bluuebunny/crossref_metadata_2025 huggingface dataset:
Acquisition and loss of secondary metabolite clusters shaped the evolutionary path of three recently emerged phytopathogens of wheat
Authors: Thynne Elisha , Mead Oliver L. , Chooi Yit-Heng , McDonald Megan C. , Solomon Peter S.
Published: March 2018

White grain disorder is a recently emerged wheat disease in Australia, caused by threeBotryosphaeriaceae spp.;Eutiarosporella darliae, E. pseudodarliae, andE. tritici-australis. The disease cycle of these pathogens and the molecular basis of their interaction with wheat are poorly understood. To address this, we undertook a comparative genomics approach to identify potential pathogenicity factors.

Subsequent genome analysis revealed that each of the white grain disorder species harbour modular polyketide synthase genes. To our knowledge, this is the first report of fungi harbouring such genes. Further comparative analysis using the modular polyketide synthase genes discovered their presence in the closely relatedMacrophomina phaseolina. Phylogenetic analysis implicates horizontal acquisition of these genes from a bacterial or a protist species.

BothE. darliaeandE. pseudodarliaepossess a secondary metabolite cluster with multiple polyketide/non-ribosomal peptide synthase genes (Hybrid-1, -2, and -3). In contrast, only remnant and partial genes homologous to this cluster were identified at a syntenic locus inE. tritici-australissuggesting loss of this cluster. Homologues ofHybrid-2in other fungi have been proposed to facilitate disease induction in woody plants. Subsequent assays confirmed thatE. darliaeandE. pseudodarliaewere both pathogenic on woody plant hosts, butE. tritici-australiswas not, implicating woody plants as potential host reservoirs for the fungi. We hypothesise that loss of the cluster inE. tritici-australisrepresents a committed lifestyle jump to grasses.

Combined, our observations relating to the secondary metabolite potential of the WGDEutiarosporella spp.have contributed novel data to the field by expanding the range of known fungal secondary metabolite genes, and helped develop our understanding of the lifestyle and potential host-range of a recently emerged pathogen of wheat.
The expansion in lymphoid organs of IL-4+BATF+ T follicular helper cells is linked to IgG4 class switchingin vivo
Authors: Maehara Takashi , Mattoo Hamid , Mahajan Vinay S. , Murphy Samuel J.H. , Yuen Grace J. , Ishiguro Noriko , Ohta Miho , Moriyama Masafumi , Saeki Takako , Yamamoto Hidetaka , Yamauchi Masaki , Daccache Joe , Kiyoshima Tamotsu , Nakamura Seiji , Stone John H. , Pillai Shiv
Published: March 2018

Distinct TFHsubsets that influence specific class-switching events are assumed to exist, but the accumulation of isotype-specific TFHsubsets in secondary and tertiary lymphoid organs has not been hitherto demonstrated. IL-4 expressing TFHcells are surprisingly sparse in human secondary lymphoid organs. In sharp contrast, in IgG4-related disease (IgG4-RD), a disorder characterized by polarized Ig class switching, most TFHcells in tertiary and secondary lymphoid organs make IL-4. Human IL-4+TFHcells do not express GATA-3 but express nuclear BATF, and the transcriptomes of IL-4 secreting TFHcells differ both from PD1hiTFHcells that do not secrete IL-4 and IL4-secreting non-TFHcells. Unlike IgG4-RD, IL-4+TFHcells are rarely found in tertiary lymphoid organs in Sjögren’s syndrome, a disorder in which IgG4 is not elevated. The proportion of CD4+IL-4+BATF+T cells as well as of CD4+IL-4+CXCR5+T cells in IgG4-RD tissues correlates tightly with tissue IgG4 plasma cell numbers and plasma IgG4 levels in patients but not with the total plasma levels of other isotypes. These data describe a disease-related TFHsub-population in human tertiary and secondary lymphoid organs that is linked to IgG4 class switching.
Paracingulate sulcus morphology and hallucinations in clinical and non-clinical groups
Authors: Garrison Jane R. , Fernyhough Charles , McCarthy-Jones Simon , Simons Jon S. , Sommer Iris E.C.
Published: March 2018

