bluuebunny/crossref_metadata_2025 huggingface dataset:
Gendered Care Work as “Free Labor” in State Employment: School Social Workers in the Education Welfare (Investment) Priority Project in South Korea
Authors: Song Jesook
Published: July 2017

This article draws on ethnographic research to elucidate ways in which young women's care labor is appropriated by the state as “free labor” in South Korea. Building upon John Krinsky's notion of free labor as state-orchestrated exploitation of public sector workers and Kyounghee Kim's research on gendered care labor, this article examines the gendered experience of school social workers who are certified at a lower level than professional social workers, and are hired, laid off, and rehired by the state-sponsored Education Welfare Priority Project. It traces recent unionization efforts by school social workers and attempts to explain why these workers do not recognize care work as a source of exploitation. Finally, the author presents analytical tools to better understand the intersection of state employment, exploitation, and gendered care labor as an emerging neoliberal form of labor.
Improving patient experiences of mental health inpatient care: a randomised controlled trial
Authors: Wykes T. , Csipke E. , Williams P. , Koeser L. , Nash S. , Rose D. , Craig T. , McCrone P.
Published: July 2017

Background

Poorer patient views of mental health inpatient treatment predict both further admissions and, for those admitted involuntarily, longer admissions. As advocated in the UK Francis report, we investigated the hypothesis that improving staff training improves patients’ views of ward care.

Method

Cluster randomised trial with stepped wedge design in 16 acute mental health wards randomised (using the ralloc procedure in Stata) by an independent statistician in three waves to staff training. A psychologist trained ward staff on evidence-based group interventions and then supported their introduction to each ward. The main outcome was blind self-report of perceptions of care (VOICE) before or up to 2 years after staff training between November 2008 and January 2013.

Results

In total, 1108 inpatients took part (616 admitted involuntarily under the English Mental Health Act). On average 51.6 staff training sessions were provided per ward. Involuntary patient's perceptions of, and satisfaction with, mental health wards improved after staff training (N582, standardised effect −0·35, 95% CI −0·57 to −0·12, p = 0·002; interaction p value 0·006) but no benefit to those admitted voluntarily (N469, −0.01, 95% CI −0.23 to 0.22, p = 0.955) and no strong evidence of an overall effect (N1058, standardised effect −0.18 s.d., 95% CI −0.38 to 0.01, p = 0.062). The training costs around £10 per patient per week. Resource allocation changed towards patient perceived meaningful contacts by an average of £12 (95% CI −£76 to £98, p = 0.774).

Conclusion

Staff training improved the perceptions of the therapeutic environment in those least likely to want an inpatient admission, those formally detained. This change might enhance future engagement with all mental health services and prevent the more costly admissions.
Comorbidity indices: a call for the integration of physical and mental health
Authors: Nowels Molly A. , VanderWielen Lynn M.
Published: July 2017

Comorbidity indices are commonly used in health services research as a measure of, or as a control for, the severity of a person’s medical state. Currently, there is not a comorbidity index for mental health diagnoses, despite the fact that almost half of Americans have a diagnosable mental health condition at least once in their lifetime. This commentary calls for the integration of mental and behavioral health in comorbidity indices to appropriately account for the role of mental health in overall morbidity and mortality.
Disabling Labelling in Indonesia: Invoking WTO Laws in the Wake of Halal Policy Objectives
Authors: LIMENTA MICHELLE , EDIS BAYAN M. , FERNANDO OSCAR
Published: July 2017

The 2014 Halal Product Assurance Act (Halal Act) is the first law in Indonesia requiring mandatory Halal certification and labelling. Local and foreign business entities, while in agreement that Halal assurance through certification and labelling is important for Muslim consumers, have expressed their anxiety over whether such requirements will mean extra costs, particularly for small and medium enterprises. At the same time, the mandatory labelling regime involves several WTO issues under the TBT Agreement, which raise questions regarding Indonesia's compliance with its obligations. As a defence, Indonesia could argue that its mandatory halal labelling measure falls under the exception for protecting ‘public morals’. The WTO panel in theUS–Gamblingdispute noted that the meaning of ‘public morals’ and ‘public order’ varied depending on a range of factors, including prevailing social, cultural, ethical, and religious values. Should the WTO allow all types of moral and religious belief, even if they restrict trade? How can public moral policy objectives be applied in ways that do not violate WTO law? This paper seeks to examine the WTO consistency of the new Indonesian Halal Act, and whether the public moral objective underlying mandatory halal certification/labelling can be defended as an exception in the context of the TBT Agreement.
A CATEGORIFICATION OF A QUANTUM FROBENIUS MAP
Authors: Qi You
Published: July 2017

A quantum Frobenius map a la Lusztig for $\mathfrak{s}\mathfrak{l}_{2}$ is categorified at a prime root of unity.
Theorizing or Negotiating the Law?: A Response to Devika Hovell
Authors: Tzanakopoulos Antonios
Published: July 2017

