bluuebunny/crossref_metadata_2025 huggingface dataset:
Narrow Band Imaging for Surveillance in Inflammatory Bowel Disease
Authors: Lv Xiu-He , Wang Bo-Ling , Cao Guo-Wu
Published: August 2018

Background:

The role of narrow band imaging (NBI) for surveillance colonoscopy in patients with inflammatory bowel disease (IBD) is debatable. We aim to compare NBI versus other endoscopic techniques in surveillance of IBD basing on current evidences.

Methods:

A systematic search of PubMed, Embase, and the Cochrane Library databases was conducted for relevant studies. To assess the detection efficacy, we estimated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. To assess the differentiation efficacy, we estimated sensitivity and specificity of NBI with reference to histology. All outcome variables were pooled using a random-effects model. Heterogeneity was tested by the Q statistic and I
2 statistic.

Results:

A total of 10 studies involving 938 participants were included. Statistically significant differences were not found in the likelihood of detecting patients with dysplastic lesions [RR, 1.11; 95% confidence interval (CI), 0.83-1.48] nor in the likelihood of detecting dysplastic lesions by targeted biopsies (RR, 0.76; 95% CI, 0.51-1.12) between NBI and other techniques, and there was also no difference in the likelihood of detecting dysplastic subtypes. NBI required shorter procedural time compared with other techniques (MD, −10.23; 95% CI, −11.53 to −8.92). The sensitivity and specificity of NBI to differentiate neoplastic lesions from non-neoplastic lesions were 0.64 (95% CI, 0.50-0.77) and 0.74 (95% CI, 0.69-0.79), respectively, and the area under the curve (AUC) was 0.7626.

Conclusions:

Although a shorter procedural time is needed, the clinical application of NBI for both dysplasia detection and neoplasia differentiation in IBD is not superior to other endoscopic techniques.
Chronic rejection in vascularized composite allotransplantation
Authors: Morelon Emmanuel , Petruzzo Palmina , Kanitakis Jean
Published: August 2018

Purpose of review

Vascularized composite allografts (VCA), which restore severely damaged body parts that cannot be repaired with conventional surgical techniques, often undergo acute skin rejection episodes in the early postgraft period. Although the risk of human VCA to be affected by chronic rejection was initially unknown, such cases were recently observed.

Recent findings

Chronic rejection targets preferentially the skin (dermal sclerosis, adnexal atrophy, necrosis) and vessels (graft vasculopathy) and may cause graft dysfunction, often resulting in ischemic graft loss. Both immune (cell-mediated and antibody-mediated) and nonimmune mechanisms seem to be involved. The early diagnosis and management of chronic rejection are challenging. Changes of chronic rejection may be seen macroscopically on the skin and can be confirmed with skin and deep tissue biopsies. New noninvasive imaging techniques, which allow visualization of the allograft vasculature, seem promising for the noninvasive detection of graft vasculopathy.

Although some features of chronic rejection of VCA start to be known, several important questions remain to be answered, concerning namely the proper definition of chronic rejection, precise diagnostic criteria, better understanding of triggering factors and pathogenetic mechanisms involved and, most importantly, adequate treatment. Ideally, chronic rejection should be prevented in the future by efficient tolerance-inducing protocols.
Bronchoscopy and Bronchoalveolar Lavage in the Diagnosis and Management of Pulmonary Infections in Immunocompromised Children
Authors: Rizik Suha , Hakim Fahed , Bentur Lea , Arad-Cohen Nira , Kassis Imad
Published: August 2018

Background:

Immunocompromised children are at high risk of rapid deterioration and of developing life-threatening pulmonary infections. Etiologies in this setting are diverse, including those that are infectious and noninfectious, and many etiologies may coexist. Accurate diagnosis is required for the rational use of medications. Fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) can identify infectious causes in this population.

Objectives:

The aims of this study were to evaluate diagnostic rate, safety, and changes in treatment following FOB with BAL, when applied with advanced laboratory diagnostic techniques.

Patients and methods:

We reviewed the records of children who underwent FOB with BAL during the period spanning from 2006 to 2014 in the Hematology-Oncology Department. BAL samples were processed in microbiology, virology, cytology, and molecular laboratories.

Results:

Antimicrobials were initiated in 91 of 117 children. BAL yielded an infectious etiology in 55 episodes. Management was altered in 74 patients following a positive (40/55) or a negative (30/54) result (4 patients had missing data). No severe complications associated with the procedures occurred.

Conclusions:

Most immunocompromised patients with pulmonary manifestations are treated empirically with multiple medications. Evaluation FOB/BAL is a useful diagnostic tool, and seems to have changed the course of therapy in more than half of patients, by initiation or cessation of treatment. FOB/BAL is a safe diagnostic tool for the evaluation of pulmonary manifestations in this setting.
Relationship of Staff Information Sharing and Advice Networks to Patient Safety Outcomes
Authors: Brewer Barbara B. , Carley Kathleen M. , Benham-Hutchins Marge M. , Effken Judith A. , Reminga Jeffrey , Kowalchuck Michael
Published: August 2018

OBJECTIVE

The aim of this study was to compare information sharing and advice networks' relationships with patient safety outcomes.

BACKGROUND

Communication contributes to medical errors, but rarely is it clear what elements of communication are key.

