bluuebunny/crossref_metadata_2025 huggingface dataset:
Classic Vulvar Intraepithelial Neoplasia With Superimposed Lichen Simplex Chronicus: A Unique Variant Mimicking Differentiated Vulvar Intraepithelial Neoplasia
Authors: Watkins Jaclyn C. , Yang Eric , Crum Christopher P. , Herfs Michael , Gheit Tarik , Tommasino Massimo , Nucci Marisa R.
Published: May 2018

High-grade vulvar intraepithelial neoplasia, a precursor lesion to vulvar squamous cell carcinoma, is subdivided into 2 types, classic or usual vulvar intraepithelial neoplasia (CVIN) and differentiated vulvar intraepithelial neoplasia (DVIN). CVIN, which is a human papilloma virus (HPV)-dependent lesion, is typically distinguished from DVIN, a p53 mutation-dependent process, by its distinct histomorphologic and immunohistochemical characteristics. However, distinguishing between the 2 entities becomes challenging in cases of CVIN with superimposed inflammatory changes, especially lichen simplex chronicus (LSC). Twelve cases of DVIN, 9 cases of LSC, and 9 cases of CVIN with superimposed LSC were assessed for a number of morphologic features, including hyperkeratosis, hypergranulosis, acanthosis, hypercellularity, abnormal maturation (i.e. abnormal keratinization close to the base and/or dyskeratosis), hyperchromasia, and basal atypia. Immunohistochemistry for p53, p16, and MIB-1 was performed for all cases. When sufficient tissue was available, HPV genotyping was performed for cases of CVIN with superimposed LSC. DVIN uniformly demonstrated abnormal maturation, and atypia involving the basal cell layer; they were all p16 negative and demonstrated p53 positivity of moderate to strong intensity in a basal and parabasal distribution. CVIN with superimposed LSC frequently displayed hyperchromasia involving the basal 3 to 4 cell layers, basal to full-thickness atypia, and apoptosis. CVIN with superimposed LSC demonstrated intense p16 positivity extending from the basal cells to the mid-epithelium and a reduction or loss of staining in maturing keratinocytes. P53 staining revealed a unique pattern of parabasal and mid-epithelial weak to moderate staining with sparing of the basal layer. Cases of LSC demonstrated heterogenous p53 positivity and were negative for p16. MIB-1 staining showed a similar range of positivity for all diagnoses. HPV genotyping revealed HPV 16 in all 5 cases of CVIN with LSC that underwent testing. We conclude that, although CVIN with superimposed LSC can closely resemble DVIN, morphologic features such as nuclear hyperchromasia uniformly involving the basal 3 to 4 cell layers, apoptosis, and absent or less pronounced cytoplasmic maturation are more suggestive of CVIN with superimposed LSC. In cases where the morphology remains ambiguous, immunohistochemistry for both p16 and p53 can be helpful. In particular, p53 parabasal and mid-epithelial staining without involvement of the basal layer appears to be a characteristic finding in CVIN with superimposed LSC. MIB-1 staining is of little utility in distinguishing between these entities and should not be routinely performed.
An Epithelioid Smooth Muscle Neoplasm Mimicking a Signet Ring Cell Carcinoma in the Ovary
Authors: Xing Deyin , Berrebi Alexander A. , Liu Chengbao , Richmond Abby , Vang Russell , Ronnett Brigitte M.
Published: May 2018

A 53-yr-old woman who presented with elevated renal indices was discovered to have a 4.5 cm right renal mass and an incidental 9.7 cm left ovarian mass on imaging studies. She underwent a partial nephrectomy and bilateral salpingo-oophorectomy, revealing a chromophobe renal cell carcinoma and an unusual ovarian neoplasm with epithelioid cells displaying prominent signet ring cell-like morphology. Immunohistochemical analysis of the ovarian neoplasm demonstrated that the tumor cells were diffusely immunoreactive for smooth muscle markers and negative for all tested cytokeratins and epithelial membrane antigen. On the basis of these results, the tumor was interpreted as an unusual epithelioid smooth muscle neoplasm with extensive signet ring cell-like features. Along with primary ovarian signet ring stromal tumors and sclerosing stromal tumors, this example adds epithelioid smooth muscle neoplasms with unusual cytologic alterations to the list of uncommon nonepithelial tumors that can simulate metastatic signet ring cell carcinoma (Krukenberg tumor) in the ovary.
First-in-human randomized clinical trials of the safety and efficacy of tanezumab for treatment of chronic knee osteoarthritis pain or acute bunionectomy pain
Authors: Walicke Patricia A. , Hefti Franz , Bales Roxanne , Lu Shiao-Ping , Ruckle Jon L. , Brown Mark T. , West Christine R. , Shelton David L.
Published: May 2018

Introduction:

The neurotrophin nerve growth factor has a demonstrated role in pain transduction and pathophysiology.