Devika Hovell’s article is a very welcome and useful contribution to the debate regarding the “accountability” (whatever the term may mean) of international organizations, and the United Nations in particular. The author argues that scholarship has tended to focus on (descriptive) state practice to the detriment of (normative) theoretical appeal, and so the relevant discussion “has received inadequate theoretical attention.” In response, she sets out to tell the story of the United Nations being held to account through a highly theorized (and, if I may venture even at the outset, perhaps a bit stylized) scheme of contrasting “instrumentalist,” “dignitarian,” and “public interest” approaches to due process. This she applies to two case studies, one regarding targeted sanctions imposed by the UN Security Council, mainly in the context of antiterrorism; and one regarding the cholera outbreak in Haiti, where the United Nations has been implicated. Hovell critiques both the instrumentalist and dignitarian approaches, which correspond in broad terms to legal action at the international, and the domestic/regional level, respectively, and argues in favor of a “public interest” approach as better reflecting a “value-based” due process.
Un-Accountable?: A Response to Devika Hovell
Authors: Freedman Rosa
Published: July 2017

Devika Hovell has provided an excellent call to arms for academics to move beyond the question of whether the United Nations has due process deficiencies: By now we all know that it does. She invites us to focus instead on making “the normative case for adopting due process safeguards in UN decision making,” insisting that until now scholars have failed to ask the important theoretical questions underpinning their policy research. Hovell uses two case studies to demonstrate why resort to judicial mechanisms ought not to be the answer when seeking to find ways to ensure due process. She first focuses on targeted sanctions and then turns attention to cholera in Haiti.
The Scope and Limitations of the Presumption against Extraterritoriality
Authors: Buxbaum Hannah L.
Published: July 2017

In RJR Nabisco v. European Community, the Supreme Court addressed the extraterritorial application of U.S. law for the third time in six years—in this case examining the geographic scope of the Racketeer Influenced and Corrupt Organizations Act (RICO). The decision consolidates and in certain respects expands upon the test for analyzing extraterritoriality issues that the Court had introduced in Morrison v. National Australia Bank and refined in Kiobel v. Royal Dutch Petroleum. It also provides further evidence of the Court’s continuing quest to identify categorical, territory-based rules governing the application of U.S. statutes in cases involving significant foreign elements. As I will argue, however, like other recent decisions, RJR raises doubt as to the sufficiency of such rules to address the messy and often unpredictable patterns of transnational economic activity.
Introduction to Symposium on Nienke Grossman, “Achieving Sex-Representative International Court Benches”
Authors: Linos Katerina
Published: July 2017

In “Achieving Sex-Representative International Court Benches,” Nienke Grossman begins with embarrassing statistics. Despite decades of progress on gender equality, women are still quite scarce on international benches. Grossman reframes the debate on gender equity in a powerful way. Most promisingly, she suggests that greater meritocracy and greater gender equity go hand in hand. As she argues, “international judgeships are often used to reward political loyalty” and “political horse-trading among states” abounds. For these reasons, reforms to broaden the pool of candidates and to increase the transparency of the selection process would also result in the appointment of more women, in all likelihood. In addition, Grossman puts forth a provocative legal claim—she argues that “states are legally required to take steps to understand and remedy the paucity of women judges on most international court benches.”
Leaving Legacies Open-Ended: An Invitation for an Inclusive Debate on International Criminal Justice
Authors: Benvenisti Eyal , Nouwen Sarah M.H.
Published: July 2017

As a response to the Symposium on the International Criminal Tribunals for the former Yugoslavia and Rwanda published by the American Journal of International Law on the occasion of the tribunals’ closure, this AJIL Unbound Symposium intends to broaden the debate on the “legacies” of those courts. The AJIL Symposium contains articles on the creation of the International Criminal Tribunal for the former Yugoslavia (ICTY) and the International Criminal Tribunal for Rwanda (ICTR); the ad hoc tribunals’ jurisprudential contributions; and their extra-legal impacts and legacies. The concept of “legacy” is itself contested and the appropriateness of the courts’ own efforts to consolidate it may be questioned, especially as they have barely ended (or are about to end) their work. Nevertheless, their over two decades of existence does provide an occasion to assess all they have done and not done, and have affected, intentionally and unintentionally. Against that background, we have invited a group of scholars to respond to the AJIL Symposium and to reflect upon the work of the tribunals with a view to enriching the debate with more voices, from different regions, from different interest groups, and from different disciplines.
Neuroticism and the Overlap Between Autistic and ADHD Traits: Findings From a Population Sample of Young Adult Australian Twins
Authors: Park Shin-Ho , Guastella Adam J. , Lynskey Michael , Agrawal Arpana , Constantino John N. , Medland Sarah E. , Song Yun Ju C. , Martin Nicholas G. , Colodro-Conde Lucía
Published: July 2017

Neuroticism, a ‘Big Five’ personality trait, has been associated with sub-clinical traits of both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The objective of the current study was to examine whether causal overlap between ASD and ADHD traits can be accounted for by genetic and environmental risk factors that are shared with neuroticism. We performed twin-based structural equation modeling using self-report data from 12 items of the Neo Five-Factor Inventory Neuroticism domain, 11 Social Responsiveness Scale items, and 12 Adult ADHD Self-Report Scale items obtained from 3,170 young adult Australian individual twins (1,081 complete pairs). Univariate analysis for neuroticism, ASD, and ADHD traits suggested that the most parsimonious models were those with additive genetic and unique environmental components, without sex limitation effects. Heritability of neuroticism, ASD, and ADHD traits, as measured by these methods, was moderate (between 40% and 45% for each respective trait). In a trivariate model, we observed moderate phenotypic (between 0.45 and 0.62), genetic (between 0.56 and 0.71), and unique environmental correlations (between 0.37and 0.55) among neuroticism, ASD, and ADHD traits, with the highest value for the shared genetic influence between neuroticism and self-reported ASD traits (rg = 0.71). Together, our results suggest that in young adults, genetic, and unique environmental risk factors indexed by neuroticism overlap with those that are shared by ASD and ADHD.
Autophagosome maturation mediated by Rab7 contributes to neuroprotection of hypoxic preconditioning against global cerebral ischemia in rats
Authors: Zhan Lixuan , Chen Siyuan , Li Kongping , Liang Donghai , Zhu Xinyong , Liu Liu , Lu Zhiwei , Sun Weiwen , Xu En
Published: July 2017

