to the medical field to demonstrate the processes involved in effective negotiating. They then outlined a strategy for physicians to adopt when negotiating and showed how this strategy can be used to add value. The six foundations include: developing a personal bargaining style, setting realistic goals, determining authoritative standards, establishing relationships, exploring the other party's interests, and gaining leverage. As physicians complete training, the ability to solely focus on medical knowledge and clinical patient care disappears. It is crucial that physicians invest the time and energy into preparing for the business aspects of this profession in much the same way they prepare for the clinical care of patients. This overview seeks to define the basics of negotiation, characterize the application of negotiation principles toward clinical medicine, and lay the foundation for further discussion and investigation.
A study of the effect of gliding arc non-thermal plasma on almonds decontamination
Authors: Khalili Fatemeh , Shokri Babak , Khani Mohammad-Reza , Hasani Mohammad , Zandi Farzaneh , Aliahmadi Atousa
Published: October 2018

Escherichia coli is responsible for more than 90% of food poisoning cases and can survive for long periods under adverse conditions and refrigeration temperature. In this study, the effect of gliding arc plasma processing on infected Almond with Escherichia coli was investigated. The optimal conditions during the different applied powers and treatment time were determined. Moreover, the optimum condition was examined on other gram-negative bacteria as Salmonella and Shigella. The viability of almond bacteria was studied using colony-counting analysis and evaluation of active species in plasma was made by the optical emission spectroscopy (OES) method. Scanning electron microscopy (SEM) analysis was carried out to illustrate the morphological change and color measuring analysis was performed to investigate food quality after almond plasma treatment. Finally, it was shown that plasma technique has the capability of food industrialization and potential of method extension.
Determining barotrauma in the Pictus catfish, Pimelodus pictus, experimentally exposed to simulated hydropower turbine passage
Authors: Beirão Bernardo V. , Silva Luiz G. M. , Brown Richard S. , Walker Ricardo W.
Published: October 2018

Hydropower development poses severe threats to the aquatic diversity and ecosystem services. One such threat is the exposure of fish to extreme conditions within hydropower facilities. Fish may suffer rapid decompression when passing through turbines or when entering the draft tubes, which can lead to barotrauma and mortality. We aimed to evaluate the effects of rapid decompression on the Amazonian benthic species Pimelodus pictus (Pictus catfish), by simulating in hypo–hyperbaric chambers. The most frequent injuries in Pictus catfish exposed to simulated rapid decompression were swim-bladder rupture, intestine rupture, internal haemorrhage and embolism. The occurrence and magnitude of internal haemorrhaging and emboli were related to the ratio of pressure change and the decompression timespan, whereas swim-bladder rupture occurred even at relatively low ratios. Emboli was present almost entirely among fish with a ruptured swim bladder. Importantly, all fish were negatively buoyant before exposure to decompression, posing challenges to data analysis. Therefore, barotrauma studies with benthic fish species are deemed to be challenging and are likely to require the use of complementary approaches. Research is needed to understand the state of buoyancy of benthic fish in the wild and to develop methods to accurately replicate these in a controlled testing environment.
pJRES Binning Algorithm (JBA): a new method to facilitate the recovery of metabolic information from pJRES 1H NMR spectra
Authors: Rodriguez-Martinez Andrea , Ayala Rafael , Posma Joram M , Harvey Nikita , Jiménez Beatriz , Sonomura Kazuhiro , Sato Taka-Aki , Matsuda Fumihiko , Zalloua Pierre , Gauguier Dominique , Nicholson Jeremy K , Dumas Marc-Emmanuel
Published: October 2018

Motivation

Data processing is a key bottleneck for 1H NMR-based metabolic profiling of complex biological mixtures, such as biofluids. These spectra typically contain several thousands of signals, corresponding to possibly few hundreds of metabolites. A number of binning-based methods have been proposed to reduce the dimensionality of 1 D 1H NMR datasets, including statistical recoupling of variables (SRV). Here, we introduce a new binning method, named JBA (“pJRES Binning Algorithm”), which aims to extend the applicability of SRV to pJRES spectra.

Results

The performance of JBA is comprehensively evaluated using 617 plasma 1H NMR spectra from the FGENTCARD cohort. The results presented here show that JBA exhibits higher sensitivity than SRV to detect peaks from low-abundance metabolites. In addition, JBA allows a more efficient removal of spectral variables corresponding to pure electronic noise, and this has a positive impact on multivariate model building

Availability and implementation

The algorithm is implemented using the MWASTools R/Bioconductor package.