Objectives:

Two randomized, double-blind, placebo-controlled, phase 1 studies were conducted to evaluate safety, tolerability, and analgesic efficacy of single doses of tanezumab, a humanized anti–nerve growth factor monoclonal antibody, in chronic or acute pain.

Methods:

In the first study (CL001), patients with moderate to severe pain from osteoarthritis (OA) of the knee received a single intravenous infusion of tanezumab (3–1000 μg/kg) or placebo in a dose-escalation (part 1; N = 42) or parallel-arm (part 2; N = 79) study design. The second study (CL002) was a placebo-controlled dose-escalation (tanezumab 10–1000 μg/kg; N = 50) study in patients undergoing bunionectomy surgery.

Results:

Adverse event rates were generally similar across treatments. Most adverse events were generally mild to moderate in severity and no patients discontinued as a result of adverse events. Adverse events of abnormal peripheral sensation were more common with higher doses of tanezumab (≥100 μg/kg) than with placebo. These were generally mild to moderate in severity. Tanezumab provided up to 12 weeks of effective analgesia for OA knee pain, with statistically significant improvements at doses ≥100 μg/kg (P < 0.05). By contrast, no trend for analgesic activity was found when tanezumab was administered 8 to 16 hours before bunionectomy.

Conclusions:

The demonstration of a favorable safety profile and clinical efficacy in OA pain supports clinical development of tanezumab as a potential treatment for chronic pain conditions.
Role of letermovir for prevention of cytomegalovirus infection after allogeneic haematopoietic stem cell transplantation
Authors: Razonable Raymund R.
Published: May 2018

Purpose of review

Cytomegalovirus (CMV) infection is a common opportunistic infection after allogeneic haematopoietic stem cell transplantation (HSCT). CMV surveillance-preemptive therapy is the current preferred approach for preventing CMV disease after HSCT. In contrast, antiviral prophylaxis is not commonly used due to myelosuppressive effects of valganciclovir. In this article, the role of the newly approved antiviral compound, letermovir, is reviewed.

Recent findings

Letermovir inhibits CMV by interfering viral terminase complex. In a phase 3 randomized placebo-controlled clinical study that enrolled 495 CMV-seropositive HSCT recipients, the primary end point of clinically significant CMV infection was significantly reduced by letermovir prophylaxis. Letermovir was well tolerated without risk of myelotoxicity and nephrotoxicity. Experimental in-vitro data suggest that letermovir may possess low genetic barrier to resistance. In prophylaxis trials, two breakthrough infections were reported due to selection of CMV UL56 V236M mutation.

Letermovir is an important addition to the current strategies for CMV prevention after allogeneic HSCT. Its favourable efficacy and safety profile re-opens door for antiviral prophylaxis another first-line option, similar to CMV surveillance-preemptive therapy, for preventing CMV in allogeneic HSCT recipients.
Quality and Safety in Health Care, Part XXXIX
Authors: Harolds Jay A.
Published: May 2018

Models to predict patient risk in undergoing a percutaneous coronary intervention (PCI) have been put forward by authors studying data from the CathPCI Registry. CathPCI data can be used to improve processes and decrease the rate of complications. Outcome data from the CathPCI Registry can be used to assess not only institutional performance but also the performance of the physicians performing the PCI. CathPCI data can also be used to assess the complication rate from various types of vascular closure devices.
Quality and Safety in Health Care, Part XXXVIII
Authors: Harolds Jay A.
Published: May 2018

The CathPCI Registry was started in 1998 to improve health quality for those patients having a percutaneous coronary intervention or diagnostic cardiac catheterization. This registry studies complications, outcomes from placing coronary artery stents of different types, appropriateness of performing the procedures, special indications for performing the procedures, safety of devices, patient characteristics, possible relationships between volume of procedures and quality, models to adjust for patient risk, and so on. The registry encourages using the information to promote research and quality improvement and public reporting of the data.
Right Ureteral Carcinoma Suggested by 99mTc-DTPA Renography in a Patient With Left Pyelocaliceal Carcinoma
Authors: Wang Wei , Yuan Leilei , Kan Ying , Liu Jie , Yang Jigang
Published: May 2018

Abdominal enhanced CT of a 72-year-old woman demonstrated 1 enhancing lesion in the left kidney, which suggested malignancy. No significant findings were reported in the right kidney and ureter. A 99mTc-DTPA renography was performed as part of the presurgical evaluation. However, the dynamics of urine elimination by the left kidney was normal, whereas elimination of the urine on the right one delayed, which was unexpected. The patient's CT images were further analyzed. An enhancing lesion in the right ureter was noted by further review, suggesting malignancy, which was subsequently pathologically proven as low-grade papillary urothelial carcinoma.
18F-FDG PET/CT in Anti-NMDA Receptor Encephalitis
Authors: Moubtakir Abdenasser , Dejust Sébastien , Godard François , Messaoud Leila , Morland David
Published: May 2018