Autophagy disruption leads to neuronal damage in hypoxic–ischemic brain injury. Rab7, a member of the Rab GTPase superfamily, has a unique role in the regulation of autophagy. Hypoxic preconditioning (HPC) provides neuroprotection against transient global cerebral ischemia (tGCI). However, the underlying mechanisms remain poorly understood. Thus, the current study explored the potential molecular mechanism of the neuroprotective effect of HPC by investigating how Rab7 mediates autophagosome (AP) maturation after tGCI in adult rats. We found that HPC attenuated AP accumulation in the hippocampal CA1 region after tGCI via restoration of autophagic flux. We also confirmed that this HPC-induced neuroprotection was not caused by the increase in lysosomes or the improvement of lysosomal function after tGCI. Electron microscopic analysis then revealed an increase in autolysosomes in CA1 neurons of HPC rats. Moreover, the inhibition of autophagosome-lysosome fusion by chloroquine significantly aggravated neuronal death in CA1, indicating that AP maturation contributes to HPC-induced neuroprotection against neuronal injury after tGCI. Furthermore, the activation of Rab7 was found to be involved in the neuroprotective effect of AP maturation after HPC. At last, the knockdown of ultraviolet radiation resistance-associated gene (UVRAG) in vivo disrupted the interaction between Vps16 and Rab7, attenuated the activation of Rab7, interrupted autophagic flux, and ultimately abrogated the HPC-induced neuroprotection against tGCI. Our results indicated that AP maturation was enhanced by the activation of Rab7 via UVRAG-Vps16 interaction, which further demonstrated the potential neuroprotective role of Rab7 in HPC against tGCI-induced neuronal injury in adult rats.
Humanin G (HNG) protects age-related macular degeneration (AMD) transmitochondrial ARPE-19 cybrids from mitochondrial and cellular damage
Authors: Nashine Sonali , Cohen Pinchas , Chwa Marilyn , Lu Stephanie , Nesburn Anthony B , Kuppermann Baruch D , Kenney M Cristina
Published: July 2017

Age-related macular degeneration (AMD) ranks third among the leading causes of visual impairment with a blindness prevalence rate of 8.7%. Despite several treatment regimens, such as anti-angiogenic drugs, laser therapy, and vitamin supplementation, being available for wet AMD, to date there are no FDA-approved therapies for dry AMD. Substantial evidence implicates mitochondrial damage and retinal pigment epithelium (RPE) cell death in the pathogenesis of AMD. However, the effects of AMD mitochondria and Humanin G (HNG), a more potent variant of the mitochondrial-derived peptide (MDP) Humanin, on retinal cell survival have not been elucidated. In this study, we characterized mitochondrial and cellular damage in transmitochondrial cybrid cell lines that contain identical nuclei but possess mitochondria from either AMD or age-matched normal (Older-normal (NL)) subjects. AMD cybrids showed (1) reduced levels of cell viability, lower mtDNA copy numbers, and downregulation of mitochondrial replication/transcription genes and antioxidant enzyme genes; and (2) elevated levels of genes related to apoptosis, autophagy and ER-stress along with increased mtDNA fragmentation and higher susceptibility to amyloid-β-induced toxicity compared to NL cybrids. In AMD cybrids, HNG protected the AMD mitochondria, reduced pro-apoptosis gene and protein levels, upregulated gp130 (a component of the HN receptor complex), and increased the protection against amyloid-β-induced damage. In summary, in cybrids, damaged AMD mitochondria mediate cell death that can be reversed by HNG treatment. Our results also provide evidence of Humanin playing a pivotal role in protecting cells with AMD mitochondria. In the future, it may be possible that AMD patient’s blood samples containing damaged mitochondria may be useful as biomarkers for this condition. In conclusion, HNG may be a potential therapeutic target for treatment of dry AMD, a debilitating eye disease that currently has no available treatment. Further studies are needed to establish HNG as a viable mitochondria-targeting therapy for dry AMD.
A model for the regulation of follicular dendritic cells predicts invariant reciprocal‐time decay of post‐vaccine antibody response
Authors: Almudevar Anthony
Published: July 2017