METHODS

We investigated relationships of information-sharing and advice networks to patient safety outcomes in 24 patient care units from 3 hospitals over 7 months. Web-based questionnaires completed via Android tablets provided data to create 2 networks using ORA, a social network analysis application. Each hospital provided nurse-sensitive patient safety outcomes.

RESULTS

In both networks, medication errors correlated positively with node count and average distance and negatively with clustering coefficient. Density and weighted density negatively correlated with medication errors and falls in both networks. Eigenvector and total degree centrality correlated negatively with both safety outcomes, whereas betweenness centrality positively related to falls in the information-sharing network.

CONCLUSION

Technology-enabled social network analysis data collection is feasible and can provide managers actionable system-level information.
A Qualitative Study of Specialized Clinical Nurses’ Perceptions of Good Care in Practice
Authors: Valizadeh Leila , Zamanzadeh Vahid , Rassouli Maryam , Ghahramanian Akram , M. Archibald Mandy , Asghari Elnaz
Published: August 2018

Purpose/Aims:

The aim of this study was to explore specialized clinical nurses’ (SCNs’) perceptions of “good care” through descriptions of actual care experiences.

Design:

We used a qualitative design with a conventional content analysis approach.

Methods:

We conducted semistructured interviews with 24 SCNs. These nurses have passed specialized clinical courses, are master’s or bachelor’s degree prepared, have additional course work beyond the bachelor degree, and practice with an expanded scope of responsibility. The participants were purposively sampled from general and specialty hospitals, and 6 field notes were collected.

Results:

We identified 3 overarching themes to classify the findings: patient-centered care, knowledge-based care, and skillful practice. Participants regarded these 3 components as interdependent and related, which we conceptualize as 3 sides of an equilateral triangle termed the Good Care Triangle.

Conclusions:

The Good Care Triangle provides a heuristic approach to consider professional standards from the perspectives of SCNs and provides needed insight into SCNs’ perspectives on the fundamental yet underexplored concept of good care. Clinical leaders can consider how the 3 themes identified are reflected and enacted in the care practices of SCNs. Future research could examine the utility of the Good Care Triangle in guiding nursing education and evaluating SCNs’ perspectives of the care that they are providing.
When Family Matters Most: A Test of the Association Between Sexual Minority Identity Disclosure Context and Diurnal Cortisol in Sexual Minority Young Adults
Authors: Manigault Andrew W. , Figueroa Wilson S. , Hollenbeck Cari R. , Mendlein Anna E. , Woody Alex , Hamilton Katrina R. , Scanlin Matt C. , Johnson Ryan C. , Zoccola Peggy M.
Published: August 2018

Objective

Revealing one's sexual identity to others is a complex process marked by a shift in the types of stressors faced by sexual minority young adults. Such stressors influence the secretion of health-relevant hormones, including cortisol, yet how dimensions of disclosure (i.e., the degree and context) influence neuroendocrine functioning remains poorly understood. The current study examined the association between disclosure context (disclosure to family members, friends/co-workers/acquaintances, and members of religious groups) and diurnal cortisol while allowing disclosure to vary in degree (i.e., how much is disclosed).

Methods

One hundred twenty-one sexual minority young adults (aged 18–35 years, 54.5% female, free of major psychiatric/endocrine disorders) completed an initial survey that assessed the degree and context of sexual minority identity disclosure. A randomly selected subset (n = 58) also provided salivary cortisol samples at wake, 45 minutes after wake, 12 hours after wake, and at bedtime for 1 week.

Results

Greater total disclosure and greater disclosure to family members were associated with reduced cortisol output, defined as Area Under the Curve relative to ground (AUCg; F(1,230) = 5.95, p = .015, and F(1,231) = 10.90, p = .001, respectively). Disclosure to co-workers, friends, acquaintances, or religious groups was unrelated to cortisol AUCg. All disclosure contexts tested were unrelated to the shape of diurnal cortisol slopes (including the cortisol awakening response).

Conclusions

Disclosure to family members uniquely predicted cortisol AUCg. Therefore, these results suggest that effects of disclosure on diurnal cortisol and its associated health outcomes may occur in the context of familial relationships.
Interscanner and Intrascanner Comparison of Virtual Unenhanced Attenuation Values Derived From Twin Beam Dual-Energy and Dual-Source, Dual-Energy Computed Tomography
Authors: Obmann Markus M. , Kelsch Vanessa , Cosentino Aurelio , Hofmann Verena , Boll Daniel T. , Benz Matthias R.
Published: August 2018

Objective

The aim of the current study was to evaluate the reliability and comparability of virtual unenhanced (VUE) attenuation values derived from scans of a single-source, dual-energy computed tomography using a split-filter (tbDECT) to a dual-source dual-energy CT (dsDECT).

Materials and Methods

In this retrospective study, comparisons for tbDECT and dsDECT were made within and between different dual-energy platforms. For the interscanner comparison, 126 patients were scanned with both scanners within a time interval of 224 ± 180 days; for the intrascanner comparison, another 90 patients were scanned twice with the same scanner within a time interval of 136 ± 140 days. Virtual unenhanced images were processed off of venous phase series. Attenuation values of 7 different tissues were recorded. Disagreement for VUE HU measurements greater than 10 HU between 2 scans was defined as inadequate.

Results

The interscanner analysis showed significant difference between tbDE and dsDE VUE CT values (P < 0.01) for 6 of 7 organs. Percentage of cases that had more than 10 HU difference between tbDE and dsDE for an individual patient ranged between 15% (left kidney) and 62% (spleen).