We report the case of a 28-year-old woman presenting behavior disorders of subacute onset. She was referred in our institution for a suspicion of limbic encephalitis. 18F-FDG PET/CT did not show any mesiotemporal abnormality but depicted a decreased uptake of bilateral parietal and occipital lobes. This atypical pattern was compatible with an anti-N-methyl-D-aspartate receptor encephalitis that was later confirmed.
Progression of Multiple Myeloma Detected on Cardiac Scintigraphy with 99mTc Sestamibi
Authors: Bulzan Jonathan , Revels Jonathan , Byun Kathy
Published: May 2018

It is important to understand normal and abnormal radiotracer biodistribution patterns in patients who undergo cardiac 99mTc-2-methoxyisobutyl-isonitrile (99mTc-sestamibi) scans to provide important clinical guidance. Our case describes a 75-year-old man with a history of multiple myeloma in remission, who presented to the emergency department for unrelated chest pain and shortness of breath. The patient underwent a nuclear cardiac stress test with 99mTc-sestamibi scintigraphy as part of his cardiac workup. The images demonstrated diffuse radiotracer uptake in the skeletal structures raising concern for progression of multiple myeloma, of which, subsequent biopsy confirmed the presence of recurrent disease.
Two Different Causes of Decreased Activity on Ipsilateral Iliac Artery in Renal Transplant Scintigraphy
Authors: Yazici Bulent , Oral Aylin , Yilmaz Mumtaz , Akgün Aysegül , Toz Huseyin
Published: May 2018

In 2 patients, perfusion images of renal transplant scintigraphy showed similarly decreased activity on ipsilateral iliac artery. One's graft was photopenic because of arterial thrombosis. However, the other's graft had sufficient perfusion and no abnormality in iliac arteries, but he had femoral arteriovenous graft for hemodialysis on the contralateral side. So, in this patient, decreased activity on ipsilateral iliac artery was probably related to increased arterial flow of the contralateral side. It should be considered that decreased activity on ipsilateral iliac artery in perfusion images is not only due to ipsilateral problem; the cause could be on the contralateral side.
The Detection of Uterine Leiomyoma (Fibroid) Calcifications on 18F-NaF PET/CT
Authors: Al-Zaghal Abdullah , Werner Thomas J. , Høilund-Carlsen Poul F. , Alavi Abass
Published: May 2018

Uterine leiomyomas (fibroids) are the most common type of uterine neoplasms in premenopausal women. Leiomyomas are estrogen dependent and tend to atrophy and shrink in size after menopause. Dystrophic calcification, cystic changes, and necrosis are among the changes that indicate uterine fibroid involution. We are presenting a calcified uterine leiomyoma in a 61-year-old woman as incidentally detected on 18F-NaF PET/CT scanning. Many previous publications have reported the accumulation of 18F-NaF in soft tissue calcifications; these findings further set new directions in the evaluation of the metabolic activity of macrocalcification and microcalcification using molecular imaging probes.
Solitary Breast Metastasis From Rhabdomyosarcoma Shown on FDG PET/CT
Authors: Bai Xia , Wang Xuemei
Published: May 2018

Rhabdomyosarcoma rarely metastasizes to breast. A 15-year-old adolescent girl underwent FDG PET/CT scan for staging a newly diagnosed alveolar rhabdomyosarcoma. The images showed not only the abnormal activity in the region of the right maxillary sinus, consistent with the known primary tumor, but also an intense focal activity in the right breast. The right breast lesion was excised, and the pathological results showed alveolar rhabdomyosarcoma.
Capillary Hemangioma as an Unusual Cause of Doughnut Sign on Bone Scan
Authors: Samarah Omar Q. , Tayyem Mohammad I. , Abu shahin Nisreen , AlMuhaisen Ghadeer , Juweid Malik E.
Published: May 2018

Abstracts

A 28-year-old woman presented with a mass in her right leg, which, on plain radiograph, appeared as a lytic lesion in the mid-shaft of the tibia with cortical thinning but without periosteal reaction. 99mTc-MDP 3-phase bone scan demonstrated intense uptake in the periphery of the mass with a photopenic center, the so-called doughnut sign. Histopathology revealed a capillary hemangioma. This case demonstrates that the doughnut sign on bone scan can be caused by capillary hemangioma in addition to other reported bone pathologies, including aneurysmal bone cyst, giant cell tumor, and telangiectatic osteosarcoma.
Lymphangioma on 68Ga-NOTA-Evans Blue PET/MRI
Authors: Hou Guozhu , Li Xiaoqing , Hou Bo , Zhou Weixun , Cheng Wuying
Published: May 2018