Hallucinations are a characteristic symptom of psychotic mental health conditions that are also experienced by many individuals without a clinical diagnosis. Research has linked the experience of hallucinations in schizophrenia to differences in the length of the paracingulate sulcus (PCS), a structure in the medial prefrontal cortex of the brain which has previously been associated with the ability to differentiate perceived and imagined information. We investigated whether this notion of a specific morphological basis for hallucinations in the paracingulate cortex extends to individuals without a clinical diagnosis by testing the hypothesis that non-clinical individuals with hallucinations have shorter PCS than non-clinical individuals without hallucinations. Structural MRI scans were examined from three demographically matched groups of individuals: 50 patients with psychotic diagnoses who experienced auditory verbal hallucinations, 50 non-clinical individuals with auditory verbal hallucinations, and 50 healthy control subjects with no life-time history of hallucinations. Measurements of paracingulate sulcal length were compared between the groups and the results verified using automated data-driven gyrification analyses. Patients with hallucinations had shorter PCS than both healthy controls and non-clinical individuals with hallucinations, with no difference between non-clinical individuals with hallucinations and healthy controls. These findings suggest that the association of shorter PCS length with hallucinations is specific to patients with a psychotic disorder. This presents challenges for continuum models of psychosis and suggests possible differences in the mechanisms underlying hallucinations in clinical and non-clinical groups.
Finding reliable phenotypes and detecting artefacts among in vivo and in vitro assays to characterize the refractory transcriptional activator Sxy (TfoX) in Escherichia coli
Authors: Alshabib Ebtihal Y. , Fitzgerald Stephen F. , Chao Tzu-Chiao , Cameron Rhiannon C. , Redfield Rosemary J. , Sinha Sunita , Cameron Andrew D.S.
Published: March 2018

The Sxy (TfoX) protein is required for expression of a distinct subset of the genes regulated by the cAMP receptor protein (CRP) in the model organisms Escherichia coli, Haemophilus influenzae, and Vibrio cholerae. Genetic studies have established that CRP and Sxy co-activate transcription at gene promoters containing DNA binding sites called CRP-S sites. In contrast, CRP acts without Sxy at gene promoters containing canonical CRP-N sites, suggesting that Sxy makes physical contacts with CRP and/or DNA to assist in transcriptional activation at CRP-S promoters. Despite growing interest in Sxy’s activity as a transcription factor, Sxy remains poorly characterized due to a lack of reliable phenotypes in E. coli. Experiments are further hampered by growth inhibition and formation of inclusion bodies when Sxy is overexpressed. In this study we applied diverse phenotypic and molecular assays to test for postulated Sxy functions and interactions. Mutations in conserved regions of Sxy and truncations in the Sxy C-terminus abolish transcriptional activation of a CRP-S promoter, and a 37 amino acid truncation of the C-terminus relieves the growth inhibition normally caused by Sxy overexpression. Sxy was unable to augment weakened CRP interactions to restore carbon metabolism phenotypes. Bandshift analysis and chromatin pull-down assays of Sxy-CRP-DNA interactions yielded intriguing evidence of CRP-Sxy and Sxy-DNA physical interactions. However, despite the careful application of standard protein purification protocols and quality control steps for nickel affinity column purification, protein mass spectrometry revealed the enrichment of additional DNA-binding proteins in nickel column eluates, presenting a probable source of artefactual protein-protein and protein-DNA interaction results. These findings highlight the importance of extensive controls and phenotypic assays for the study of poorly characterized and recalcitrant proteins like Sxy.
Genome-specific histories of divergence and introgression between an allopolyploid unisexual salamander lineage and two sexual species
Authors: Denton Robert D. , Morales Ariadna E. , Gibbs H. Lisle
Published: March 2018

Quantifying genetic introgression between sexual species and polyploid lineages traditionally thought to be asexual is an important step in understanding what factors drive the longevity of putatively asexual groups. However, the presence of multiple distinct subgenomes within a single lineage provides a significant logistical challenge to evaluating the origin of genetic variation in most polyploids. Here, we capitalize on three recent innovations—variation generated from ultraconserved elements (UCEs), bioinformatic techniques for assessing variation in polyploids, and model-based methods for evaluating historical gene flow—to measure the extent and tempo of introgression over the evolutionary history of an allopolyploid lineage of all-female salamanders and two ancestral sexual species. We first analyzed variation from more than a thousand UCEs using a reference mapping method developed for polyploids to infer subgenome specific patterns of variation in the all-female lineage. We then used PHRAPL to choose between sets of historical models that reflected different patterns of introgression and divergence between the genomes of the parental species and the same genomes found within the polyploids. Our analyses support a scenario in which the genomes sampled in unisexuals salamanders were present in the lineage ∼3.4 million years ago, followed by an extended period of divergence from their parental species. Recent secondary introgression has occurred at different times between each sexual species and their representative genomes within the unisexuals during the last 500,000 years. Sustained introgression of sexual genomes into the unisexual lineage has been the defining characteristic of their reproductive mode, but this study provides the first evidence that unisexual genomes have also undergone long periods of divergence without introgression. Unlike other unisexual, sperm-dependent taxa in which introgression is rare, the alternating periods of divergence and introgression between unisexual salamanders and their sexual relatives could reveal the scenarios in which the influx of novel genomic material is favored and potentially explain why these salamanders are among the oldest described unisexual animals.
Mind the gaps – ignoring errors in long read assemblies critically affects protein prediction
Authors: Watson Mick
Published: March 2018