Follicular dendritic cells (FDC) play a crucial role in the regulation of humoral immunity. They are believed to be responsible for long‐term persistence of antibody, due to their role in antibody response induction and their ability to retain antigen in immunogenic form for long periods. In this article, a regulatory control model is proposed which links persistence of humoral immunity with cellular processes associated with FDCs. The argument comprises three elements. The first is a literature review of population‐level studies of post‐vaccination antibody persistence. It is found that reciprocal‐time (∝1/t) decay of antibody levels is widely reported, over a range of ages, observation times and vaccine types. The second element is a mathematical control model for cell population decay for which reciprocal‐time decay is a stable attractor. Additionally, control effectors are easily identified, leading to models of homeostatic control of the reciprocal‐time decay rate. The final element is a literature review of FDC functionality. This reveals a striking concordance between cell properties required by the model and those widely observed of FDCs, some of which are unique to this cell type. The proposed model is able to unify a wide range of disparate observations of FDC function under one regulatory principle, and to characterize precisely forms of FDC regulation and dysregulation. Many infectious and immunological diseases are increasingly being linked to FDC regulation, therefore a precise understanding of the underlying mechanisms would be of significant benefit for the development of new therapies.
A role for the cell-wall protein silacidin in cell size of the diatomThalassiosira pseudonana
Authors: Kirkham Amy R , Richthammer Patrick , Schmidt Katrin , Wustmann Martin , Maeda Yoshiaki , Hedrich René , Brunner Eike , Tanaka Tsuyoshi , van Pée Karl-Heinz , Falciatore Angela , Mock Thomas
Published: July 2017

Diatoms contribute 20% of global primary production and form the basis of many marine food webs. Although their species diversity correlates with broad diversity in cell size, there is also an intraspecific cell-size plasticity owing to sexual reproduction and varying environmental conditions. However, despite the ecological significance of the diatom cell size for food-web structure and global biogeochemical cycles, our knowledge about genes underpinning the size of diatom cells remains elusive. Here, a combination of reverse genetics, experimental evolution and comparative RNA-sequencing analyses enabled us to identify a previously unknown genetic control of cell size in the diatom Thalassiosira pseudonana. In particular, the targeted deregulation of the expression of the cell-wall protein silacidin caused a significant increase in valve diameter. Remarkably, the natural downregulation of the silacidin gene transcript due to experimental evolution under low temperature also correlated with cell-size increase. Our data give first evidence for a genetically controlled regulation of cell size in T. pseudonana and possibly other centric diatoms as they also encode the silacidin gene in their genomes.
Unusual metabolic diversity of hyperalkaliphilic microbial communities associated with subterranean serpentinization at The Cedars
Authors: Suzuki Shino , Ishii Shun’ichi , Hoshino Tatsuhiko , Rietze Amanda , Tenney Aaron , Morrill Penny L , Inagaki Fumio , Kuenen J Gijs , Nealson Kenneth H
Published: July 2017

Water from The Cedars springs that discharge from serpentinized ultramafic rocks feature highly basic (pH=~12), highly reducing (Eh<−550 mV) conditions with low ionic concentrations. These conditions make the springs exceptionally challenging for life. Here, we report the metagenomic data and recovered draft genomes from two different springs, GPS1 and BS5. GPS1, which was fed solely by a deep groundwater source within the serpentinizing system, was dominated by several bacterial taxa from the phyla OD1 (‘Parcubacteria’) and Chloroflexi. Members of the GPS1 community had, for the most part, the smallest genomes reported for their respective taxa, and encoded only archaeal (A-type) ATP synthases or no ATP synthases at all. Furthermore, none of the members encoded respiration-related genes and some of the members also did not encode key biosynthesis-related genes. In contrast, BS5, fed by shallow water, appears to have a community driven by hydrogen metabolism and was dominated by a diverse group of Proteobacteria similar to those seen in many terrestrial serpentinization sites. Our findings indicated that the harsh ultrabasic geological setting supported unexpectedly diverse microbial metabolic strategies and that the deep-water-fed springs supported a community that was remarkable in its unusual metagenomic and genomic constitution.
Role of plant–fungal nutrient trading and host control in determining the competitive success of ectomycorrhizal fungi
Authors: Hortal Sara , Plett Krista Lynn , Plett Jonathan Michael , Cresswell Tom , Johansen Mathew , Pendall Elise , Anderson Ian Charles
Published: July 2017

Multiple ectomycorrhizal fungi (EMF) compete to colonise the roots of a host plant, but it is not known whether their success is under plant or fungal control, or a combination of both. We assessed whether plants control EMF colonisation by preferentially allocating more carbon to more beneficial partners in terms of nitrogen supply or if other factors drive competitive success. We combined stable isotope labelling and RNA-sequencing approaches to characterise nutrient exchange between the plant host Eucalyptus grandis and three Pisolithus isolates when growing alone and when competing either indirectly (with a physical barrier) or directly. Overall, we found that nitrogen provision to the plant does not explain the amount of carbon that an isolate receives nor the number of roots that it colonises. Differences in nutrient exchange among isolates were related to differences in expression of key fungal and plant nitrogen and carbon transporter genes. When given a choice of partners, the plant was able to limit colonisation by the least cooperative isolate. This was not explained by a reduction in allocated carbon. Instead, our results suggest that partner choice in EMF could operate through the upregulation of defence-related genes against those fungi providing fewer nutrients.
Exact sequence variants should replace operational taxonomic units in marker-gene data analysis
Authors: Callahan Benjamin J , McMurdie Paul J , Holmes Susan P
Published: July 2017