Supplementary information

Supplementary data are available at Bioinformatics online.
Staphylococcus aureus Decolonization of Mice With Monoclonal Antibody Neutralizing Protein A
Authors: Chen Xinhai , Sun Yan , Missiakas Dominique , Schneewind Olaf
Published: October 2018

Staphylococcus aureus persistently colonizes the nasopharynx of about one-third of the human population, a key risk factor for community- and hospital-acquired invasive infections. Current strategies for S. aureus decolonization include topical and systemic administration of antibiotics, which is associated with selection for antibiotic resistance and posttreatment recolonization. Using a mouse model for S. aureus colonization, we show here that systemic administration of a recombinant monoclonal antibody neutralizing staphylococcal protein A (SpA) can stimulate antibacterial immunoglobulin G and immunoglobulin A responses and promote S. aureus decolonization. These results suggest that antibody neutralizing SpA, a B-cell superantigen, may also be useful for S. aureus decolonization in humans.
Familial Risks and Mortality in Second Primary Cancers in Melanoma
Authors: Chattopadhyay Subhayan , Hemminki Akseli , Försti Asta , Sundquist Kristina , Sundquist Jan , Hemminki Kari
Published: October 2018

Background

Malignant melanoma (MM) patients are at increasing risk of developing second primary cancers (SPCs). We assessed mortality and risk of SPCs in MM patients with siblings or parents affected with same cancer compared with that of the general population.

Methods

We used the Swedish Family-Cancer Database to assess relative risks (RRs) and causes of death in SPCs until 2015 in patients with a MM diagnosis between 1958 and 2015. We identified 35 451patients with MM among whom 3212 received a subsequent diagnosis of SPC. RRs of SPCs after MM diagnosis were calculated stratifying over concordant family history of cancer in first-degree relatives.

Results

Familial RRs were increased for second melanoma (RR = 19.28, 95% CI = 16.71 to 22.25), squamous cell skin cancer (RR = 7.58, 95% CI = 5.57 to 10.29), leukemia (RR = 5.69, 95% CI = 2.96 to 10.94), bladder (RR = 4.15, 95% CI = 2.50 to 6.89), ovarian (RR = 3.89, 95% CI = 1.46 to 10.37), kidney cancer (RR = 3.77, 95% CI = 1.57 to 9.06), cancer of unknown primary (RR = 3.67, 95% CI = 1.65 to 8.16), nervous system (RR = 2.88, 95% CI = 1.20 to 6.93), breast (RR = 2.34, 95% CI = 1.92 to 2.84), lung (RR = 2.24, 95% CI = 1.50 to 3.35), and prostate cancer (RR = 2.22, 95% CI = 1.89 to 2.61) with statistical significance. For all cancers, familial RR was in excess (2.09, 95% CI = 2.02 to 2.16 vs 1.78, 95% CI = 1.69 to 1.87; Ptrend < .0001). Cause of death in MM patients with SPC is shown to be dependent on the cancer site though SPCs contributed to majority of deaths.

Conclusions

SPCs appear higher with prior family history of cancer and contribute to mortality. SPC was the most common cause of death in patients with SPC and is almost uniformly the major contributing cause of death for all cancer sites. For improved survival in MM patients, prevention and early detection of SPCs would be important.
Part IV Guide to Key Substantive Issues, 19 The Law Applicable in Investment Treaty Arbitration
Authors: Yas Banifatemi
Published: October 2018

Investment treaty arbitration, being an arbitral process, in no way differs from international commercial arbitration in that the principle of party autonomy is the primary rule governing the arbitration, including as regards the law applicable to the substance of the dispute. When the applicable law has been chosen by the parties, the arbitrators have a duty to apply such law and nothing but such law. It is only in the absence of a choice by the parties that the arbitrators are entitled to exercise a degree of discretion in the determination of the applicable law. This chapter examines each of these situations in turn, before considering whether the specific nature of investment protection treaties has implications in terms of choice of law process.
Part V Remedies and Costs, 24 Interim Relief in Investment Treaty Arbitration
Authors: Gabrielle Kaufmann-Kohler , Aurélia Antonietti , Michele Potestà
Published: October 2018

This chapter reviews the requirements for a party to obtain interim relief from an arbitral tribunal, the measures that can be ordered, their nature, and effects. It also considers whether the parties to the dispute can seek interim relief from domestic courts rather than from the arbitral tribunal. The scope of the interim relief available in the context of investor-state disputes is broad enough to meet the parties’ legitimate needs for temporary protection, subject to limitations which may be found in the relevant treaty, such as the ones contained in NAFTA Article 1134. However, applicants are also faced with a high threshold when seeking to establish that the interim relief requested is urgent and needed. This may explain the reluctance of many tribunals to grant interim relief in the context of investor-state arbitration, whether in the International Centre for Settlement of Investment Dispute (ICSID) system or under the United Nations Commission on International Trade Law Rules.
Gleeson on the International Regulation of Banking
Authors: Gleeson Simon
Published: October 2018