A 17-year-old adolescent boy with a history of hypoproteinemia underwent 68Ga-NEB PET/MRI to evaluate possible lymphatic disorders suggested by FDG PET/CT imaging. The images revealed multiple lesions with increased 68Ga-NEB uptake and high signal on T2-weighted images, consistent with likely lymphatic disorder. Histopathological examination from biopsied specimen confirmed lymphangioma.
Dietary Cellulose Supplementation Modulates the Immune Response in a Murine Endotoxemia Model
Authors: Di Caro Valentina , Cummings Jessica L. , Alcamo Alicia M. , Piganelli Jon D. , Clark Robert S.B. , Morowitz Michael J. , Aneja Rajesh K.
Published: May 2018

The role of dietary fiber in chronic inflammatory disorders has been explored, but very little is known about its benefits in acute inflammation. Previously, we have demonstrated that dietary cellulose supplementation confers protection in a murine model of sepsis by promoting the growth of the gut microbiota that are linked to metabolic health. The survival benefit is associated with a decrease in serum concentration of proinflammatory cytokines, reduced neutrophil infiltration in the lungs, and diminished hepatic inflammation. Here, we aim to understand if the benefit of manipulating the gut microbiome exerts a broader “systemic” influence on the immune system in a lethal murine endotoxemia model. We hypothesize that mice-fed high-fiber cellulose (HF) diet will demonstrate a reduction in activated macrophages and dendritic cells (DCs) and a concomitant increase in the suppressive capacity of T-regulatory cells (Tregs) toward T cells responsiveness. We characterized the immunological profile and activation status of macrophages, DCs, and T cells in mice on HF diet that were then subjected to endotoxemia. Supplementation with HF diet decreased the number and activation of splenic macrophages and DCs in mice after LPS administration. Similarly, HF diet amplified the suppressive function of Tregs and induced anergy in T cells as compared with mice on a regular diet. Our data suggest that the use of HF diet can be a simple, yet effective tool that decreases the hepatic DNA-binding activity of NF-κB leading to a reduction in proinflammatory cytokine response in a murine endotoxemia model.
Female Veterans With Diagnoses of Both Chronic Pelvic Pain and Overactive Bladder; How Do They Compare to Women Diagnosed With Interstitial Cystitis?
Authors: Volpe Katherine A. , Cichowski Sara B. , Komesu Yuko K. , Rogers Rebecca G. , Murata Allison , Murata Glen
Published: May 2018

Objective

The objective of this study was to compare women with a known diagnosis of interstitial cystitis (IC) to a population that might be at risk for the diagnosis of IC, women with diagnoses of both chronic pelvic pain (CPP) and overactive bladder (OAB).

Methods

We conducted a retrospective study of data from the Veterans Affairs Corporate Data Warehouse. The cohort included all female veterans who had established care with a primary care provider from 1997 to present. International Classification of Diseases, Ninth Revision codes were used to identify women with a diagnosis of IC, CPP, and OAB. Demographic data and comorbidities were compared between groups.

Results

A total of 596,815 women were identified. Two thousand three hundred one women (0.4%) were diagnosed with IC; 4459 women (0.7%) were diagnosed with CPP and OAB. At baseline, women with OAB and CPP were more likely to identify as minority (P < 0.001). Anxiety (57.3% vs 49.5%), depression (39.0% vs 46.0%), and posttraumatic stress disorder (29.7 vs 26.4%) were all more common in the CPP and OAB group than in the IC group. In the multivariable model, women with CPP and OAB were more likely to identify as a minority, use tobacco, and carry a diagnosis of anxiety.

Conclusions

There were more patients diagnosed with CPP and OAB compared with patients diagnosed with IC in this population of female veterans. Given the high rate of comorbid anxiety and depression in both groups, further study is warranted to determine whether these women are misdiagnosed.
The changing landscape of motor neuron disease imaging: the transition from descriptive studies to precision clinical tools
Authors: Bede Peter , Querin Giorgia , Pradat Pierre-François
Published: May 2018

Purpose of review

Neuroimaging in motor neuron disease (MND) has traditionally been seen as an academic tool with limited direct relevance to individualized patient care. This has changed radically in recent years as computational imaging has emerged as a viable clinical tool with true biomarker potential. This transition is not only fuelled by technological advances but also by important conceptual developments.

Recent findings

The natural history of MND is now evaluated by presymptomatic, postmortem and multi-timepoint longitudinal imaging studies. The anatomical spectrum of MND imaging has also been expanded from an overwhelmingly cerebral focus to innovative spinal and muscle applications. In contrast to the group-comparisons of previous studies, machine-learning and deep-learning approaches are increasingly utilized to model real-life diagnostic dilemmas and aid prognostic classification. The focus from evaluating focal structural changes has shifted to the appraisal of network integrity by connectivity-based approaches. The armamentarium of MND imaging has also been complemented by novel PET-ligands, spinal toolboxes and the availability of magnetoencephalography and high-field magnetic resonance (MR) imaging platforms.

In addition to the technological and conceptual advances, collaborative multicentre research efforts have also gained considerable momentum. This opinion-piece reviews emerging trends in MND imaging and their implications to clinical care and drug development.
Tourette syndrome: clinical spectrum, mechanisms and personalized treatments
Authors: Hartmann Andreas , Worbe Yulia
Published: May 2018

Purpose of review

To describe recent advances regarding the disease spectrum in Tourette syndrome, offer new mechanistic insights into tic generation and provide clues for personalized treatments in this disorder.