Recent advances have made it possible to analyze high-throughput marker-gene sequencing data without resorting to the customary construction of molecular operational taxonomic units (OTUs): clusters of sequencing reads that differ by less than a fixed dissimilarity threshold. New methods control errors sufficiently such that amplicon sequence variants (ASVs) can be resolved exactly, down to the level of single-nucleotide differences over the sequenced gene region. The benefits of finer resolution are immediately apparent, and arguments for ASV methods have focused on their improved resolution. Less obvious, but we believe more important, are the broad benefits that derive from the status of ASVs as consistent labels with intrinsic biological meaning identified independently from a reference database. Here we discuss how these features grant ASVs the combined advantages of closed-reference OTUs—including computational costs that scale linearly with study size, simple merging between independently processed data sets, and forward prediction—and of de novo OTUs—including accurate measurement of diversity and applicability to communities lacking deep coverage in reference databases. We argue that the improvements in reusability, reproducibility and comprehensiveness are sufficiently great that ASVs should replace OTUs as the standard unit of marker-gene analysis and reporting.
Slow conformational exchange and overall rocking motion in ubiquitin protein crystals
Authors: Kurauskas Vilius , Izmailov Sergei A. , Rogacheva Olga N. , Hessel Audrey , Ayala Isabel , Woodhouse Joyce , Shilova Anastasya , Xue Yi , Yuwen Tairan , Coquelle Nicolas , Colletier Jacques-Philippe , Skrynnikov Nikolai R. , Schanda Paul
Published: July 2017

Proteins perform their functions in solution but their structures are most frequently studied inside crystals. Here we probe how the crystal packing alters microsecond dynamics, using solid-state NMR measurements and multi-microsecond MD simulations of different crystal forms of ubiquitin. In particular, near-rotary-resonance relaxation dispersion (NERRD) experiments probe angular backbone motion, while Bloch–McConnell relaxation dispersion data report on fluctuations of the local electronic environment. These experiments and simulations reveal that the packing of the protein can significantly alter the thermodynamics and kinetics of local conformational exchange. Moreover, we report small-amplitude reorientational motion of protein molecules in the crystal lattice with an ~3–5° amplitude on a tens-of-microseconds time scale in one of the crystals, but not in others. An intriguing possibility arises that overall motion is to some extent coupled to local dynamics. Our study highlights the importance of considering the packing when analyzing dynamics of crystalline proteins.
Dynamical sensitivity control of a single-spin quantum sensor
Authors: Lazariev Andrii , Arroyo-Camejo Silvia , Rahane Ganesh , Kavatamane Vinaya Kumar , Balasubramanian Gopalakrishnan
Published: July 2017

The Nitrogen-Vacancy (NV) defect in diamond is a unique quantum system that offers precision sensing of nanoscale physical quantities at room temperature beyond the current state-of-the-art. The benchmark parameters for nanoscale magnetometry applications are sensitivity, spectral resolution, and dynamic range. Under realistic conditions the NV sensors controlled by conventional sensing schemes suffer from limitations of these parameters. Here we experimentally show a new method called dynamical sensitivity control (DYSCO) that boost the benchmark parameters and thus extends the practical applicability of the NV spin for nanoscale sensing. In contrast to conventional dynamical decoupling schemes, where π pulse trains toggle the spin precession abruptly, the DYSCO method allows for a smooth, analog modulation of the quantum probe’s sensitivity. Our method decouples frequency selectivity and spectral resolution unconstrained over the bandwidth (1.85 MHz–392 Hz in our experiments). Using DYSCO we demonstrate high-accuracy NV magnetometry without |2π| ambiguities, an enhancement of the dynamic range by a factor of 4 · 103, and interrogation times exceeding 2 ms in off-the-shelf diamond. In a broader perspective the DYSCO method provides a handle on the inherent dynamics of quantum systems offering decisive advantages for NV centre based applications notably in quantum information and single molecule NMR/MRI.
An Integrative Computational Approach to Evaluate Genetic Markers for Bipolar Disorder
Authors: Xu Yong , Wang Jun , Rao Shuquan , Ritter McKenzie , Manor Lydia C. , Backer Robert , Cao Hongbao , Cheng Zaohuo , Liu Sha , Liu Yansong , Tian Lin , Dong Kunlun , Yao Shugart Yin , Wang Guoqiang , Zhang Fuquan
Published: July 2017

Studies to date have reported hundreds of genes connected to bipolar disorder (BP). However, many studies identifying candidate genes have lacked replication, and their results have, at times, been inconsistent with one another. This paper, therefore, offers a computational workflow that can curate and evaluate BP-related genetic data. Our method integrated large-scale literature data and gene expression data that were acquired from both postmortem human brain regions (BP case/control: 45/50) and peripheral blood mononuclear cells (BP case/control: 193/593). To assess the pathogenic profiles of candidate genes, we conducted Pathway Enrichment, Sub-Network Enrichment, and Gene-Gene Interaction analyses, with 4 metrics proposed and validated for each gene. Our approach developed a scalable BP genetic database (BP_GD), including BP related genes, drugs, pathways, diseases and supporting references. The 4 metrics successfully identified frequently-studied BP genes (e.g. GRIN2A, DRD1, DRD2, HTR2A, CACNA1C, TH, BDNF, SLC6A3, P2RX7, DRD3, and DRD4) and also highlighted several recently reported BP genes (e.g. GRIK5, GRM1 and CACNA1A). The computational biology approach and the BP database developed in this study could contribute to a better understanding of the current stage of BP genetic research and assist further studies in the field.
Elucidation of the biosynthetic pathway of cis-jasmone in Lasiodiplodia theobromae
Authors: Matsui Ryo , Amano Naruki , Takahashi Kosaku , Taguchi Yodai , Saburi Wataru , Mori Hideharu , Kondo Norio , Matsuda Kazuhiko , Matsuura Hideyuki
Published: July 2017