The intrascanner analysis showed no significant difference between repeat scans for both tbDECT and dsDECT (P > 0.05). However, intrascanner disagreements for the VUE HU measurements greater than 10 HU were recorded in 10% of patients scanned on the tbDECT and 0% of patients scanned on the dsDECT. The organs with the highest portion of greater than 10 HU errors were the liver and the aorta (both 20%).

Conclusions

Dual-energy techniques vary in reproducibility of VUE attenuation values. In the current study, tbDECT demonstrated higher variation in VUE HU measurements in comparison to a dsDECT. Virtual unenhanced HU measurements cannot be reliably compared on follow-up CT, if these 2 different dual-energy CT platforms are used.
Oxygen Perfusion (Persufflation) of Human Pancreata Enhances Insulin Secretion and Attenuates Islet Proinflammatory Signaling
Authors: Kelly Amy C. , Smith Kate E. , Purvis William G. , Min Catherine G. , Weber Craig S. , Cooksey Amanda M. , Hasilo Craig , Paraskevas Steven , Suszynski Thomas M. , Weegman Bradley P. , Anderson Miranda J. , Camacho Leticia E. , Harland Robert C. , Loudovaris Thomas , Jandova Jana , Molano Diana S. , Price Nicholas D. , Georgiev Ivan G. , Scott William E. , Manas Derek M.D. , Shaw James A.M. , O'Gorman Doug , Kin Tatsuya , McCarthy Fiona M. , Szot Gregory L. , Posselt Andrew M. , Stock Peter G. , Karatzas Theodore , Shapiro A.M. James , Lynch Ronald M. , Limesand Sean W. , Papas Klearchos K.
Published: August 2018

Background

All human islets used in research and for the clinical treatment of diabetes are subject to ischemic damage during pancreas procurement, preservation, and islet isolation. A major factor influencing islet function is exposure of pancreata to cold ischemia during unavoidable windows of preservation by static cold storage (SCS). Improved preservation methods may prevent this functional deterioration. In the present study, we investigated whether pancreas preservation by gaseous oxygen perfusion (persufflation) better preserved islet function versus SCS.

Methods

Human pancreata were preserved by SCS or by persufflation in combination with SCS. Islets were subsequently isolated, and preparations in each group matched for SCS or total preservation time were compared using dynamic glucose-stimulated insulin secretion as a measure of β-cell function and RNA sequencing to elucidate transcriptomic changes.

Results

Persufflated pancreata had reduced SCS time, which resulted in islets with higher glucose-stimulated insulin secretion compared to islets from SCS only pancreata. RNA sequencing of islets from persufflated pancreata identified reduced inflammatory and greater metabolic gene expression, consistent with expectations of reducing cold ischemic exposure. Portions of these transcriptional responses were not associated with time spent in SCS and were attributable to pancreatic reoxygenation. Furthermore, persufflation extended the total preservation time by 50% without any detectable decline in islet function or viability.

Conclusions

These data demonstrate that pancreas preservation by persufflation rather than SCS before islet isolation reduces inflammatory responses and promotes metabolic pathways in human islets, which results in improved β cell function.
Multifocal motor neuropathy
Authors: Beadon Katie , Guimarães-Costa Raquel , Léger Jean-Marc
Published: August 2018

Purpose of review

Multifocal motor neuropathy (MMN) has specific clinical and electrophysiologic features but can be difficult to diagnose if cases are not typical. Intravenous immunoglobulin (IVIg) remains the core initial and long-term treatment. In this review, recent advances in the diagnosis, monitoring and treatment of MMN are discussed.

Recent findings

The pathology of MMN likely depends on immune-mediated attack of the nodes of Ranvier and paranodal regions leading to conduction block. Antiganglioside antibodies are present in over 50% of patients. The sensitivity of antibody detection can be improved by testing for GM1/galactocerebroside (GM1/GalC) complexes. Complement activation plays a key role in the pathophysiology of MMN. Subcutaneous immunoglobulins are an efficacious alternative to IVIg for maintenance therapy in MMN. Complement inhibitor eculizumab may be a potential future treatment, but further studies are necessary.

The European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) guidelines for the diagnosis of MMN are currently widely used but probably need revision. Nerve ultrasound and plexus/nerve MRI can be helpful in diagnostic dilemmas. Monitoring of disease and response to treatment may improve using disease-specific evaluation scales such as MMN-Rasch-built overall disability scale. Further research into the pathophysiology of MMN is necessary to direct future treatment strategies.
Choosing the right label for single-molecule tracking in live bacteria: Side-by-side comparison of photoactivatable fluorescent protein and Halo tag dyes
Authors: Banaz Nehir , Mäkelä Jarno , Uphoff Stephan
Published: August 2018