Financial capital regulation drives almost every aspect of the financial markets, from the structures of financial groups and the way they raise capital to the development of investment structures and financial engineering such as derivatives, securitisations, structured finance, credit derivatives, repos, and stock lending. This third edition of the leading guide on the structure of bank financial regulation is invaluable for lawyers and other non-statisticians interested in the regulatory drivers which shape modern financial transactions and techniques. The legal and regulatory principles which underlie the regulations are articulated here in a structured and accessible format. Since the publication of the second edition, the final form of the Basel 3 international regulatory framework for banks has been agreed, and the new edition covers both Basel 3 and references the first tranche of rulebooks and secondary legislation to ensue as a result. The new edition also covers the new formal bank resolution and recovery regime which came into force in November 2016 requiring UK banks, building societies, and the large investment firms to demonstrate minimum requirements for eligible liabilities and own funds. Another key focus of this edition is bank structural reform. Whilst the implementation of the EU initiative stalled and was ultimately withdrawn, the UK has already implemented its own version which has had, and will continue to have, a significant impact on banking regulation.
Operational Risk Requirements
Authors: Gleeson Simon
Published: October 2018

Operational risk is the ‘risk of loss resulting from inadequate or failed internal processes, people, and systems or from external events’. Banks are required to control their operational risk exposure. This chapter discusses the three approaches Basel 2 offers to determine operational risk: the basic indicator approach, the standardized approach, and the advanced measurement approach (AMA). The first two mechanisms which Basel provides for calculating operational risk eschew the analysis of operational risks themselves, and operate on a percentage of lead indicator basis. However, the third approach, i.e. the AMA, permits banks to assess the actual incidence and severity of operational risk within the institution, and to model a charge based on that information.
Liquidity Requirements
Authors: Gleeson Simon
Published: October 2018

This chapter discusses liquidity requirements under Basel 3. The basis of all liquidity regulation remains the BCBS principles for sound liquidity management, which provide detailed guidance on the risk management of liquidity and are intended to promote better risk management in this area. These are supplemented by the liquidity monitoring tools set out in the BCBS paper Basel III: The Liquidity Coverage Ratio and liquidity risk monitoring tools. There is also a move away from modelling and towards a less flexible, less risk-based architecture which prioritises comparability and even-handedness over accuracy and effectiveness. Moreover, supervisors are mandated to operate a comprehensive programme of liquidity supervision over and above the mechanical requirements.
Liquidity Coverage Ratio and Net Stable Funding Ratio
Authors: Gleeson Simon
Published: October 2018

This chapter discusses the Liquidity Coverage Ratio (LCR) and Net Stable Funding Ratio (NSFR). The LCR is designed to make sure that the bank has sufficient liquidity to survive short-term shocks; the NSFR is designed to make sure that the bank's balance sheet is not too excessively mismatched between long- and short-term funding. In essence, LCR is a requirement that the bank has sufficient liquid assets to get through a 30-day period of high stress, whilst NSFR is a requirement that the bank's long-term assets be substantially funded by long-term liabilities. Both of these tests require some heroic assumptions about access to funding, likely roll-off of liabilities, and so on.
Part V Regional Perspectives on Global Ocean Governance, 11 The African Perspective on Global Ocean Governance
Authors: Patrick Vrancken
Published: October 2018

This chapter discusses issues of global ocean governance from an African perspective. It first provides an overview of the historical lack of engagement by Africa in the 400-year long evolution of the customary international law of the sea before considering its belated entry into the international negotiation process that yielded the 1982 United Nations Convention on the Law of the Sea (UNCLOS). It then describes the developing institutional framework for African ocean governance, focusing on the African Union and its areas of competence, along with the different African regional arrangements that have been established to address maritime issues ranging from natural environmental protection and sustainable marine resource development, to maritime transport safety and security. It also examines Africa's contribution to global ocean governance framework and concludes with an assessment of the Combined Exclusive Maritime Zone of Africa (CEMZA) proposal.
Part V Regional Perspectives on Global Ocean Governance, 15 The Australian and Antarctic Perspective on Global Ocean Governance
Authors: Robin Warner
Published: October 2018

This chapter examines issues of global ocean governance in Australia and Antarctica. It first provides an overview of Australia's law and policy framework for ocean governance as well as its maritime jurisdiction before discussing issues regarding management of rights and responsibilities on Australia's extended continental shelf. It then considers Australia's engagement with regional initiatives to conserve and sustainably use marine biodiversity, and the ways it addresses global and regional maritime security. In particular, it analyses the Australian Oceans Policy on maritime security and how it evolved in response to rising instances of ‘people-smuggling’ incidents to establish both national and regional policies against this practice. The chapter goes on to assess ocean governance in Antarctica, focusing on the Antarctic Treaty and the cooperation among its partners in the development of a comprehensive environmental protection regime which applies to marine areas both within and beyond national jurisdiction.
Part V Regional Perspectives on Global Ocean Governance, 16 The Role of the World Ocean Council and the Ocean Business Community in Global Ocean Governance
Authors: Paul Holthus
Published: October 2018