In plants, cis-jasmone (CJ) is synthesized from α-linolenic acid (LA) via two biosynthetic pathways using jasmonic acid (JA) and iso-12-oxo-phytodienoic acid (iso-OPDA) as key intermediates. However, there have been no reports documenting CJ production by microorganisms. In the present study, the production of fungal-derived CJ by Lasiodiplodia theobromae was observed for the first time, although this production was not observed for Botrytis cinerea, Verticillium longisporum, Fusarium oxysporum, Gibberella fujikuroi, and Cochliobolus heterostrophus. To investigate the biosynthetic pathway of CJ in L. theobromae, administration experiments using [18,18,18-2H3, 17,17-2H2]LA (LA-d5), [18,18,18-2H3, 17,17-2H2]12-oxo-phytodienoic acid (cis-OPDA-d5), [5′,5′,5′-2H3, 4′,4′-2H2, 3′-2H1]OPC 8:0 (OPC8-d6), [5′,5′,5′-2H3, 4′,4′-2H2, 3′-2H1]OPC 6:0 (OPC6-d6), [5′,5′,5′-2H3, 4′,4′-2H2, 3′-2H1]OPC 4:0 (OPC4-d6), and [11,11-2H2, 10,10-2H2, 8,8-2H2, 2,2-2H2]methyl iso-12-oxo-phytodienoate (iso-MeOPDA-d8) were carried out, revealing that the fungus produced CJ through a single biosynthetic pathway via iso-OPDA. Interestingly, it was suggested that the previously predicted decarboxylation step of 3,7-didehydroJA to afford CJ might not be involved in CJ biosynthesis in L. theobromae.
Radiocesium concentrations in wild mushrooms after the accident at the Fukushima Daiichi Nuclear Power Station: Follow-up study in Kawauchi village
Authors: Orita Makiko , Nakashima Kanami , Taira Yasuyuki , Fukuda Toshiki , Fukushima Yoshiko , Kudo Takashi , Endo Yuko , Yamashita Shunichi , Takamura Noboru
Published: July 2017

Since the accident at the Chernobyl Nuclear Power Plant, it has become well known that radiocesium tends to concentrate in wild mushrooms. During the recovery process after the accident at the Fukushima Daiichi Nuclear Power Station (FDNPS), it is important to perform follow-up measurements of the activity concentrations of radiocesium in mushrooms. We evaluated the activity concentrations of the detected artificial radionuclides (radiocesium) in wild mushrooms collected from Kawauchi village, which is within 30 km of the FDNPS, in 2015, four years after the accident. We found that the radiocesium was determined in 147 of 159 mushroom samples (92.4%). Based on the average mushroom consumption of Japanese citizens (6.28 kg per year), we calculated committed effective doses ranging from <0.001 to 0.6 mSv. Although committed effective doses are relatively limited, even if residents have consumed mushrooms several times, continuous monitoring of the radiocesium in mushrooms in Fukushima is needed for sustained recovery from the nuclear disaster.
Associations of statin use with motor performance and myalgia may be modified by 25-hydroxyvitamin D: findings from a British birth cohort
Authors: Sharma Nikhil , Cooper Rachel , Kuh Diana , Shah Imran
Published: July 2017

The objective was to examine whether: (1) statin use was associated with muscle related outcomes at age 60–64, (2) these associations were modified by 25-hydroxyvitamin D (25(OH)D) status and explained by inflammation, body-size or lifestyle in a British birth cohort. Markers of myalgia (intrusive body pain) and myopathy (self-reported and performance-based measures) were examined in 734 men and 822 women (MRC National Survey of Health and Development). Statin use was associated with intrusive body pain, difficulty climbing stairs and slower chair rise speed. Some associations were modified by 25(OH)D e.g. the association with intrusive body pain was evident in the insufficient (13–20 ng/l) and deficient (<13 ng/l) 25(OH)D status groups (OR = 2.6,95% CI 1.7–1.1; OR = 1.8,95% CI 1.2–2.8, respectively) but not in those with status >20 ng/l (OR = 0.8,95% CI 0.5–1.4) (p = 0.003 for interaction). Associations were maintained in fully adjusted models of intrusive body pain and difficulty climbing stairs, but for chair rise speed they were fully accounted for by inflammation, body-size and lifestyle. In a nationally representative British population in early old age, statin use was associated with lower limb muscle-related outcomes, and some were only apparent in those with 25(OH)D status below 20 ng/l. Given 25(OH)D is modifiable in clinical practice, future studies should consider the links between 25(OH)D status and muscle related outcomes.
Anti-obesity and anti-inflammatory effects of synthetic acetic acid vinegar and Nipa vinegar on high-fat-diet-induced obese mice
Authors: Beh Boon Kee , Mohamad Nurul Elyani , Yeap Swee Keong , Ky Huynh , Boo Sook Yee , Chua Joelle Yi Heng , Tan Sheau Wei , Ho Wan Yong , Sharifuddin Shaiful Adzni , Long Kamariah , Alitheen Noorjahan Banu
Published: July 2017