Long read, single molecule sequencing technologies are now routinely used for whole-genome sequencing and assembly. However, even after multiple rounds of correction, many errors remain which can critically affect protein coding regions, resulting in significantly altered and often truncated protein predictions.
Region Specific Central Arbor Morphologies of Nociceptive Afferents Develop Independently of Their Peripheral Target Innervation
Authors: Olson William , Luo Wenqin
Published: March 2018

Functionally important regions of sensory maps are overrepresented in the sensory pathways and cortex, but the underlying developmental mechanisms are not clear. In the spinal cord dorsal horn (DH), we recently showed that paw innervating Mrgprd+ non-peptidergic nociceptors display distinctive central arbor morphologies that well correlate with increased synapse transmission efficiency and heightened sensitivity of distal limb skin. Given that peripheral and central arbor formation of Mrgprd+ neurons co-occurs around the time of birth, we tested whether peripheral cues from different skin areas and/or postnatal reorganization mechanisms could instruct this somatotopic difference among central arbors. We found that, while terminal outgrowth/refinement occurs during early postnatal development in both the skin and the DH, postnatal refinement of central terminals precedes that of peripheral terminals. Further, we used single-cell ablation of Ret to genetically disrupt epidermal innervation of Mrgprd+ neurons and revealed that the somatotopic difference among their central arbors was unaffected by this manipulation. Finally, we saw that region-specific Mrgprd+ central terminal arbors are present from the earliest postnatal stages, before skin terminals are evident. Together, our data indicate that region-specific organization of Mrgprd+ neuron central arbors develops independently of peripheral target innervation and is present shortly after initial central terminal formation, suggesting that either cell-intrinsic and/or DH local signaling may establish this somatotopic difference.
Farm business financial performance in local foods value chains
Authors: Ahearn Mary Clare , Liang Kathleen , Goetz Stephan
Published: March 2018

Purpose

The purpose of this paper is to identify the factors associated with farm financial success for those farms known to produce for local supply chains. The analysis considers alternative measures of farm financial performance and considers the role of the local foods supply chain in the choice to market locally.

Design/methodology/approach

The paper uses a two-stage Heckman approach which addresses the possibility of sample selection bias. In the first stage, the choice model to engage in direct marketing is estimated. In the second stage, the authors estimate a model of the financial performance of those in the sample that direct marketed which includes an IMR term calculated from the parameters of the first stage equation. The analysis uses national farm-level data from the Agricultural and Resource Management Survey of the US Department of Agriculture and combines data from 2009 to 2012 to overcome the constraint of small samples.

Findings

Indicators of the development of a local foods supply were positively related to the choice to engage in direct marketing. Factors affecting farm financial performance varied significantly between a short-term and a long-term measure. The results emphasize the importance of considering multiple outcome measures, developing local supply chains and provide implications about beginning farms.

Originality/value

If a local foods system is going to thrive, the farms that market the agricultural products in the local food system must attain a certain level of profitability. The value of the analysis is an improved understanding of the financial performance of farms producing for a small, but growing segment of the food supply chain.
Human vulnerability and robo-advisory
Authors: Beltramini Enrico
Published: March 2018

Purpose

The purpose of this paper is to introduce the work of Mark Coeckelbergh into the field of management.

Design/methodology/approach

This is a conceptual paper with interviews.

Findings

The author suggests that Coeckelberghs’ considerations of an anthropology of vulnerability have the potential to provide a rich and insightful exploration of the machine-human interface, which is not afforded by many of the current approaches taken in this field. Their development of an anthropology of vulnerability suggests an approach to the machine-human interface that re-frames the machine-human interface in terms of human vulnerability, rather than machine’s performance, and sustains that the machine-human interface can be understood in terms of the transfer of human vulnerability.

Research limitations/implications

This paper reveals some of the possibilities inherent in Coeckelbergh’s theories by providing an analysis of a specific event, the recent introduction of robo-advisors in portfolio management, from a Coeckelberghian perspective and by exploring some of the implications of this type of approach for the machine-human interface.

Originality/value

As far as the author knows, there is no previous paper on this topic.
Maintaining digital collections with declining resources, fewer staff
Authors: Walker Wendy , Keenan Teressa
Published: March 2018

Purpose

The purpose of this paper is to describe methods for restructuring workflows and efficiently using staff members and volunteers to continue work on multiple, simultaneous digital collections as budgets and resources decline.

Design/methodology/approach

This paper describes one library’s varied approaches to several digital collections supported by literature or volunteers in libraries.

Findings

In the face of continually declining resources and new, time-sensitive priorities and compliance responsibilities, librarians can continue to maintain digital collections by modifying workflows, using the services of volunteers and communicating strategically.

Practical implications

This paper is relevant to librarians, archivists and others who are looking for ways to justify and capitalize on the use of unconventional personnel in digital collections programs.