This chapter discusses the role of the World Ocean Council (WOC) and the international ocean business community in global ocean governance (GOG). It first provides an overview of the institutional development and profile of the WOC before considering the work and role and work of the WOC on ocean governance with and for the ocean business community. It then examines the Sustainable Development Goals (SDGs) in relation to ocean business and the WOC, as well as the size, complexity trends in the ocean economy and ocean business community, which are fundamental to understanding their importance to GOG. It also analyses GOG issues relevant to the ocean business community and WOC that the United Nations and its associated bodies must address and concludes with an assessment of the role of the ocean business community and WOC in the future of the GOG agenda.
Randomized Clinical Trial to Assess the Impact of the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01 on HIV-1 Persistence in Individuals on Effective ART
Authors: Riddler Sharon A , Zheng Lu , Durand Christine M , Ritz Justin , Koup Richard A , Ledgerwood Julie , Bailer Robert T , Koletar Susan L , Eron Joseph J , Keefer Michael C , Macatangay Bernard J C , Cyktor Joshua C , Mellors John W ,   the AIDS Clinical Trials Group A5342 Protocol Team, Hite Mark , Clark Jan , Currin David , Tipton Mandy , Weinman Renee , Onesi Sara , Hurley Christine , Bunce Catherine A , Storey Sheryl , Dunaway Shelia , Lambert Nina , Berzins Baiba , Gottesman Joan , Leonard Michael , Ray Graham , Kittelson Pat , Benson Connie , Muttera Leticia , Flynn Teri , Sbrolla Amy , Wiggins Ilene , Howard Jamilla , Arduino Roberto C , Villamil Aristoteles E , Kessels Lisa , Spitz Teresa , Campbell Danielle , Kudumu Mwenda , Sise Thucuma , Nair Apsara , Baer Jenifer , Epperson Kim , Perelson Alan , Jennings Cheryl , Tressler Randall , Acosta Ed , Casazza Joseph , Benns Alex
Published: October 2018

Background

Broadly neutralizing monoclonal antibodies (bnMAbs) may promote clearance of HIV-1-expressing cells through antibody-dependent cell-mediated cytotoxicity. We evaluated the effect of the CD4-binding site bnMAb, VRC01, on measures of HIV-1 persistence in chronically infected individuals.

Methods

A5342 was a phase 1, randomized, double-blind, placebo-controlled, parallel-arm study. Participants on effective antiretroviral therapy (ART) were randomized to receive 2 infusions of VRC01 (40 mg/kg) at entry and week 3, and 2 infusions of placebo (saline) at weeks 6 and 9; or 2 infusions of placebo at entry and week 3, and 2 infusions of VRC01 at weeks 6 and 9.

Results

Infusion of VRC01 was safe and well tolerated. The median fold-change in the cell-associated HIV-1 RNA/DNA ratio from baseline to week 6 was 1.12 and 0.83 for the VRC01 and placebo arms, respectively, with no significant difference between arms (P = .16). There were no significant differences in the proportions with residual plasma viremia ≥1 copies/mL or in phorbol 12-myristate 13-acetate/ionomycin-induced virus production from CD4+ T cells between arms (both P > .05).

Conclusions

In individuals with chronic HIV-1 infection on ART, VRC01 infusions were safe and well tolerated but did not affect plasma viremia, cellular HIV-1 RNA/DNA levels, or stimulated virus production from CD4+ T cells.

ClinicalTrials.gov Identifier

NCT02411539
Postoperative Repositioning of Inverted Descemet Membrane Endothelial Keratoplasty Grafts
Authors: Dragnea Diana C. , Nobacht Siamak , Gericke Adrian , Parker Jack , Oellerich Silke , Ham Lisanne , Melles Gerrit R.J.
Published: October 2018

Purpose:

To present 4 cases of postoperative repositioning of inverted grafts after Descemet membrane endothelial keratoplasty (DMEK).

Methods:

Retrospective case reports of 4 patients presenting with subtotal to total graft detachment after DMEK, most probably owing to upside-down graft positioning. Graft repositioning was performed 1 to 14 days after initial DMEK surgery. In 3 cases (cases 1, 3, and 4), repositioning was performed without removing the graft from the anterior chamber (AC), whereas for case 2, the graft had to be removed from the AC to attain correct graft orientation.

Results:

In all 4 cases, the initially upside-down DMEK grafts could be successfully repositioned postoperatively. Three cases showed complete graft attachment after graft repositioning with clear corneas until the last available follow-up. One case manifested a persistent central detachment with central corneal edema, eventually requiring re-DMEK. Endothelial cell density decreased from 2800 cells/mm2 preoperatively to 2373 cells/mm2 at 2 years postoperatively for case 1 and from 2600 to 600 cells/mm2 at 6 months postoperatively for case 2. Case 3 showed a clear cornea until the last available follow-up at 1 year postoperatively.

Conclusions:

In cases of upside-down grafts after DMEK, attempting to reposition the graft, with or without removing the graft from the AC, may be a cost- and tissue-efficient alternative before converting to re-DMEK.
Issues in Recruiting and Retaining Asian American Breast Cancer Survivors in a Technology-Based Intervention Study
Authors: Im Eun-Ok , Kim Sangmi , Xu Shu , Lee Chiyoung , Hamajima Yuko , Inohara Ayako , Chang Kathleen , Chee Eunice , Chee Wonshik
Published: October 2018

Background

Difficulties in recruiting and retaining Asian Americans in traditional research have been well documented. Despite an increasing number of technology-based cancer studies among racial/ethnic minorities, little is still known about potential issues in recruiting and retaining racial/ethnic minority cancer survivors for technology-based intervention research.