Recently, food-based bioactive ingredients, such as vinegar, have been proposed as a potential solution to overcome the global obesity epidemic. Although acetic acid has been identified as the main component in vinegar that contributes to its anti-obesity effect, reports have shown that vinegar produced from different starting materials possess different degrees of bioactivity. This study was performed to compare the anti-obesity and anti-inflammatory effects of synthetic acetic acid vinegar and Nipa vinegar in mice fed a high-fat diet. In this work, mice were fed a high-fat diet for 33 weeks. At the start of week 24, obese mice were orally fed synthetic acetic acid vinegar or Nipa vinegar (0.08 and 2 ml/kg BW) until the end of week 33. Mice fed a standard pellet diet served as a control. Although both synthetic acetic acid vinegar and Nipa vinegar effectively reduced food intake and body weight, a high dose of Nipa vinegar more effectively reduced lipid deposition, improved the serum lipid profile, increased adipokine expression and suppressed inflammation in the obese mice. Thus, a high dose of Nipa vinegar may potentially alleviate obesity by altering the lipid metabolism, inflammation and gut microbe composition in high-fat-diet-induced obese mice.
Conformational preludes to the latency transition in PAI-1 as determined by atomistic computer simulations and hydrogen/deuterium-exchange mass spectrometry
Authors: Petersen Michael , Madsen Jeppe B. , Jørgensen Thomas J. D. , Trelle Morten B.
Published: July 2017

Both function and dysfunction of serine protease inhibitors (serpins) involve massive conformational change in their tertiary structure but the dynamics facilitating these events remain poorly understood. We have studied the dynamic preludes to conformational change in the serpin plasminogen activator inhibitor 1 (PAI-1). We report the first multi-microsecond atomistic molecular dynamics simulations of PAI-1 and compare the data with experimental hydrogen/deuterium-exchange data (HDXMS). The simulations reveal notable conformational flexibility of helices D, E and F and major fluctuations are observed in the W86-loop which occasionally leads to progressive detachment of β-strand 2 A from β-strand 3 A. An interesting correlation between Cα-RMSD values from simulations and experimental HDXMS data is observed. Helices D, E and F are known to be important for the overall stability of active PAI-1 as ligand binding in this region can accelerate or decelerate the conformational inactivation. Plasticity in this region may thus be mechanistically linked to the conformational change, possibly through facilitation of further unfolding of the hydrophobic core, as previously reported. This study provides a promising example of how computer simulations can help tether out mechanisms of serpin function and dysfunction at a spatial and temporal resolution that is far beyond the reach of any experiment.
Morpho-functional characterization of the systemic venous pole of the reptile heart
Authors: Jensen Bjarke , Vesterskov Signe , Boukens Bastiaan J. , Nielsen Jan M. , Moorman Antoon F. M. , Christoffels Vincent M. , Wang Tobias
Published: July 2017

Mammals evolved from reptile-like ancestors, and while the mammalian heart is driven by a distinct sinus node, a sinus node is not apparent in reptiles. We characterized the myocardial systemic venous pole, the sinus venosus, in reptiles to identify the dominant pacemaker and to assess whether the sinus venosus remodels and adopts an atrium-like phenotype as observed in mammals. Anolis lizards had an extensive sinus venosus of myocardium expressing Tbx18. A small sub-population of cells encircling the sinuatrial junction expressed Isl1, Bmp2, Tbx3, and Hcn4, homologues of genes marking the mammalian sinus node. Electrical mapping showed that hearts of Anolis lizards and Python snakes were driven from the sinuatrial junction. The electrical impulse was delayed between the sinus venosus and the right atrium, allowing the sinus venosus to contract and aid right atrial filling. In proximity of the systemic veins, the Anolis sinus venosus expressed markers of the atrial phenotype Nkx2-5 and Gja5. In conclusion, the reptile heart is driven by a pacemaker region with an expression signature similar to that of the immature sinus node of mammals. Unlike mammals, reptiles maintain a sinuatrial delay of the impulse, allowing the partly atrialized sinus venosus to function as a chamber.
Identification of non-activated lymphocytes using three-dimensional refractive index tomography and machine learning
Authors: Yoon Jonghee , Jo YoungJu , Kim Min-hyeok , Kim Kyoohyun , Lee SangYun , Kang Suk-Jo , Park YongKeun
Published: July 2017

Identification of lymphocyte cell types are crucial for understanding their pathophysiological roles in human diseases. Current methods for discriminating lymphocyte cell types primarily rely on labelling techniques with magnetic beads or fluorescence agents, which take time and have costs for sample preparation and may also have a potential risk of altering cellular functions. Here, we present the identification of non-activated lymphocyte cell types at the single-cell level using refractive index (RI) tomography and machine learning. From the measurements of three-dimensional RI maps of individual lymphocytes, the morphological and biochemical properties of the cells are quantitatively retrieved. To construct cell type classification models, various statistical classification algorithms are compared, and the k-NN (k = 4) algorithm was selected. The algorithm combines multiple quantitative characteristics of the lymphocyte to construct the cell type classifiers. After optimizing the feature sets via cross-validation, the trained classifiers enable identification of three lymphocyte cell types (B, CD4+ T, and CD8+ T cells) with high sensitivity and specificity. The present method, which combines RI tomography and machine learning for the first time to our knowledge, could be a versatile tool for investigating the pathophysiological roles of lymphocytes in various diseases including cancers, autoimmune diseases, and virus infections.
In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease
Authors: Yoshino Ryunosuke , Yasuo Nobuaki , Hagiwara Yohsuke , Ishida Takashi , Inaoka Daniel Ken , Amano Yasushi , Tateishi Yukihiro , Ohno Kazuki , Namatame Ichiji , Niimi Tatsuya , Orita Masaya , Kita Kiyoshi , Akiyama Yutaka , Sekijima Masakazu
Published: July 2017