Visualizing and quantifying molecular motion and interactions inside living cells provides crucial insight into the mechanisms underlying cell function. This has been achieved by super-resolution localization microscopy and single-molecule tracking in conjunction with photoactivatable fluorescent proteins. An alternative labelling approach relies on genetically-encoded protein tags with cell-permeable fluorescent ligands which are brighter and less prone to photobleaching than fluorescent proteins but require a laborious labelling process. Either labelling method is associated with significant advantages and disadvantages that should be taken into consideration depending on the microscopy experiment planned. Here, we describe an optimised procedure for labelling Halo-tagged proteins in liveEscherichia colicells. We provide a side-by-side comparison of Halo tag with different fluorescent ligands against the popular photoactivatable fluorescent protein PAmCherry. Using test proteins with different intracellular dynamics, we evaluated fluorescence intensity, background, photostability, and single-molecule localization and tracking results. Capitalising on the brightness and extended spectral range of fluorescent Halo ligands, we also demonstrate high-speed and dual-colour single-molecule tracking.
HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma
Authors: Zou Yilong , Palte Michael J. , Deik Amy A. , Li Haoxin , Eaton John K. , Wang Wenyu , Tseng Yuen-Yi , Deasy Rebecca , Alimova Maria , Dančík Vlado , Leshchiner Elizaveta S. , Viswanathan Vasanthi S. , Signoretti Sabina , Choueiri Toni K. , Boehm Jesse S. , Wagner Bridget K. , Doench John , Clish Clary B. , Clemons Paul A. , Schreiber Stuart L.
Published: August 2018

Kidney cancers are characterized by extensive metabolic reprogramming and resistance to a broad range of anti-cancer therapies. By interrogating the Cancer Therapeutics Response Portal compound sensitivity dataset, we show that cells of clear-cell renal cell carcinoma (ccRCC) possess a lineage-specific vulnerability to ferroptosis that can be exploited by inhibiting glutathione peroxidase 4 (GPX4). Using genome-wide CRISPR screening and lipidomic profiling, we reveal that this vulnerability is driven by the HIF-2α–HILPDA pathway by inducing a polyunsaturated fatty acyl (PUFA)-lipid-enriched cell state that is dependent on GPX4 for survival and susceptible to ferroptosis. This cell state is developmentally primed by the HNF-1β–1-Acylglycerol-3-Phosphate O-Acyltransferase 3 (AGPAT3) axis in the renal lineage. In addition to PUFA metabolism, ferroptosis is facilitated by a phospholipid flippase TMEM30A involved in membrane topology. Our study uncovers an oncogenesis-associated vulnerability, delineates the underlying mechanisms and suggests targeting GPX4 to induce ferroptosis as a therapeutic opportunity in ccRCC.

HIGHLIGHTS

ccRCC cells exhibit strong susceptibility to GPX4 inhibition-induced ferroptosis

The GPX4-dependent and ferroptosis-susceptible state in ccRCC is associated with PUFA-lipid abundance

The HIF-2α–HILPDA axis promotes the selective deposition of PUFA-lipids and ferroptosis susceptibility

AGPAT3 selectively synthesizes PUFA-phospholipids and primes renal cells for ferroptosis
Theta oscillations show impaired interference detection in the elderly during selective memory retrieval
Authors: Ferreira Catarina S. , Jesús Maraver Maria , Hanslmayr Simon , Teresa Bajo
Published: August 2018

Seemingly effortless tasks, such as recognizing faces and retrieving names, become significantly harder as people get older. These age-related difficulties may be partially due to the concurrent activation of related competitors. However, it remains unclear whether older adults struggle with detecting an early interference signal or with suppressing irrelevant competitors once competition is detected. To investigate this question, we used the retrieval practice paradigm, shown to elicit interference, while recording electrophysiological activity in young and older adults. In two experiments, young participants showed the typical Retrieval Induced Forgetting (RIF) effect whereas the elderly did not. Neurally, young adults were more capable to detect interference than the older, as evidenced by an increase in mid-frontal theta power (~4-8Hz). This efficient interference detection allowed young adults to recruit inhibitory mechanisms that overcome competition, as traced by a theta power reduction across retrieval cycles. No such reduction was found for the elderly, indicating that the lack of an early interference detection signal renders older adults unable to recruit memory selection mechanisms, eliminating RIF.

AUTHORS NOTE

This research was supported by the doctoral research grants AP2009-2215 to C.S.F and BES-2013-066842 to M.J.M.; by grants PSI2012-33625; PSI2015-65502-C2-1-P from the Spanish Ministry of Economy and Competiveness, and by the Economic Council of the Andalusian Government P08-HUM-03600-Feder and P12-CTS-2369-Feder to T.B.

Declaration of interest

The authors have no conflicts of interest to disclose
A specialized MreB-dependent complex mediates the formation of stalk-specific peptidoglycan in Caulobacter crescentus
Authors: Billini Maria , Biboy Jacob , Kühn Juliane , Vollmer Waldemar , Thanbichler Martin
Published: August 2018

Many bacteria have complex cell shapes, but the mechanisms producing their distinctive morphologies are still poorly understood.Caulobacter crescentus, for instance, exhibits a stalk-like extension that carries an adhesive holdfast mediating surface attachment. This structure forms through zonal peptidoglycan biosynthesis at the old cell pole and elongates extensively under phosphate-limiting conditions. We analyzed the composition of cell body and stalk peptidoglycan and identified significant differences in the nature and proportion of peptide crosslinks, indicating that the stalk represents a distinct subcellular domain with specific mechanical properties. To identify factors that participate in stalk formation, we systematically inactivated and localized predicted components of the cell wall biosynthetic machinery ofC. crescentus. Our results show that the biosynthesis of stalk peptidoglycan involves a dedicated peptidoglycan biosynthetic complex that combines specific components of the divisome and elongasome, suggesting that the repurposing of pre-existing machinery provides a straightforward means to evolve new morphological traits.
Structure-activity relationship of flavin analogs that target the FMN riboswitch
Authors: Vicens Quentin , Mondragón Estefanía , Reyes Francis E. , Coish Philip , Berman Paul Aristoff Judd , Kaur Harpreet , Kells Kevin W. , Wickens Phil , Wilson Jeffery , Gadwood Robert C. , Schostarez Heinrich J. , Suto Robert K. , Blount Kenneth F. , Batey Robert T.
Published: August 2018