Recent findings

Apart from tics, which define Tourette syndrome, comorbidities are the rule and not the exception. They significantly define clinical presentation, disease severity and quality of life. Recent studies have highlighted the importance of screening for depression, anxiety and autism spectrum disorders in Tourette syndrome. Regarding the mechanisms of tic generation, computational models begin to emerge and provide important clues regarding the cerebral regions and networks involved, as well as information on the nature of neurotransmitter signaling, for instance phasic versus tonic dopamine release. Also, these models may inform on generation or termination of premonitory urges which underlie tic generation. Finally, personalized treatments in Tourette syndrome are both necessary because of the width of the clinical spectrum, making every patient unique from a symptom-oriented perspective; yet, difficult to achieve because of the lack of large prospective cohorts which may inform on prognostic factors and disease-modifying interventions. However, interesting developments, especially in the fields of behavioral therapy and deep brain stimulation, deserve mention and pave the way for tailored treatments in Tourette syndrome.

The recent literature offers interesting clues that sharpen our understanding of comorbidities in Tourette disorder and thereby its clinical spectrum, offers insights into the cerebral networks underlying tic generation and cautiously announces personalized interventions for Tourette disorder patients based on their symptom profile.
Movement disorders in mitochondrial disease: a clinicopathological correlation
Authors: Flønes Irene H. , Tzoulis Charalampos
Published: May 2018

Purpose of review

The scope of this review is to give an updated account of movement disorders associated with mitochondrial disease, with a particular focus on recently discovered clinicopathological correlations.

Recent findings

Movement disorders are common clinical manifestations of mitochondrial diseases, in part because of the high vulnerability of neurons controlling motor circuits to mitochondrial respiratory dysfunction and energy failure. Intriguingly, the clinicopathological correlations of movement disorders in mitochondrial disease do not always conform to established neurophysiological knowledge. In particular, nearly complete substantia nigra degeneration and nigrostriatal denervation can occur without being accompanied by any of the clinical signs traditionally associated with parkinsonism. This apparent paradox, may be because of compensation by concomitant impairment of other motor circuits involving the cerebellum and thalamus.

Movement disorders commonly accompany mitochondrial disease and may show paradoxical clinical−anatomical correlations. Further research is warranted in order to elucidate the mechanisms underlying the phenotypic expression of movement disorders in mitochondrial disease. This knowledge will advance our understanding of the pathogenesis of movement disorders in a broader clinical and pathophysiological context.
The Shifting Landscape of Disease-Modifying Therapies for Relapsing Multiple Sclerosis
Authors: Burton Jodie M. , Freedman Mark S.
Published: May 2018

Background:

Multiple sclerosis (MS) is the most common nontraumatic neurological disorder of young adults, and roughly 85% of patients present with the relapsing form of the disease. Over the past 2 decades, the treatment arsenal for relapsing MS has expanded and evolved from mildly effective and relatively benign injectable agents to potent cell-depleting monoclonal agents. The latter have the potential to achieve disease remission coupled with risk of moderate to severe adverse events with which all MS care providers will need to acquaint themselves.

Methods:

This review is based on a detailed assessment of MS pivotal trials, extension studies, and expert reviews of the agents discussed.

Results/Conclusions:

The following review should aid those practitioners directly and indirectly involved in the care of MS patients in understanding the benefits and risks associated with the medications they prescribe.
Magnetoencephalographic Mapping of Epileptic Spike Population Using Distributed Source Analysis: Comparison With Intracranial Electroencephalographic Spikes
Authors: Tanaka Naoaki , Papadelis Christos , Tamilia Eleonora , Madsen Joseph R. , Pearl Phillip L. , Stufflebeam Steven M.
Published: May 2018

Introduction:

This study evaluates magnetoencephalographic (MEG) spike population as compared with intracranial electroencephalographic (IEEG) spikes using a quantitative method based on distributed source analysis.

Methods:

We retrospectively studied eight patients with medically intractable epilepsy who had an MEG and subsequent IEEG monitoring. Fifty MEG spikes were analyzed in each patient using minimum norm estimate. For individual spikes, each vertex in the source space was considered activated when its source amplitude at the peak latency was higher than a threshold, which was set at 50% of the maximum amplitude over all vertices. We mapped the total count of activation at each vertex. We also analyzed 50 IEEG spikes in the same manner over the intracranial electrodes and created the activation count map. The location of the electrodes was obtained in the MEG source space by coregistering postimplantation computed tomography to MRI. We estimated the MEG- and IEEG-active regions associated with the spike populations using the vertices/electrodes with a count over 25.

Results:

The activation count maps of MEG spikes demonstrated the localization associated with the spike population by variable count values at each vertex. The MEG-active region overlapped with 65 to 85% of the IEEG-active region in our patient group.