Originality/value

This paper presents a case of the successful use of volunteers to accomplish digital collections-related tasks in an academic library and provides a communication-based strategy for addressing some of the challenges related to volunteers in academic libraries.
Gender is not “a dummy variable”: a discussion of current gender research in accounting
Authors: Hardies Kris , Khalifa Rihab
Published: March 2018

Purpose

The purpose of this paper is to reflect on the corpus of gender research in accounting journals, with the overall aim of evaluating the extent to which it has contributed to the understanding of the organization of accounting and its social and organizational functions.

Design/methodology/approach

Gender articles have been critically analyzed. The selection included all gender papers published between the years 2000 and 2014, in 58 journals ranked A*, A and B from the Australian Business Deans Council (ABDC) journal ranking list. Patterns within the publishing norms of those journals were identified and critically reflected upon.

Findings

Gender research has been grouped into three categories, namely, gender as a dummy (or control) variable, gender as giving voice and gender as a process and organizing principle. Of these three categories, it can be contended that using gender as a dummy variable is very common, and it proved to be the least fruitful in explicating the roles of gender in accounting. Moreover, many published papers confuse sex with gender.

Research limitations/implications

This paper discusses future avenues and approaches for research gender in accounting without, however, expanding on recent changes in gender research.

Originality/value

This paper is the first to systematically review gender research in the accounting field over the past three decades. Its key insight is to identify two persistent pitfalls within the current gender research practice, namely, the use of gender as a control variable only and the confusion of sex with gender. These pitfalls diminish the value of gender research overall and render it less relevant to the broader accounting literature. By using the term gender either as an add-on or, mistakenly, as a biological rather than cultural marker, the totality of those articles helps marginalize gender as an accounting research area because they fail to bring about the reconceptualization of accounting as a discipline. This stands in marked contrast to the achievements of gender approaches in other disciplines, such as sociology, history or work and employment. Articles that frequently decry the status of gender in accounting research turn out to be also reinforcing the marginalization of gender in accounting.
Corporate governance and cash holdings: the way forward
Authors: Akhtar Tahir , Tareq Mohamad Ali , Sakti Muhammad Rizky Prima , Khan Adnan Ahmad
Published: March 2018

Purpose

This study aims to provide a review of corporate governance and cash holdings because strong corporate governance is necessary for the efficient utilization of firm’s liquid resources such as cash, to minimize the agency cost of high cash holdings and to improve the value of cash.

Design/methodology/approach

The authors provide a literature review of corporate governance and cash holdings through a conceptual and theoretical argument rather than empirical research.

Findings

The authors review an empirical and theoretical work surrounding key corporate governance variables and identify avenues for future research. The authors find that corporate governance mechanisms and cash holdings have received much attention during the past two decades. However, the significant role of corporate governance (both country-level and the firm-level) in controlling the entrenched behaviour of the managers is discussed separately in the literature. The combined effect of both country-level and the firm-level governance is lacking in the cash holdings literature. Additionally, this study has found that much attention is paid to the developed markets, while only a few focused on the developing markets regarding cash holding literature, although the agency problems are high in developing markets.

Originality/value

The study contributes to the growing literature on corporate governance and cash holdings and provides a further understanding of the role of governance in minimizing the agency cost to increase value by assuring that firms’ assets are used efficiently and productively in the best interests of investors and other stakeholders. In addition, it provides a new idea to the policymaker and future researchers where they need to do more work.
Social network use and youth well-being: a study in India
Authors: Bharucha Jehangir
Published: March 2018

Purpose

The youth in present day India is the first generation to grow up within a world of pervasive technology. While several writers applaud these social network sites (SNSs) for transforming the social landscape of India, recent research is beginning to examine the destructive role of these SNSs. The purpose of this paper is to explore whether and to what extent social media contributes to decline in well-being, addictive behavior and other harmful social effects.

Design/methodology/approach

In the first phase, a structured questionnaire was sent via e-mail to 114 students. The second stage embraced an exploratory qualitative approach with in-depth interviews and reflections. As part of the third stage, the author devoted a lot of time reading the blogs and posts of the youth.

Findings

The analysis of qualitative data is presented in three major themes: patterns of usage, nature of online friendships and threat to well-being. Some of the respondents did experience “addiction-like” symptoms. It can be deduced that the respondents are not addicted to the medium per se; they are cultivating an addiction to certain activities they carry out online.

Practical implications

Indian newspapers have recently reported several cases how social media can mislead and corrupt the youth and some of these cases have ended in tragedy. This kind of obsessive behavior is extremely dangerous to the minds which are otherwise actually intelligent and ought to be stopped.