The flavin mononucleotide (FMN) riboswitch is an emerging target for the development of novel RNA-targeting antibiotics. We previously discovered an FMN derivative —5FDQD— that protects mice against diarrhea-causingClostridium difficilebacteria. Here, we present the structure-based drug design strategy that led to the discovery of this fluoro-phenyl derivative with antibacterial properties. This approach involved the following stages: (1) structural analysis of all available free and bound FMN riboswitch structures; (2) design, synthesis and purification of derivatives; (3)in vitrotesting for productive binding using two chemical probing methods; (4)in vitrotranscription termination assays; (5) resolution of the crystal structures of the FMN riboswitch in complex with the most mature candidates. In the process, we delineated principles for productive binding to this riboswitch, thereby demonstrating the effectiveness of a coordinated structure-guided approach to designing drugs against RNA.

GRAPHICAL ABSTRACT

Exploring the chemical structure landscape of FMN riboswitch binders.
Discovery of allele-specific protein-RNA interactions in human transcriptomes
Authors: Bahrami-Samani Emad , Xing Yi
Published: August 2018

Gene expression is tightly regulated at the post-transcriptional level through splicing, transport, translation, and decay. RNA-binding proteins (RBPs) play key roles in post-transcriptional gene regulation, and genetic variants that alter RBP-RNA interactions can affect gene products and functions. We developed a computational method ASPRIN (Allele-Specific Protein-RNA Interaction), that uses a joint analysis of CLIP-seq (cross-linking and immunoprecipitation followed by high-throughput sequencing) and RNA-seq data to identify genetic variants that alter RBP-RNA interactions by directly observing the allelic preference of RBP from CLIP-seq experiments as compared to RNA-seq. We used ASPRIN to systematically analyze CLIP-seq and RNA-seq data for 166 RBPs in two ENCODE (Encyclopedia of DNA Elements) cell lines. ASPRIN identified genetic variants that alter RBP-RNA interactions by modifying RBP binding motifs within RNA. Moreover, through an integrative ASPRIN analysis with population-scale RNA-seq data, we showed that ASPRIN can help reveal potential causal variants that affect alternative splicing via allele-specific protein-RNA interactions.
AlleleHMM: a data-driven method to identify allele-specific differences in distributed functional genomic marks
Authors: Chou Shao-Pei , Danko Charles G.
Published: August 2018

How DNA sequence variation influences gene expression remains poorly understood. Diploid organisms have two homologous copies of their DNA sequence in the same nucleus, providing a rich source of information about how genetic variation affects a wealth of biochemical processes. However, few computational methods have been developed to discover allele-specific differences in functional genomic data. Existing methods either treat each SNP independently, limiting statistical power, or combine SNPs across gene annotations, preventing the discovery of allele specific differences in unexpected genomic regions. Here we introduce AlleleHMM, a new computational method to identify blocks of neighboring SNPs that share similar allele-specific differences in mark abundance. AlleleHMM uses a hidden Markov model to divide the genome among three hidden states based on allele frequencies in genomic data: a symmetric state (state ‘S’) which shows no difference between alleles, and regions with a higher signal on the maternal (state M) or paternal (state P) allele. AlleleHMM substantially outperformed naive methods using both simulated and real genomic data, particularly when input data had realistic levels of overdispersion. Using PRO-seq data, AlleleHMM identified thousands of allele specific blocks of transcription in both coding and non-coding genomic regions. AlleleHMM is a powerful tool for discovering allele-specific regions in functional genomic datasets.
RNAmountAlign: efficient software for local, global, semiglobal pairwise and multiple RNA sequence/structure alignment
Authors: Bayegan Amir H , Clote Peter
Published: August 2018

Alignment of structural RNAs is an important problem with a wide range of applications. Since function is often determined by molecular structure, RNA alignment programs should take into account both sequence and base-pairing information for structural homology identification. A number of successful alignment programs are heuristic versions of Sankoff’s optimal algorithm. Most of them require O(n4) run time. This paper describes C++ software, RNAmountAlign, for RNA sequence/structure alignment that runs in O(n3) time and O(n2) space; moreover, our software returns a p-value (transformable to expect value E) based on Karlin-Altschul statistics for local alignment, as well as parameter fitting for local and global alignment. Using incremental mountain height, a representation of structural information computable in cubic time, RNAmountAlign implements quadratic time pairwise local, global and global/semiglobal (query search) alignment using a weighted combination of sequence and structural similarity. RNAmountAlign is capable of performing progressive multiple alignment as well. Benchmarking of RNAmountAlign against LocARNA, LARA, FOLDALIGN, DYNALIGN and STRAL shows that RNAmountAlign has reasonably good accuracy and much faster run time supporting all alignment types.