Conclusions:

Mapping the MEG spike population is valid for demonstrating the trend of spikes clustering in patients with epilepsy. In addition, comparison of MEG and IEEG spikes quantitatively may be informative for understanding their relationship.
Modeling genome-wide evolution of catalytic turnover rates: Strong epistasis shaped modern enzyme kinetics
Authors: Heckmann David , Zielinski Daniel C. , Palsson Bernhard O.
Published: May 2018

Systems biology describes cellular phenotypes as properties that emerge from the complex interactions of individual system components. Little is known about how these interactions have affected the evolution of metabolic enzymes. To address this question, we combine genome-scale metabolic modelling with population genetics models to simulate the evolution of enzyme turnover numbers (kcats) from a theoretical ancestor with inefficient enzymes. This systems view of biochemical evolution reveals strong epistatic interactions between metabolic genes that shape evolutionary trajectories and influence the magnitude of evolvedkcats. A small number of biophysically constrained enzymes suffice to induce diminishing returns epistasis that prevents enzymes from developing higherkcats in all reactions and keeps the organism far from the potential fitness optimum. In addition, multifunctional enzymes cause synergistic epistasis that slows down adaptation. The resulting fitness landscape is smooth and causeskcatevolution to be convergent. Predictedkcatparameters show a significant correlation with experimental data onin vitroandin vivoturnover rates, validating our modelling approach. Our analysis thus suggests that enzyme evolution can be predicted on a genome scale and reveals the mechanisms by which evolutionary forces shape modernkcats and the whole of cell metabolism.
Gene Set Overlap: An Impediment to Achieving High Specificity in Over-representation Analysis
Authors: Maleki Farhad , Kusalik Anthony J.
Published: May 2018

Gene set analysis methods are widely used to analyze data from high-throughput “omics” technologies. One drawback of these methods is their low specificity or high false positive rate. Over-representation analysis is one of the most commonly used gene set analysis methods. In this paper, we propose a systematic approach to investigate the hypothesis that gene set overlap is an underlying cause of low specificity in over-representation analysis. We quantify gene set overlap and show that it is a ubiquitous phenomenon across gene set databases. Statistical analysis indicates a strong negative correlation between gene set overlap and the specificity of over-representation analysis. We conclude that gene set overlap is an underlying cause of the low specificity. This result highlights the importance of considering gene set overlap in gene set analysis and explains the lack of specificity of methods that ignore gene set overlap. This research also establishes the direction for developing new gene set analysis methods.
Escherichia coliZipA organizes FtsZ polymers into dynamic ring-like protofilament structures
Authors: Krupka Marcin , Sobrinos-Sanguino Marta , Jiménez Mercedes , Rivas Germán , Margolin William
Published: May 2018

ZipA is an essential cell division protein inEscherichia coli. Together with FtsA, ZipA tethers dynamic polymers of FtsZ to the cytoplasmic membrane, and these polymers are required to guide synthesis of the cell division septum. This dynamic behavior of FtsZ has been reconstituted on planar lipid surfacesin vitro, visible as GTP-dependent chiral vortices several hundred nm in diameter, when anchored by FtsA or when fused to an artificial membrane binding domain. However, these dynamics largely vanish when ZipA is used to tether FtsZ polymers to lipids at high surface densities. This, along with somein vitrostudies in solution, has led to the prevailing notion that ZipA reduces FtsZ dynamics by enhancing bundling of FtsZ filaments. Here, we show that this is not the case. When lower, more physiological levels of the soluble, cytoplasmic domain of ZipA (sZipA) were attached to lipids, FtsZ assembled into highly dynamic vortices similar to those assembled with FtsA or other membrane anchors. Notably, at either high or low surface densities, ZipA did not stimulate lateral interactions between FtsZ protofilaments. We also usedE. colimutants that are either deficient or proficient in FtsZ bundling to provide evidence that ZipA does not directly promote bundling of FtsZ filamentsin vivo. Together, our results suggest that ZipA does not dampen FtsZ dynamics as previously thought, and instead may act as a passive membrane attachment for FtsZ filaments as they treadmill.

IMPORTANCE

Bacterial cells use a membrane-attached ring of proteins to mark and guide formation of a division septum at mid-cell that forms a wall separating the two daughter cells and allows cells to divide. The key protein in this ring is FtsZ, a homolog of tubulin that forms dynamic polymers. Here, we use electron microscopy and confocal fluorescence imaging to show that one of the proteins required to attach FtsZ polymers to the membrane duringE. colicell division, ZipA, can promote dynamic swirls of FtsZ on a lipid surfacein vitro. Importantly, these swirls are only observed when ZipA is present at low, physiologically relevant surface densities. Although ZipA has been thought to enhance bundling of FtsZ polymers, we find little evidence for bundlingin vitro. In addition, we present several lines ofin vivoevidence indicating that ZipA does not act to directly bundle FtsZ polymers.
Beyond the SNP threshold: identifying outbreak clusters using inferred transmissions
Authors: Stimson James , Gardy Jennifer , Mathema Barun , Crudu Valeriu , Cohen Ted , Colijn Caroline
Published: May 2018