Objective

This discussion article aims to examine issues in recruiting and retaining a group of racial/ethnic minorities—Asian American breast cancer survivors—for a technology-based intervention study.

Methods

The parent study is an ongoing large-scale, national-scope, technology-based intervention study among a target number of 330 Asian American breast cancer survivors. During the recruitment and retention process, research diaries were written by research team members, and the written records of weekly research team meetings were kept. The written records were analyzed using a content analysis. Then, the themes were used to support the discussion points made in the article.

Results

There existed subethnic differences in research participation; it was easier to recruit Chinese participants compared with other subethnic groups. The use of culturally matched research team members and multiple languages was essential. Gatekeepers were also elemental for recruitment and retention. Various motivation strategies were needed to retain the participants. Each subethnic group used different communication apps. Finally, trust building was essential to retain the participants in the intervention.

Conclusions

Researchers need to consider these practical issues in future technology-based intervention research.

Implications for Practice

These issues need to be considered in future program/intervention development and implementation among racial/ethnic minority cancer survivors.
IDH1 and IDH2 mutants identified in cancer lose inhibition by isocitrate because of a change in their binding sites
Authors: Bascur Juan P. , Alegría-Arcos Melissa , Araya-Durán Ingrid , Juritz Ezequiel I. , González-Nilo Fernando D. , Almonacid Daniel E.
Published: October 2018

IDH1 and IDH2 are human enzymes that convert isocitrate (ICT) into α-ketoglutarate (AKG). However, mutations in positions R132 of IDH1 and R140 and R172 of IDH2 cause these enzymes to convert AKG into 2-hydroxyglutarate (2HG). Concurrently, accumulation of 2HG in the cell is correlated with the development of cancer. This activity change is mainly due to the loss of the competitive inhibition by ICT of these enzymes, but the molecular mechanism behind this loss of inhibition is currently unknown. In this work we characterized the inhibition and loss of inhibition of IDH1 and IDH2 by means of the binding energies derived from molecular docking calculations. We characterized the substrate binding sites and how they differ among the mutant and wild type enzymes using a Jaccard similarity coefficient based on the residues involved in binding the substrates. We found that molecular docking effectively identifies the inhibition by ICT in the wild type and mutant enzymes that do not appear in tumors, and the loss of inhibition in the mutant enzymes that appear in tumors. Additionally, we found that the binding sites of the mutant enzymes are different among themselves. Finally, we found that the regulatory segment of IDH1 plays a prominent role in the change of binding sites between the mutant enzymes and the wild-type enzymes. Our findings show that the loss of inhibition is related to variations in the enzyme binding sites. Additionally, our findings show that a drug capable of targeting all IDH1 and IDH2 mutations in cancer is unlikely to be found due to significant differences among the binding sites of these paralogs. Moreover, the methodology developed here, which combines molecular docking calculations with binding site similarity estimation, can be useful for engineering enzymes, for instance, when aiming to modify the substrate affinity of an enzyme.
The TMCrys server for supporting crystallization of transmembrane proteins
Authors: Varga Julia K. , Tusnády Gábor E.
Published: October 2018

Motivation

Due to their special properties, the structures of transmembrane proteins are extremely hard to determine. Several methods exist to predict the propensity of successful completion of the structure determination process. However, available predictors incorporate data of any kind of proteins, hence they can hardly differentiate between crystallizable and non-crystallizable membrane proteins.

Results

We implemented a web server to simplify running TMCrys prediction method that was developed specifically to separate crystallizable and non-crystallizable proteins.

Availability

http://tmcrys.enzim.ttk.mta.hu

Contact

tusnady.gabor@ttk.mta.hu

varga.julia@ttk.mta.hu
Causal Effects of Blood Lipids on Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study
Authors: Zeng Ping , Zhou Xiang
Published: October 2018

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disorder that is predicted to increase across the globe by ~70% in the following decades. Understanding the disease causal mechanism underlying ALS and identifying modifiable risks factors for ALS hold the key for the development of effective preventative and treatment strategies. Here, we investigate the causal effects of four blood lipid traits that include high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG) on the risk of ALS. By leveraging instrument variables from multiple large-scale genome-wide association studies in both European and East Asian populations, we carry out one of the largest and most comprehensive Mendelian randomization analyses performed to date on the causal relationship between lipids and ALS. Among the four lipids, we found that only LDL is causally associated with ALS and that higher LDL level increases the risk of ALS in both the European and East Asian populations. Specifically, the odds ratio of ALS per one standard deviation (i.e. 39.0 mg/dL) increase of LDL is estimated to be 1.14 (95% CI 1.05 - 1.24, p = 1.38E-3) in the European and population and 1.06 (95% CI 1.00 - 1.12, p = 0.044) in the East Asian population. The identified causal relationship between LDL and ALS is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our study provides important evidence supporting the causal role of higher LDL on increasing the risk of ALS, paving ways for the development of preventative strategies for reducing the disease burden of ALS across multiple nations.
Regrowth-delay Body as a Bacterial Subcellular Structure marking multidrug tolerant Persisters
Authors: Yu Jiayu , Liu Yang , Yin Huijia , Chang Zengyi
Published: October 2018