Originality/value

There is no doubt that the Indian youth is developing a dependence on this technological advance that fuses people all over the world. We are still in the infant stages of understanding these issues in the Indian context. This study adds value to the negligible empirical evidence in India till date.
Financing social entrepreneurship
Authors: Castellas Erin I-Ping , Ormiston Jarrod , Findlay Suzanne
Published: March 2018

Purpose

This paper aims to explore the emergence and nature of impact investment in Australia and how it is shaping the development of the social enterprise sector.

Design/methodology/approach

Impact investment is an emerging approach to financing social enterprises that aims to achieve blended value by delivering both impact and financial returns. In seeking to deliver blended value, impact investment combines potentially conflicted logics from investment, philanthropy and government spending. This paper utilizes institutional theory as a lens to understand the nature of these competing logics in impact investment. The paper adopts a sequential exploratory mixed methods approach to study the emergence of impact investment in Australia. The mixed methods include 18 qualitative interviews with impact investors in the Australian market and a subsequent online questionnaire on characteristics of impact investment products, activity and performance.

Findings

The findings provide empirical evidence of the rapid growth in impact investment in Australia. The analysis reveals the nature of institutional complexity in impact investment and highlights the risk that the impact logic may become overshadowed by the investment logic if the difference in rigor around financial performance measurement and impact performance measurement is maintained. The paper discusses the implications of these findings for the development of the Australian social enterprise sector.

Originality/value

This paper provides empirical evidence on the emergence of impact investment in Australia and contributes to a growing global body of evidence about the nature, size and characteristics of impact investment.
Bound nuclear spin states of H2 in an anisotropic potential induced by a stepped metal surface
Authors: Arguelles Elvis F. , Kasai Hideaki
Published: March 2018

The authors report an investigation of the nuclear spin bound states of H2 molecularly chemisorbed on a Pd(210) surface. They found that the adiabatic potential energy surface obtained from total energy density functional theory-based calculations is strongly anisotropic originating from the symmetry of surface-molecule bonding. Such a potential anisotropy causes a significant splitting of the J, states resulting in a relatively larger desorption energy difference between ortho and para isomers than on flat metal surfaces. Rotational–vibrational calculations show that two lowest bound state levels belong to para and ortho species, respectively. The corresponding wave functions show a highly localized adsorption character on top of the step-edge Pd and molecular orientation θ = π/2.
Effects of reverberation and noise on speech intelligibility in normal-hearing and aided hearing-impaired listeners
Authors: Xia Jing , Xu Buye , Pentony Shareka , Xu Jingjing , Swaminathan Jayaganesh
Published: March 2018

Many hearing-aid wearers have difficulties understanding speech in reverberant noisy environments. This study evaluated the effects of reverberation and noise on speech recognition in normal-hearing listeners and hearing-impaired listeners wearing hearing aids. Sixteen typical acoustic scenes with different amounts of reverberation and various types of noise maskers were simulated using a loudspeaker array in an anechoic chamber. Results showed that, across all listening conditions, speech intelligibility of aided hearing-impaired listeners was poorer than normal-hearing counterparts. Once corrected for ceiling effects, the differences in the effects of reverberation on speech intelligibility between the two groups were much smaller. This suggests that, at least, part of the difference in susceptibility to reverberation between normal-hearing and hearing-impaired listeners was due to ceiling effects. Across both groups, a complex interaction between the noise characteristics and reverberation was observed on the speech intelligibility scores. Further fine-grained analyses of the perception of consonants showed that, for both listener groups, final consonants were more susceptible to reverberation than initial consonants. However, differences in the perception of specific consonant features were observed between the groups.
Acoustically sticky topographic metasurfaces for underwater sound absorption
Authors: Lee Hunki , Jung Myungki , Kim Minsoo , Shin Ryung , Kang Shinill , Ohm Won-Suk , Kim Yong Tae
Published: March 2018

A class of metasurfaces for underwater sound absorption, based on a design principle that maximizes thermoviscous loss, is presented. When a sound meets a solid surface, it leaves a footprint in the form of thermoviscous boundary layers in which energy loss takes place. Considered to be a nuisance, this acoustic to vorticity/entropy mode conversion and the subsequent loss are often ignored in the existing designs of acoustic metamaterials and metasurfaces. The metasurface created is made of a series of topographic meta-atoms, i.e., intaglios and reliefs engraved directly on the solid object to be concealed. The metasurface is acoustically sticky in that it rather facilitates the conversion of the incident sound to vorticity and entropy modes, hence the thermoviscous loss, leading to the desired anechoic property. A prototype metasurface machined on a brass object is tested for its anechoicity, and shows a multitude of absorption peaks as large as unity in the 2–5 MHz range. Computations also indicate that a topographic metasurface is robust to hydrostatic pressure variation, a quality much sought-after in underwater applications.
Auditory distraction by speech: Sound masking with speech-shaped stationary noise outperforms −5 dB per octave shaped noise
Authors: Renz Tobias , Leistner Philip , Liebl Andreas
Published: March 2018