Availability

RNAmountAlign is publicly available at http://bioinformatics.bc.edu/clotelab/RNAmountAlign.
Functional proteomic atlas of HIV-infection in primary human CD4+ T cells
Authors: Naamati Adi , Williamson James C , Greenwood Edward JD , Marelli Sara , Lehner Paul J , Matheson Nicholas J
Published: August 2018

Viruses manipulate host cells to enhance their replication, and the identification of host factors targeted by viruses has led to key insights in both viral pathogenesis and cellular physiology. We previously described global changes in cellular protein levels during human immunodeficiency virus (HIV) infection using transformed CEM-T4 T cells as a model. In this study, we develop an HIV reporter virus displaying a streptavidin-binding affinity tag at the surface of infected cells, allowing facile one-step selection with streptavidin-conjugated magnetic beads. We use this system to obtain pure populations of HIV-infected primary human CD4+ T cells for detailed proteomic analysis, including quantitation of >9,000 proteins across 4 different donors, and temporal profiling during T cell activation. Remarkably, amongst 650 cellular proteins significantly perturbed during HIV infection of primary T cells (q<0.05), almost 50% are regulated directly or indirectly by the viral accessory proteins Vpr, Vif, Nef and Vpu. The remainder have not been previously characterised, but include novel Vif-dependent targets FMR1 and DPH7, and 192 targets not identified and/or regulated in T cell lines, such as AIRD5A and PTPN22. We therefore provide a high-coverage functional proteomic atlas of HIV infection, and a mechanistic account of HIV-dependent changes in its natural target cell.
Development of whole-porcine monoclonal antibodies with potent neutralization activity against classical swine fever virus (CSFV) from single B cells
Authors: Dong Haisi , Lv Dongmei , Su Ang , Ma Lerong , Dong Jianwei , Guo Nannan , Ren Linzhu , Jiao Huping , Pang Daxin , Ouyang Hongsheng
Published: August 2018

Classical swine fever (CSF) is a highly contagious swine disease found worldwide that has caused devastating economic losses. However, there are few efficacious mAbs against the CSF virus (CSFV) that can be used for treatment because most mAbs against CSFV are derived from mouse hybridoma cells and these murine mAbs have disadvantages of inefficient effector functions elicitations and high immunogenicity in vivo. Accordingly, we characterized whole-porcine anti-CSFV neutralizing mAbs (NAbs) isolated directly from single B cells sorted from a CSFV-vaccinated pig using the fluoresceinated conserved linear neutralizing epitope of the CSFV E2 protein and fluorophore conjugated goat anti-pig IgG. Immunoglobulin (Ig) genes were isolated via nested PCR, and two porcine mAbs termed HK24 and HK44 were produced. We determined that these mAbs can bind to E2 protein and recognize sites within this major antigenic epitope. In addition, we found that mAbs HK24 and HK44 exhibit potent neutralizing activity against CSFV, and they can protect PK-15 cells from infections in vitro with potent IC50 values of 9.3 μg/ml and 0.62 μg/ml, respectively. Notably, we demonstrated that these two mAbs can be used as novel reagents for detecting virus infection. These data suggest that our results not only provide a method for efficiently obtaining mAbs against CSFV but also offer promising mAb candidates for development of antibody-based diagnostic and antiviral agents.

Importance

Neutralizing monoclonal antibodies (NAbs) can prevent and may slow the spread of virus infection. The discovery of NAbs that recognize classical swine fever virus (CSFV) necessitates new technologies because the NAbs produced by immunization and hybridoma technology could not be transferred to in vivo research. Multiple full-length human therapeutic antibodies have been produced via single-cell polymerase chain reactions but whole-porcine NAbs for CSFV have not been generated. In this study, two whole-porcine mAbs, named HK24 and HK44, were isolated from epitope-specific single B cells. We demonstrate that these two mAbs have potent neutralizing activity against CSFV and can protect cells against viral infection. Therefore, they may facilitate the development of vaccines or antiviral drugs that offer the advantages of stability and low immunogenicity.
The C-terminal tail of the bacterial translocation ATPase SecA modulates its activity
Authors: Jamshad Mohammed , Knowles Timothy J. , White Scott A. , Ward Douglas G. , Mohammed Fiyaz , Rahman Kazi , Hughes Gareth W. , Kramer Günter , Bukau Bernd , Huber Damon
Published: August 2018

In bacteria, the translocation of a subset of proteins across the cytoplasmic membrane by the Sec machinery requires SecA. Although SecA can recognise nascent polypeptides, the mechanism of cotranslational substrate protein recognition is not known. Here, we investigated the role of the C-terminal tail (CTT) of SecA, which consists of a flexible linker (FLD) and a small metal-binding domain (MBD), in its interaction with nascent polypeptides. Phylogenetic analysis and ribosome binding experiments indicated that the MBD interacts with 70S ribosomes. Disruption of the entire CTT or the MBD alone had opposing effects on ribosome binding, substrate-protein binding, ATPase activity and in vivo function. Autophotocrosslinking, mass spectrometry, x-ray crystallography and small-angle x-ray scattering experiments provided insight into the CTT-mediated conformational changes in SecA. Finally, photocrosslinking experiments indicated that binding of SecA to substrate protein affected its interaction with the ribosome. Taken together, our results suggest a mechanism for substrate protein recognition.