Bacteria have long been recognized to be capable of entering a phenotypically non-growing persister state, in which the cells exhibit an extended regrowth lag and a multidrug tolerance, thus posing a great challenge in treating infectious diseases. Owing to their non-inheritability, low abundance of existence, lack of metabolic activities, and high heterogeneity, properties of persisters remain poorly understood. Here, we report our accidental discovery of a hitherto unreported subcellular structure that we term the regrowth-delay body, which is formed only in non-growing bacterial cells and sequesters multiple key proteins. As of now, this structure, that dissolves when the cell resumes growth, is the most distinguishable subcellular structure marking persisters. Our studies also indicate that persisters exhibit different depth of persistence, as determined by the status of their regrowth-delay bodies. Our findings imply that suppressing the formation and/or promoting the dissolution of regrowth-delay bodies could be viable strategies for eradicating persisters.
Occurrence of ordered and disordered structural elements in postsynaptic proteins supports optimization for interaction diversity
Authors: Kiss-Tóth Annamária , Dobson Laszlo , Péterfia Bálint , Ángyán Annamária F. , Ligeti Balázs , Lukács Gergely , Gáspári Zoltán
Published: October 2018

The human postsynaptic density is an elaborate network comprising thousands of proteins, playing a vital role in the molecular events of learning and the formation of memory. Despite our growing knowledge of specific proteins and their interactions, atomic-level details of their full three-dimensional structure and their rearrangements are mostly elusive. Advancements in structural bioinformatics enabled us to depict the characteristic features of proteins involved in different processes aiding neurotransmission. We show that postsynaptic protein-protein interactions are mediated through the delicate balance of intrinsically disordered regions and folded domains, and this duality is also imprinted in the amino acid sequence. We introduce Diversity of Potential Interactions (DPI), a structure and regulation based descriptor to assess the diversity of interactions. Our approach reveals that the postsynaptic proteome has its own characteristic features and these properties reliably discriminate them from other proteins of the human proteome. Our results suggest that postsynaptic proteins are especially susceptible to forming diverse interactions with each other, which might be key in the reorganization of the PSD in molecular processes related to learning and memory.
Phoneme-level processing in low-frequency cortical responses to speech explained by acoustic features
Authors: Daube Christoph , Ince Robin A. A. , Gross Joachim
Published: October 2018

When we listen to speech, we have to make sense of a waveform of sound pressure. Hierarchical models of speech perception assume that before giving rise to its final semantic meaning, the signal is transformed into unknown intermediate neuronal representations. Classically, studies of such intermediate representations are guided by linguistically defined concepts such as phonemes. Here we argue that in order to arrive at an unbiased understanding of the mechanisms of speech comprehension, the focus should instead lie on representations obtained directly from the stimulus. We illustrate our view with a strongly data-driven analysis of a dataset of 24 young, healthy humans who listened to a narrative of one hour duration while their magnetoencephalogram (MEG) was recorded. We find that two recent results, a performance gain of an encoding model based on acoustic and annotated linguistic features over a model based on acoustic features alone as well as the decoding of subgroups of phonemes from phoneme-locked responses, can be explained with an encoding model entirely based on acoustic features. These acoustic features capitalise on acoustic edges and outperform Gabor-filtered spectrograms, features with the potential to describe the spectrotemporal characteristics of individual phonemes. We conclude that models of brain responses based on linguistic features can serve as excellent benchmarks. However, we put forward that linguistic concepts are better used when interpreting models, not when building them. In doing so, we find that the results of our analyses favour syllables over phonemes as candidate intermediate speech representations visible with fast non-invasive neuroimaging.
Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease
Authors: Moss Joshua , Magenheim Judith , Neiman Daniel , Zemmour Hai , Loyfer Netanel , Korach Amit , Samet Yaacov , Maoz Myriam , Druid Henrik , Arner Peter , Fu Keng-Yeh , Kiss Endre , Spalding Kirsty L. , Landesberg Giora , Zick Aviad , Grinshpun Albert , Shapiro AM James , Grompe Markus , Wittenberg Avigail Dreazan , Glaser Benjamin , Shemer Ruth , Kaplan Tommy , Dor Yuval
Published: October 2018

Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated usingin silicosimulations as well asin vitromixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure which can be easily adapted to study the cellular contributors to cfDNA in many settings, opening a broad window into healthy and pathologic human tissue dynamics.
The three dimensional structure of Bovine Salivary Protein 30b (BSP30b) and its interaction with specific rumen bacteria
Authors: Zhang Heng , Burrows Judith , Card Graeme L. , Attwood Graeme , Wheeler Thomas T. , Arcus Vickery L.
Published: October 2018