Sound masking can reduce the distraction due to ambient sounds in open-plan offices. This paper compares a typical masking sound with a slope of −5 dB per octave to a steady-state signal with the spectrum of the disturbing speech signal. Subjects had to complete a number recall task and a questionnaire in a laboratory experiment. The sound conditions with the spectrally-matched noise resulted in similar error rates at 3 dB higher speech-to-noise ratios as compared to the standard noise. Using a speech-shaped steady-state noise as masking sound could reduce the effect of distracting speech in the work place more efficiently.
Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata
Authors: Bader Justin C. , Lakota Elizabeth A. , Flanagan Shawn , Ong Voon , Sandison Taylor , Rubino Christopher M. , Bhavnani Sujata M. , Ambrose Paul G.
Published: March 2018

Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against
Aspergillus
and
Candida
species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three intravenous rezafungin regimens: (i) a single 400 mg dose, (ii) 400 mg for week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the nonclinical PK-PD targets associated with net fungal stasis and 1-log
10
CFU reductions from baseline for
Candida albicans
and
Candida glabrata
were calculated for each rezafungin regimen. At the MIC
90
for
C. albicans
and
C. glabrata
, a single 400 mg dose of rezafungin achieved probabilities of PK-PD target attainment of ≥90% through week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple-dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through week 6 following administration of the weekly regimens at or above the MIC
100
values for
C. albicans
and
C. glabrata
based on contemporary
in vitro
surveillance data. These analyses support the use of single and once-weekly rezafungin regimens for the treatment of patients with candidemia and/or candidiasis due to
C. albicans
or
C. glabrata
.
Cytokines, Antibodies, and Histopathological Profiles during Giardia Infection and Variant-Specific Surface Protein-Based Vaccination
Authors: Serradell Marianela C. , Gargantini Pablo R. , Saura Alicia , Oms Sergio R. , Rupil Lucía L. , Berod Luciana , Sparwasser Tim , Luján Hugo D.
Published: March 2018

Giardiasis is one of the most common human intestinal diseases worldwide. Several experimental animal models have been used to evaluateGiardiainfections, with gerbils (Meriones unguiculatus) being the most valuable model due to their high susceptibility toGiardiainfection, abundant shedding of cysts, and pathophysiological alterations and signs of disease similar to those observed in humans. Here, we report cytokine and antibody profiles both during the course ofGiardiainfection in gerbils and after immunization with a novel oral vaccine comprising a mixture of purified variant-specific surface proteins (VSPs). Transcript levels of representative cytokines of different immune profiles as well as macro- and microtissue alterations were assessed in Peyer's patches, mesenteric lymph nodes, and spleens. During infection, cytokine responses showed a biphasic profile: an early induction of Th1 (gamma interferon [IFN-γ], interleukin-1β [IL-1β], IL-6, and tumor necrosis factor [TNF]), Th17 (IL-17), and Th2 (IL-4) cytokines, together with intestinal alterations typical of inflammation, followed by a shift toward a predominant Th2 (IL-5) response, likely associated with a counterregulatory mechanism. Conversely, immunization with an oral vaccine comprising the entire repertoire of VSPs specifically showed high levels of IL-17, IL-6, IL-4, and IL-5, without obvious signs of inflammation. Both immunized and infected animals developed local (intestinal secretory IgA [S-IgA]) and systemic (serum IgG) humoral immune responses against VSPs; however, only infected animals showed evident signs of giardiasis. This is the first comprehensive report of cytokine expression and anti-Giardiaantibody production during infection and VSP vaccination in gerbils, a reliable model of the human disease.
Uninfected Bystander Cells Impact the Measurement of HIV-Specific Antibody-Dependent Cellular Cytotoxicity Responses
Authors: Richard Jonathan , Prévost Jérémie , Baxter Amy E. , von Bredow Benjamin , Ding Shilei , Medjahed Halima , Delgado Gloria G. , Brassard Nathalie , Stürzel Christina M. , Kirchhoff Frank , Hahn Beatrice H. , Parsons Matthew S. , Kaufmann Daniel E. , Evans David T. , Finzi Andrés
Published: March 2018