Whole genome sequencing (WGS) is increasingly used to aid in understanding pathogen transmission [1]. Very often the number of single nucleotide polymorphisms (SNPs) separating isolates collected during an epidemiological study are used to identify sets of cases that are potentially linked by direct transmission. However, there is little agreement in the literature as to what an appropriate SNP cut-off threshold should be, or indeed whether a simple SNP threshold is appropriate for identifying sets of isolates to be treated as “transmission clusters”. The SNP thresholds that have been adopted for inferring transmission vary widely even for one pathogen. As an alternative to reliance on a strict SNP threshold, we suggest that the key inferential target when studying the spread of an infectious disease is the number of transmission events separating cases. Here we describe a new framework for deciding whether two pathogen genomes should be considered as part of the same transmission cluster, based jointly on the number of SNP differences and the length of time over which those differences have accumulated. Our approach allows us to probabilistically characterize the number of inferred transmission events that separate cases. We show how this framework can be modified to consider variable mutation rates across the genome (e.g. SNPs associated with drug resistance) and we indicate how the methodology can be extended to incorporate epidemiological data such as spatial proximity. We use recent data collected from tuberculosis studies from British Columbia, Canada and the Republic of Moldova to apply and compare our clustering method to the SNP threshold approach. In the British Columbia data, different cases break off from the main clusters as cut-off thresholds are lowered; the transmission-based method obtains slightly different clusters than the SNP cut-offs. For the Moldova data, straightforward application of the methods shows no appreciable difference, but when we take into account the fact that resistance conferring sites likely do not follow the same mutation clock as most sites due to selection, the transmission-based approach differs from the SNP cut-off method. Outbreak simulations confirm that our transmission based method is at least as good at identifying direct transmissions as a SNP cut-off. We conclude that the new method is a promising step towards establishing a more robust identification of outbreaks.
Genome rearrangements and selection in multi-chromosome bacteria Burkholderia spp
Authors: Bochkareva Olga O , Moroz Elena V , Davydov Iakov I , Gelfand Mikhail S
Published: May 2018

Background

The genus Burkholderia consists of species that occupy remarkably diverse ecological niches. Its best known members are important pathogens, B. mallei and B. pseudomallei, which cause glanders and melioidosis, respectively. Burkholderia genomes are unusual due to their multichromosomal organization.

Results

We performed integrated genomic analysis of 127 Burkholderia strains. The pan-genome is open with the saturation to be reached between 86,000 and 88,000 genes. The reconstructed rearrangements indicate a strong avoidance of intra-replichore inversions that is likely caused by selection against the transfer of large groups of genes between the leading and the lagging strands. Translocated genes also tend to retain their position in the leading or the lagging strand, and this selection is stronger for large syntenies. Integrated reconstruction of chromosome rearrangements in the context of strains phylogeny reveals parallel rearrangements that may indicate inversion-based phase variation and integration of new genomic islands. In particular, we detected parallel inversions in the second chromosomes of B. pseudomallei with breakpoints formed by genes encoding membrane components of multidrug resistance complex, that may be linked to a phase variation mechanism. Two genomic islands, spreading horizontally between chromosomes, were detected in the B. cepacia group.

Conclusions

This study demonstrates the power of integrated analysis of pan-genomes, chromosome rearrangements, and selection regimes. Non-random inversion patterns indicate selective pressure, inversions are particularly frequent in a recent pathogen B. mallei, and, together with periods of positive selection at other branches, may indicate adaptation to new niches. One such adaptation could be a possible phase variation mechanism in B. pseudomallei.
Maf links Neuregulin1 signaling to cholesterol synthesis in myelinating Schwann cells
Authors: Kim Minchul , Wende Hagen , Walcher Jan , Kühnemund Johannes , Cheret Cyril , Kempa Stefan , McShane Erik , Selbach Matthias , Lewin Gary R. , Birchmeier Carmen
Published: May 2018

Cholesterol is a major constituent of myelin membranes, which insulate axons and allow saltatory conduction. Therefore, Schwann cells, the myelinating glia of the peripheral nervous system, need to produce large amounts of cholesterol. Here, we define a crucial role of the transcription factor Maf in myelination and cholesterol biosynthesis and show that Maf acts downstream from Neuregulin1 (Nrg1). Maf expression is induced when Schwann cells begin myelination. Genetic ablation of Maf resulted in hypomyelination that resembled mice with defective Nrg1 signaling. Importantly, loss of Maf or Nrg1 signaling resulted in a down-regulation of the cholesterol synthesis program, and Maf directly binds to enhancers of cholesterol synthesis genes. Furthermore, we identified the molecular mechanisms by which Nrg1 signaling regulates Maf levels. Transcription of Maf depends on calmodulin-dependent kinases downstream from Nrg1, whereas Nrg1–MAPK signaling stabilizes Maf protein. Our results delineate a novel signaling cascade regulating cholesterol synthesis in myelinating Schwann cells.
Neurodynamics-based leader-follower formation tracking of multiple nonholonomic vehicles
Authors: Yi Guo , Mao Jianxu , Wang Yaonan , Zhang Hui , Miao Zhiqiang
Published: May 2018

Purpose

The purpose of this paper is to consider the leader-following formation control problem for nonholonomic vehicles based on a novel biologically inspired neurodynamics approach.