Bovine Salivary Protein 30b (BSP30b) is a member of the tubular lipid-binding (TULIP) superfamily that includes the human bactericidal/permeability-increasing proteins (BPI), lipopolysaccharide binding proteins (LBP) and palate, lung, and nasal epithelium carcinoma-21 associated proteins (PLUNC). BSP30b is most closely related to the PLUNC family and is predominantly found in bovine saliva. There are four BSP30 isoforms (BSP30a-d) and collectively, they are the most abundant protein component of bovine saliva. The PLUNC family members are proposed to be lipid binding proteins, although in most cases their lipid ligands are unknown. Here, we present the X-ray crystal structure of BSP30b at 2.0 Å resolution. We used a double methionine mutant and Se-Met SAD phasing to solve the structure. The structure adopts a curved cylindrical form with a hydrophobic channel formed by an α/β wrap, which is consistent with the TULIP superfamily. The structure of BSP30b in complex with oleic acid is also presented where the ligand is accommodated within the hydrophobic channel. The electron density for oleic acid suggests that the ligand is only partially occupied in the binding site implying that oleic acid may not be the preferred ligand. GFP-tagged BSP30b binds to the surface of olive oil droplets, as observed under fluorescent microscopy, and acts as a surfactant consistent with its association with decreased susceptibility to bloat in cattle. Bacteria extracted directly from bovine rumen contents indicate that the GFP_BSP30b fusion protein binds to a small number of selected bacterial speciesin vivo. These results suggest that BSP30b may bind to bacterial lipids from specific species and that this abundant protein may have important biological roles via interacting with rumen bacteria during feeding and rumination.
Enhanced plasticity of programmed DNA elimination boosts adaptive potential in suboptimal environments
Authors: Vitali Valerio , Hagen Rebecca , Catania Francesco
Published: October 2018

The impact of ecological changes on the development of new somatic genomes has thus far been neglected. This oversight yields an incomplete understanding of the mechanisms that underlie environmental adaptation and can be tackled leveraging the biological properties of ciliates. WhenParameciumreproduces sexually, its polyploid somatic genome regenerates from the germline genome via a developmental process, Programmed DNA elimination (PDE), that involves the removal of thousands of ORF-interrupting germline sequences. Here, we demonstrate that exposure to sub-optimal temperatures impacts PDE efficiency, prompting the emergence of hundreds of alternative DNA splicing variants that dually embody cryptic (germline) variation andde novoinduced (somatic) mutations. In contrast to trivial biological errors, many of these alternative DNA isoforms display a patterned genomic topography, are epigenetically controlled, inherited trans-somatically, and under purifying selection. Developmental thermoplasticity inParameciumis a likely source of evolutionary innovation.
Selective advantages favour high genomic AT-contents in intracellular elements
Authors: Dietel Anne-Kathrin , Merker Holger , Kaltenpoth Martin , Kost Christian
Published: October 2018

Extrachromosomal genetic elements generally exhibit increased AT-contents relative to their hosts’ DNA. The AT-bias of endosymbiotic genomes is commonly explained by neutral evolutionary processes. Here we show experimentally that an increased AT-content of host-dependent elements can be selectively favoured on the host level. Manipulating the nucleotide composition of bacterial cells by introducing A+T-or G+C-rich plasmids, we demonstrate that cells containing GC-rich plasmids are less fit than cells containing AT-rich plasmids. Moreover, the cost of GC-rich elements could be compensated by providing G+C-, but not A+T-precursors, thus linking the observed fitness effects to the cytoplasmic availability of nucleotides. Our work identifies selection as a strong evolutionary force that drives the genomes of intracellular genetic elements toward higher A+T contents.

Author Summary

Genomes of endosymbiotic bacteria are commonly more AT-rich than the ones of their free-living relatives. Interestingly, genomes of other intracellular elements like plasmids or bacteriophages also tend to be richer in AT than the genomes of their hosts. The AT-bias of endosymbiotic genomes is commonly explained by neutral evolutionary processes. However, since A+T nucleotides are both more abundant and energetically less expensive than G+C nucleotides, an alternative explanation is that selective advantages drive the nucleotide composition of intracellular elements. Here we provide strong experimental evidence that intracellular elements, whose genome is more AT-rich than the genome of the host, are selectively favored on the host level. Thus, our results emphasize the importance of selection for shaping the DNA base composition of extrachromosomal genetic elements.
Statistical Considerations in the Design and Analysis of Longitudinal Microbiome Studies
Authors: Silverman Justin D , Shenhav Liat , Halperin Eran , Mukherjee Sayan , David Lawrence A
Published: October 2018

Longitudinal studies of microbial communities have emphasized that host-associated microbiota are highly dynamic as well as underscoring the potential biomedical relevance of understanding these dynamics. Despite this increasing appreciation, statistical challenges in the design and analysis of longitudinal microbiome studies such as sequence counting, technical variation, signal aliasing, contamination, sparsity, missing data, and algorithmic scalability remain. In this review we discuss these challenges and highlight current progress in the field. Where possible, we try to provide guidelines for best practices as well as discuss how to tailor design and analysis to the hypothesis and ecosystem under study. Overall, this review is intended to serve as an introduction to longitudinal microbiome studies for both statisticians new to the microbiome field as well as biologists with little prior experience with longitudinal study design and analysis.
Encapsulated mononuclear stem cells: paracrine action for the treatment of acute myocardial infarction
Authors: Tobar Santiago A. , Andrades M. , Olsen V , Silvello D. , Phaelante A , Lopes A , Biolo A , Matte U , Rohde LE , Clausell NO
Published: October 2018