The conformation of the HIV-1 envelope glycoprotein (Env) substantially impacts antibody recognition and antibody-dependent cellular cytotoxicity (ADCC) responses. In the absence of the CD4 receptor at the cell surface, primary Envs sample a “closed” conformation that occludes CD4-induced (CD4i) epitopes. The virus controls CD4 expression through the actions of Nef and Vpu accessory proteins, thus protecting infected cells from ADCC responses. However, gp120 shed from infected cells can bind to CD4 present on uninfected bystander cells, sensitizing them to ADCC mediated by CD4i antibodies (Abs). Therefore, we hypothesized that these bystander cells could impact the interpretation of ADCC measurements. To investigate this, we evaluated the ability of antibodies to CD4i epitopes and broadly neutralizing Abs (bNAbs) to mediate ADCC measured by five ADCC assays commonly used in the field. Our results indicate that the uninfected bystander cells coated with gp120 are efficiently recognized by the CD4i ligands but not the bNabs. Consequently, the uninfected bystander cells substantially affect
in vitro
measurements made with ADCC assays that fail to identify responses against infected versus uninfected cells. Moreover, using an mRNA flow technique that detects productively infected cells, we found that the vast majority of HIV-1-infected cells in
in vitro
cultures or
ex vivo
samples from HIV-1-infected individuals are CD4 negative and therefore do not expose significant levels of CD4i epitopes. Altogether, our results indicate that ADCC assays unable to differentiate responses against infected versus uninfected cells overestimate responses mediated by CD4i ligands.

IMPORTANCE
Emerging evidence supports a role for antibody-dependent cellular cytotoxicity (ADCC) in protection against HIV-1 transmission and disease progression. However, there are conflicting reports regarding the ability of nonneutralizing antibodies targeting CD4-inducible (CD4i) Env epitopes to mediate ADCC. Here, we performed a side-by-side comparison of different methods currently being used in the field to measure ADCC responses to HIV-1. We found that assays which are unable to differentiate virus-infected from uninfected cells greatly overestimate ADCC responses mediated by antibodies to CD4i epitopes and underestimate responses mediated by broadly neutralizing antibodies (bNAbs). Our results strongly argue for the use of assays that measure ADCC against HIV-1-infected cells expressing physiologically relevant conformations of Env to evaluate correlates of protection in vaccine trials.
The
Escherichia coli
Phospholipase PldA Regulates Outer Membrane Homeostasis via Lipid Signaling
Authors: May Kerrie L. , Silhavy Thomas J.
Published: March 2018

The outer membrane (OM) bilayer of Gram-negative bacteria is biologically unique in its asymmetrical organization of lipids, with an inner leaflet composed of glycerophospholipids (PLs) and a surface-exposed outer leaflet composed of lipopolysaccharide (LPS). This lipid organization is integral to the OM’s barrier properties. Perturbations of the outer leaflet by antimicrobial peptides or defects in LPS biosynthesis or transport to the OM cause a compensatory flipping of PLs to the outer leaflet. As a result, lipid asymmetry is disrupted and OM integrity is compromised. Recently, we identified an
Escherichia coli
mutant that exhibits aberrant accumulation of surface PLs accompanied by a cellular increase in LPS production. Remarkably, the observed hyperproduction of LPS is PldA dependent. Here we provide evidence that the fatty acids generated by PldA at the OM are transported into the cytoplasm and simultaneously activated by thioesterification to coenzyme A (CoA) by FadD. The acyl-CoAs produced ultimately inhibit LpxC degradation by FtsH. The increased levels of LpxC, the enzyme that catalyzes the first committed step in LPS biosynthesis, increases the amount of LPS produced. Our data suggest that PldA acts as a sensor for lipid asymmetry in the OM. PldA protects the OM barrier by both degrading mislocalized PLs and generating lipid second messengers that enable long-distance signaling that prompts the cell to restore homeostasis at a distant organelle.

IMPORTANCE
The outer membrane of Gram-negative bacteria is an effective permeability barrier that protects the cell from toxic agents, including antibiotics. Barrier defects are often manifested by phospholipids present in the outer leaflet of this membrane that take up space normally occupied by lipopolysaccharide. We have discovered a signaling mechanism that operates across the entire cell envelope used by the cell to detect these outer membrane defects. A phospholipase, PldA, that functions to degrade these mislocalized phospholipids has a second, equally important function as a sensor. The fatty acids produced by hydrolysis of the phospholipids act as second messengers to signal the cell that more lipopolysaccharide is needed. These fatty acids diffuse across the periplasm and are transported into the cytoplasm by a process that attaches coenzyme A. The acyl-CoA molecule produces signals to inhibit the degradation of the critical enzyme LpxC by the ATP-dependent protease FtsH, increasing lipopolysaccharide production.
The Gathering Storm: Is Untreatable Typhoid Fever on the Way?
Authors: Levine Myron M. , Simon Raphael
Published: March 2018

Klemm et al. (mBio 9:e00105-18, 2018,
https://doi.org/10.1128/mBio.00105-18
) present comprehensive antibiotic sensitivity patterns and genomic sequence data on
Salmonella enterica
serovar Typhi blood culture isolates from typhoid fever cases during an epidemic in Pakistan. Microbiologic and genomic data pinpoint the identities and locations of the antimicrobial resistance genes and the outbreak strain’s lineage. They propose that
Salmonella enterica
serovar Typhi be added to the list of bacterial pathogens of public health importance that have become extensively drug resistant (XDR). This paper portends possible dire scenarios for typhoid fever control if XDR strains disseminate globally. Since the outbreak strain is of the H58 haplotype, known for its ability to spread worldwide and displace endemic
S
. Typhi, this concern is well-founded. The report of Klemm et al. forewarns the global community to address control of typhoid fever more aggressively through prevention, should therapeutic options disappear. This Commentary frames the Klemm et al. findings within a historic perspective.
Gene Co-occurrence Networks Reflect Bacteriophage Ecology and Evolution
Authors: Shapiro Jason W. , Putonti Catherine
Published: March 2018