Impact Statement

SecA is an evolutionarily conserved ATPase that is required for the translocation of a subset of proteins across the cytoplasmic membrane in bacteria. We investigated how SecA recognises its substrate proteins at the ribosome as they are still being synthesised (i.e. cotranslationally).
Kappa opioid receptor modulation on GABAergic inputs onto ventral periaqueductal gray dopamine neurons
Authors: Li Chia , Kash Thomas L.
Published: August 2018

The kappa opioid receptor (KOR) system has been implicated in regulation of many behaviors including pain. While there are numerous studies suggesting KOR-regulation of pain being mediated spinally, there have been reports of pain-like behaviors regulated by central KOR signaling. In particular, oxytocin-induced analgesia appears to be mediated by KOR receptors within the ventrolateral periaqueductal gray (vlPAG). The vlPAG is a brain region that has long been known to be involved in the regulation of pain. We recently found that dopamine (DA) neurons within the vlPAG represent a specific population of neurons that can regulate pain-like behaviors. In this study, we sought to determine the impact of KOR signaling on GABAergic inputs to the vlPAG DA neurons, and determine the mechanism of inhibition. We found that activation of KOR significantly reduced GABAergic transmission onto vlPAG DA neurons. In addition, our data suggest this effect is mediated pre-synaptically via the G-protein βγ subunit. These data suggest the possibility that KOR-activation disinhibits vlPAG dopamine neurons, which could lead to altered regulation of pain-related behaviors.
Impaired expected value computations in schizophrenia are associated with a reduced ability to integrate reward probability and magnitude of recent outcomes
Authors: Dennis Hernaus , Frank Michael J. , Brown Elliot C. , Brown Jaime K. , Gold James M. , Waltz James A.
Published: August 2018

Background

Motivational deficits in people with schizophrenia (PSZ) are associated with an inability to integrate the magnitude and probability of previous outcomes. The mechanisms that underlie probability-magnitude integration deficits, however, are poorly understood. We hypothesized that increased reliance on “value-less” stimulus-response associations, in lieu of expected value (EV)-based learning, could drive probability-magnitude integration deficits in PSZ with motivational deficits.

Methods

Healthy volunteers (n= 38) and PSZ (n=49) completed a reinforcement learning paradigm consisting of four stimulus pairs. Reward magnitude (3/2/1/0 points) and probability (90%/80%/20%/10%) together determined each stimulus’ EV. Following a learning phase, new and familiar stimulus pairings were presented. Participants were asked to select stimuli with the highest reward value.

Results

PSZ with high motivational deficits made increasingly less optimal choices as the difference in reward value (probability*magnitude) between two competing stimuli increased. Using a previously-validated computational hybrid model, PSZ relied less on EV (“Q-learning”) and more on stimulus-response learning (“actor-critic”), which correlated with SANS motivational deficit severity. PSZ specifically failed to represent reward magnitude, consistent with model demonstrations showing that response tendencies in the actor-critic were preferentially driven by reward probability.

Conclusions

Probability-magnitude deficits in PSZ with motivational deficits arise from underutilization of EV in favor of reliance on value-less stimulus-response associations. Consistent with previous work and confirmed by our computational hybrid framework, probability-magnitude integration deficits were driven specifically by a failure to represent reward magnitude. This work reconfirms the importance of decreased Q-learning/increased actor-critic-type learning as an explanatory framework for a range of EV deficits in PSZ.
Hierarchical Complexity of the Adult Human Structural Connectome
Authors: Smith Keith , Bastin Mark E. , Cox Simon R. , Hernández Maria C. Valdés , Wiseman Stewart , Escudero Javier , Sudlow Catherine
Published: August 2018

The structural network of the human brain has a rich topology which many have sought to characterise using standard network science measures and concepts. However, this characterisation remains incomplete and the non-obvious features of this topology have largely confounded attempts towards comprehensive constructive modelling. This calls for new perspectives. Hierarchical complexity is an emerging paradigm of complex network topology based on the observation that complex systems are composed of hierarchies within which the roles of hierarchically equivalent nodes display highly variable connectivity patterns. Here we test the hierarchical complexity of the human structural connectomes of a group of seventy-nine healthy adults. Binary connectomes are found to be more hierarchically complex than three benchmark random network models. This provides a new key description of brain structure, revealing a rich diversity of connectivity patterns within hierarchically equivalent nodes. Dividing the connectomes into four tiers based on degree magnitudes indicates that the most complex nodes are neither those with the highest nor lowest degrees but are instead found in the middle tiers. Spatial mapping of the brain regions in each hierarchical tier reveals consistency with the current anatomical, functional and neuropsychological knowledge of the human brain. The most complex tier (Tier 3) involves regions believed to bridge high-order cognitive (Tier 1) and low-order sensorimotor processing (Tier 2). We then show that such diversity of connectivity patterns aligns with the diversity of functional roles played out across the brain, demonstrating that hierarchical complexity can characterise functional diversity strictly from the network topology.
Hexokinase: A central player in the synergism of high-intensity intermittent exercise and every-other-day intermittent fasting regimen on energy metabolism adaptations
Authors: Real-Hohn Antonio , Navegantes Clarice , Ramos Katia , Ramos-Filho Dionisio , Cahuê Fábio , Galina Antonio , Salerno Verônica P.
Published: August 2018