Cell therapy is considered as a treatment option for acute myocardial infarction (AMI). Released molecules by cells paracrine action may promote tissue regeneration. Therefore we used bone-marrow mononuclear cells (BMMNCs) from GFP+ Wistar rats encapsulated in sodium alginate for AMI treatment. Animals were randomly allocated into groups – empty (EC); BMMNC capsules; or sham. AMI was induced by occlusion of left anterior artery and capsules were delivered intrathoracically. Troponin I was measured 24h after AMI and echocardiography was performed at 48h and 7d after AMI. On day 7 animals were euthanized and their hearts were harvested. Tissue levels of TNF-α, IL-6, IL-10, cleaved caspase-3, and catalase were measured. Technical procedures were performed by blinded operators. There was no difference in either heart morphofunctional parameters or biochemical analysis between AMI groups. We conclude that the paracrine effects of BMMNCs lacks efficacy to modulate events associated with AMI in the rat.
Old fibroblasts secrete inflammatory cytokines that drive variability in reprogramming efficiency and may affect wound healing between old individuals
Authors: Mahmoudi Salah , Mancini Elena , Moore Alessandra , Xu Lucy , Jahanbani Fereshteh , Hebestreit Katja , Srinivasan Rajini , Li Xiyan , Devarajan Keerthana , Prélot Laurie , Ang Cheen Euong , Shibuya Yohei , Benayoun Bérénice A. , Chang Anne Lynn S. , Wernig Marius , Wysocka Joanna , Longaker Michael T. , Snyder Michael P. , Brunet Anne
Published: October 2018

Age-associated chronic inflammation (inflammaging) has emerged as a central hallmark of aging1-3, but its impact on specific cells is still largely unknown. Fibroblasts are present in all tissues and contribute to wound healing4-6. They are also the cell type that is mostly used for induced pluripotent stem cell (iPSC) reprogramming7– a process that has implications for regenerative medicine and rejuvenation strategies8-17. Here we show that primary fibroblasts from old mice secrete inflammatory cytokines and that there is an increased variability in reprogramming efficiency between fibroblast cultures from old individuals. Individual-to-individual variability is emerging as a key feature of old age18-21, which could reflect distinct aging trajectories, but the underlying causes remain unknown. To identify drivers of this variability, we perform a multi-omic assessment of young and old fibroblast cultures with different reprogramming efficiency. This approach, coupled with single cell transcriptomics, reveals that old fibroblast cultures are heterogeneous and show a greater proportion of ‘activated fibroblasts’ that secrete inflammatory cytokines, which correlates with reprogramming efficiency. We experimentally validate that activated fibroblasts express inflammatory cytokinesin vivoand that their presence is linked to enhanced reprogramming efficiency in culture. Conditioned-media swapping experiments show that extrinsic factors secreted by activated fibroblasts are more critical than intrinsic factors for the individual-to-individual variability in reprogramming efficiency, and we identify TNFα as a key inflammatory cytokine underlying this variability. Interestingly, old mice also exhibit variability in wound healing efficiencyin vivoand old wounds show an increased subpopulation of activated fibroblasts with a unique TNFα signature. Our study shows that a switch in fibroblast composition, and the ratio of inflammatory cytokines they secrete, drives variability in reprogrammingin vitroand may influence wound healingin vivo. These findings could help identify personalized strategies to improve iPSC generation and wound healing in older individuals.
Transduction of the Geomagnetic Field as Evidenced from Alpha-band Activity in the Human Brain
Authors: Wang Connie X. , Hilburn Isaac A. , Wu Daw-An , Mizuhara Yuki , Cousté Christopher P. , Abrahams Jacob N. H. , Bernstein Sam E. , Matani Ayumu , Shimojo Shinsuke , Kirschvink Joseph L.
Published: October 2018

Magnetoreception, the perception of the geomagnetic field, is a sensory modality well-established across all major groups of vertebrates and some invertebrates, but its presence in humans has been tested rarely, yielding inconclusive results. We report here a strong, specific human brain response to ecologically-relevant rotations of Earth-strength magnetic fields. Following geomagnetic stimulation, a drop in amplitude of EEG alpha oscillations (8-13 Hz) occurred in a repeatable manner. Termed alpha event-related desynchronization (alpha-ERD), such a response is associated with sensory and cognitive processing of external stimuli. Biophysical tests showed that the neural response was sensitive to the dynamic components and axial alignment of the field but also to the static components and polarity of the field. This pattern of results implicates ferromagnetism as the biophysical basis for the sensory transduction and provides a basis to start the behavioral exploration of human magnetoreception.