Chagas disease results from infection by Trypanosoma cruzi and is a neglected tropical disease (NTD). Although some treatment drugs are available, their use is associated with severe problems, including adverse effects and limited effectiveness during the chronic disease phase. To develop a novel anti-Chagas drug, we virtually screened 4.8 million small molecules against spermidine synthase (SpdSyn) as the target protein using our super computer “TSUBAME2.5” and conducted in vitro enzyme assays to determine the half-maximal inhibitory concentration values. We identified four hit compounds that inhibit T. cruzi SpdSyn (TcSpdSyn) by in silico and in vitro screening. We also determined the TcSpdSyn–hit compound complex structure using X-ray crystallography, which shows that the hit compound binds to the putrescine-binding site and interacts with Asp171 through a salt bridge.
OsFH15, a class I formin, interacts with microfilaments and microtubules to regulate grain size via affecting cell expansion in rice
Authors: Sun Tiantian , Li Shanwei , Ren Haiyun
Published: July 2017

Grain size is an important agronomic trait determining rice yield and is mainly restricted by spikelet hull size. However, it remains largely unknown how the spikelet hull size is regulated. In this study, OsFH15, a class I formin protein in Oryza sativa, was found to be able to regulate the size of cells and spikelet hull. OsFH15-Cas9 and OsFH15-RNAi mutants had decreased grain size with reduced cell length, cell width and cell area of inner epidermal cells of the lemma compared with wild-type plants. By contrast, OsFH15-overexpressed plants had increased grain size with larger cells, as well as more abundant microtubules (MTs) and actin filaments (AFs) arrays. OsFH15 was mainly expressed in shoot apical meristem (SAM), spikelets, spikelet hulls and seeds in rice. In vitro biochemical experiments showed that OsFH15 can efficiently nucleate actin polymerization with or without profilin, can cap the barbed end of AFs, and can bind and bundle both AFs and MTs. OsFH15 can also crosslink AFs with MTs, and preferentially bind MTs to AFs. These results demonstrated that OsFH15 played an important role in grain-size control by affecting cell expansion through regulating AFs and MTs.
In-vivo loss of carbapenem resistance by extensively drug-resistant Klebsiella pneumoniae during treatment via porin expression modification
Authors: Bialek-Davenet Suzanne , Mayer Noémie , Vergalli Julia , Duprilot Marion , Brisse Sylvain , Pagès Jean-Marie , Nicolas-Chanoine Marie-Hélène
Published: July 2017

Klebsiella pneumoniae, an Enterobacteriaceae that mostly causes hospital-acquired infections, belongs to the recently published WHO’s list of antibiotic-resistant pathogens that pose the greatest threat to human health. Indeed, K. pneumoniae is the enterobacterial species most concerned by both resistance to extended-spectrum cephalosporins, due to extended-spectrum β-lactamase (ESBL) production, and resistance to carbapenems, i.e. the β-lactams with the broadest activity. Carbapenem resistance is related not only to carbapenemase production, but also the production of ESBL or AmpC and the loss of general porins. Here, we characterized the mechanisms that deprived a urinary ESBL-producing, porin-deficient K. pneumoniae isolate, isolated 13 days after the end of a 40-day course of imipenem treatment, of its carbapenem resistance. These mechanisms were observed in two in-vivo derivatives of this isolate and consisted of mutations in genes encoding molecules that participate in the downregulation of the synthesis of PhoE, a porin specialized in phosphate transport. We obtained three new derivatives from one of the two original derivatives, following in-vitro antibiotic pressure, in which the carbapenem resistance was restored because of mutations in genes encoding molecules that participate in the upregulation of PhoE synthesis. Thus, we uncovered novel mechanisms of carbapenem resistance/susceptibility switching in K. pneumoniae.
Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy
Authors: Benischke Anne-Sophie , Vasanth Shivakumar , Miyai Takashi , Katikireddy Kishore Reddy , White Tomas , Chen Yuming , Halilovic Adna , Price Marianne , Price Francis , Liton Paloma B. , Jurkunas Ula V.
Published: July 2017

Human corneal endothelial cells (HCEnCs) are terminally differentiated cells that have limited regenerative potential. The large numbers of mitochondria in HCEnCs are critical for pump and barrier function required for corneal hydration and transparency. Fuchs Endothelial Corneal Dystrophy (FECD) is a highly prevalent late-onset oxidative stress disorder characterized by progressive loss of HCEnCs. We previously reported increased mitochondrial fragmentation and reduced ATP and mtDNA copy number in FECD. Herein, carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced mitochondrial depolarization decreased mitochondrial mass and Mfn2 levels, which were rescued with mitophagy blocker, bafilomycin, in FECD. Moreover, electron transport chain complex (I, V) decrease in FECD indicated deficient mitochondrial bioenergetics. Transmission electron microscopy of FECD tissues displayed an increased number of autophagic vacuoles containing degenerated and swollen mitochondria with cristolysis. An elevation of LC3-II and LAMP1 and downregulation of Mfn2 in mitochondrial fractions suggested that loss of fusion capacity targets fragmented mitochondria to the pre-autophagic pool and upregulates mitophagy. CCCP-induced mitochondrial fragmentation leads to Mfn2 and LC3 co-localization without activation of proteosome, suggesting a novel Mfn2 degradation pathway via mitophagy. These data indicate constitutive activation of mitophagy results in reduction of mitochondrial mass and abrogates cellular bioenergetics during degeneration of post-mitotic cells of ocular tissue.