Visceral lipid accumulation, organ hypertrophy and a reduction in skeletal muscle strength are all signs associated with the severity of obesity related disease. Intermittent fasting (IF) and high-intensity intermittent exercise (HIIE) are natural strategies that, individually, can prevent and ameliorate obesity along with metabolic syndrome and its associated diseases. However, the combinatorial effect of IF and HIIF on energetic metabolism is currently not well understood. We hypothesized that their combination could have a potential for more than strictly additive benefits. Here, we show that two months of every-other-day intermittent fasting regimen combined with a high-intensity intermittent exercise protocol (IF/HIIE) produce a synergetic effect, preventing fat accumulation, enhancing physical performance and optimizing energy production. The IF/HIIE group presented increased glucose uptake, lower levels of serum insulin and a global activation of hexokinases in skeletal muscle, heart and liver comparing to control, IF and HIIE groups. IF/HIIE synergism led to activation of the FoF1 ATP synthase and promoted a more oxidative profile of mitochondria in observed skeletal muscle. Additionally, high-resolution respirometry of muscle fibers showed that animals in the IF/HIIE group presented characteristics suggestive of augmented mitochondrial mass and efficiency. Finally, an important reduction in serum oxidative stress markers were observed in IF/HIIE group. These findings provide new insights for the implementation of non-pharmaceutical strategies to prevent/treat metabolic syndrome and associated diseases.
Mitochondrial hypoxic stress induces widespread RNA editing by APOBEC3G in lymphocyte
Authors: Sharma Shraddha , Wang Jianmin , Portwood Scott , Cortes-Gomez Eduardo , Maguire Orla , Basse Per H. , Wang Eunice S. , Baysal Bora E.
Published: August 2018

Protein recoding by RNA editing is required for normal health and evolutionary adaptation. However, de novo induction of RNA editing in response to environmental factors is an uncommon phenomenon. While APOBEC3A edits many mRNAs in monocytes/macrophages in response to hypoxia and interferons, the physiological significance of such editing is unclear. Here we show that the related APOBEC3G cytidine deaminase induces site-specific C-to-U RNA editing in natural killer (NK), CD8+ T cells and lymphoma cell lines upon cellular crowding and hypoxia. RNASeq analysis of hypoxic NK cells reveals widespread C-to-U recoding mRNA editing that is enriched for genes involved in mRNA translation. APOBEC3G promotes Warburg-like metabolic remodeling and reduces proliferation of HuT78 T cells under similar conditions. Hypoxia-induced RNA editing by APOBEC3G can be mimicked by the inhibition of mitochondrial respiration, and occurs independently of HIF-1α. Thus, APOBEC3G is an endogenous RNA editing enzyme, which is induced by mitochondrial hypoxic stress to promote adaptation in lymphocytes.
How social influence and personality affect users’ social network fatigue and discontinuance behavior
Authors: Shokouhyar Sajad , Siadat Seyed Hossein , Razavi Mojde Khazeni
Published: August 2018

Purpose

The purpose of this paper is to focus on understanding how social influence and personality of individuals differentiate between users’ social network fatigue and discontinuance behavior. Furthermore, the most common discontinuance behavior among users was investigated.

Design/methodology/approach

The research model was tested with the data from 163 Instagram users based on online and offline surveys. The partial least squares method was used to test the proposed hypotheses of this study.

Findings

The results indicate that social influence affects users’ discontinuance behavior and social network fatigue. Social network fatigue is greater in users with higher reported social influence compared to those with a lower one. Moreover, in response to social network fatigue, users prefer to keep their activities under control instead of switching to alternative social network sites (SNSs) or a short break in social network activities.

Practical implications

By achieving a better understanding of users’ feeling and behaviors, social network providers may codify their strategies more efficiently.

Originality/value

The study is novel in exploring users’ SNS fatigue and their discontinuance behavior by integrating social influence and personality. The authors defined a new concept of effect of social influence on social network fatigue. Additionally, the authors examined which discontinuance behaviors in individuals were more prevalent.
Internet of Things adoption for reconfiguring decision-making processes in asset management
Authors: Brous Paul , Janssen Marijn , Herder Paulien
Published: August 2018

Purpose

Managers are increasingly looking to adopt the Internet of Things (IoT) to include the vast amount of big data generated in their decision-making processes. The use of IoT might yield many benefits for organizations engaged in civil infrastructure management, but these benefits might be difficult to realize as organizations are not equipped to handle and interpret this data. The purpose of this paper is to understand how IoT adoption affects decision-making processes.

Design/methodology/approach

In this paper the changes in the business processes for managing civil infrastructure assets brought about by IoT adoption are analyzed by investigating two case studies within the water management domain. Propositions for effective IoT adoption in decision-making processes are derived.

Findings

The results show that decision processes in civil infrastructure asset management have been transformed to deal with the real-time nature of the data. The authors found the need to make organizational and business process changes, development of new capabilities, data provenance and governance and the need for standardization. IoT can have a transformative effect on business processes.

Research limitations/implications

Because of the chosen research approach, the research results may lack generalizability. Therefore, researchers are encouraged to test the propositions further.

Practical implications

The paper shows that data provenance is necessary to be able to understand the value and the quality of the data often generated by various organizations. Managers need to adapt new capabilities to be able to interpret the data.

Originality/value

This paper fulfills an identified need to understand how IoT adoption affects decision-making processes in asset management in order to be able to achieve expected benefits and mitigate risk.