Bacteriophages are the most abundant and diverse biological entities on the planet, and new phage genomes are being discovered at a rapid pace. As more phage genomes are published, new methods are needed for placing these genomes in an ecological and evolutionary context. Phages are difficult to study by phylogenetic methods, because they exchange genes regularly, and no single gene is conserved across all phages. Here, we demonstrate how gene-level networks can provide a high-resolution view of phage genetic diversity and offer a novel perspective on virus ecology. We focus our analyses on virus host range and show how network topology corresponds to host relatedness, how to find groups of genes with the strongest host-specific signatures, and how this perspective can complement phage host prediction tools. We discuss extensions of gene network analysis to predicting the emergence of phages on new hosts, as well as applications to features of phage biology beyond host range.

IMPORTANCE
Bacteriophages (phages) are viruses that infect bacteria, and they are critical drivers of bacterial evolution and community structure. It is generally difficult to study phages by using tree-based methods, because gene exchange is common, and no single gene is shared among all phages. Instead, networks offer a means to compare phages while placing them in a broader ecological and evolutionary context. In this work, we build a network that summarizes gene sharing across phages and test how a key constraint on phage ecology, host range, corresponds to the structure of the network. We find that the network reflects the relatedness among phage hosts, and phages with genes that are closer in the network are likelier to infect similar hosts. This approach can also be used to identify genes that affect host range, and we discuss possible extensions to analyze other aspects of viral ecology.
First Evidence for Internal Ribosomal Entry Sites in Diverse Fungal Virus Genomes
Authors: Chiba Sotaro , Jamal Atif , Suzuki Nobuhiro
Published: March 2018

In contrast to well-established internal ribosomal entry site (IRES)-mediated translational initiation in animals and plants, no IRESs were established in fungal viral or cellular RNAs. To identify IRES elements in mycoviruses, we developed a luciferase-based dual-reporter detection system in
Cryphonectria parasitica
, a model filamentous fungus for virus-host interactions. A bicistronic construct entails a codon-optimized
Renilla
and firefly luciferase (
ORluc
and
OFluc
, respectively) gene, between which potential IRES sequences can be inserted. In this system, ORluc serves as an internal control, while OFluc represents IRES activity. Virus sequences in the 5′ untranslated regions (UTRs) of the genomes of diverse positive-sense single-stranded RNA and double-stranded RNA (dsRNA) viruses were analyzed. The results show relatively high IRES activities for Cryphonectria hypovirus 1 (CHV1) and CHV2 and faint but measurable activity for CHV3. The weak IRES signal of CHV3 may be explained by its monocistronic nature, differing from the bicistronic nature of CHV1 and CHV2. This would allow these three hypoviruses to have similar rates of translation of replication-associated protein per viral mRNA molecule. The importance of 24 5′-proximal codons of CHV1 as well as the 5′ UTR for IRES function was confirmed. Furthermore, victoriviruses and chrysoviruses tested IRES positive, whereas mycoreoviruses, partitiviruses, and quadriviruses showed similar Fluc activities as the negative controls. Overall, this study represents the first development of an IRES identification system in filamentous fungi based on the codon-optimized dual-luciferase assay and provides evidence for IRESs in filamentous fungi.

IMPORTANCE
Cap-independent, internal ribosomal entry site (IRES)-mediated translational initiation is often used by virus mRNAs and infrequently by cellular mRNAs in animals and plants. However, no IRESs have been established in fungal virus RNAs or cellular RNAs in filamentous fungi. Here, we report the development of a dual-luciferase assay system and measurement of the IRES activities of fungal RNA viruses in a model filamentous fungal host,
Cryphonectria parasitica
. Viruses identified as IRES positive include hypoviruses (positive-sense RNA viruses, members of the expanded
Picornavirus
supergroup), totiviruses (nonsegmented dsRNA viruses), and chrysoviruses (tetrasegmented dsRNA viruses). No IRES activities were observed in the 5′ untranslated regions of mycoreoviruses (11-segmented dsRNA viruses), quadriviruses (tetrasegmented dsRNA viruses), or partitiviruses (bisegmented dsRNA viruses). This study provides the first evidence for IRES activities in diverse RNA viruses in filamentous fungi and is a first step toward identifying
trans
-acting host factors and
cis
-regulatory viral RNA elements.