Design/methodology/approach

The interactions among the networked multi-vehicle system is modeled by an undirected graph. First, a distributed estimation law is proposed for each follower vehicle to estimate the state including the position, orientation and linear velocity of the leader. Then, a distributed formation tracking control law is designed based on the estimated state of the leader, where a bio-inspired neural dynamic is introduced to solve the impractical velocity jumps problem. Explicit stability and convergence analyses are presented using Lyapunov tools.

Findings

The effectiveness and efficiency of the proposed control law are demonstrated by numerical simulations and physical vehicle experiments. Consequently, the proposed protocol can successfully achieve the desired formation under connected topologies while tracking the trajectory generated by the leader.

Originality/value

This paper proposes a neurodynamics-based leader–follower formation tracking algorithm for multiple nonholonomic vehicles.
An electrochemical method based on OCP fluctuations for anti-corrosion alloy composition optimization
Authors: Chen Mindong , Zhang Huijie , Chen Liang , Fu Dongmei
Published: May 2018

Purpose

An electrochemical method based on the open circuit potential (OCP) fluctuations was put forward. It can be used to optimize the alloy compositions for improving the corrosion resistance of rust layer.

Design/methodology/approach

The potential trends and potential fluctuations of carbon steels in seawater were separated by Hodrick–Prescott filter. The Spearman correlation coefficient and max information coefficient were used to explore the correlation of alloy compositions and potential fluctuations.

Findings

After long-term immersion, potential fluctuation resistance (PFR) can be used to characterize the corrosion resistance of metals and its rust layers. In the 1,500 to 2,500 h exposure period, Fe, C and S compositions have strong negative correlations, whereas PFR and P composition have weak negative correlations. Mn, Cu and Ti alloy compositions help the rust layer of carbon steels have higher PFRs. These elements that exhibit higher PFRs in this period have been confirmed to have the effect on improving the corrosion resistance of rust layer.

Originality/value

A new computing method for alloy composition optimization of carbon steels based on the OCP fluctuations was put forward. This method combines electrochemical monitoring with the long-term actual seawater environmental tests of various carbon steels.
The mechanism and effectiveness of credit scoring of P2P lending platform
Authors: Li Qiang , Chen Liwen , Zeng Yong
Published: May 2018

Purpose

The purpose of this paper is to investigate the mechanism how the platform obtains and uses undisclosed information to determine individual borrowers’ credit score and to examine the effectiveness of credit scoring in predicting default. The motivation stems from the fact that there is little evidence about the role of P2P platform, which has been positioned as a kind of information intermediary.

Design/methodology/approach

Using a sample of 5,176 unsecured P2P loans having expired before December 31, 2015 on Renrendai.com and an approach of two-stage regression, the paper first estimates the undisclosed information embedded in credit score by regressing credit score on four types of public information about a borrower’s creditworthiness. Then, the authors use a Logit regression to examine the role of the excess information in predicting the default probability.

Findings

The certification information provided by the platform is the most important determinant for a borrower’s credit score and the undisclosed information embedded in credit score can predict the loan performance better than the public information of posted listings. Moreover, the predictive ability of the undisclosed information is better for high-risk borrowers than for low-risk ones.

Research limitations/implications

Providing a credit score for each individual is a way for P2P platforms to play an information intermediary role. More evidence about whether or how a platform plays its role are worthy to be exploited by investigating a platform’s operating policies in detail and doing cross-platform comparative studies.

Practical implications

The results about the effect of various types of information on loan performance can provide an insightful guidance for P2P platforms to optimize their mechanism on information disclosure and credit scoring.

Originality/value

The existing literature mainly focuses on the effects of information voluntarily disclosed by borrowers and the behaviors of investors on P2P lending outcomes. The paper highlights the information intermediary role played by the platform and presents empirical evidence that credit scoring for individual borrowers is a way for P2P platforms to promote the direct lending for individual.
Empirical differences between the overnight and day trading hour returns
Authors: DU Juan
Published: May 2018

Purpose

The purpose of this paper is to provide a stable model which covers market information of return to examine the empirical differences between the returns during night and day in Chinese commodity futures market.

Design/methodology/approach

Commodity indices are constructed using principal components analysis to represent the market returns for day and night trading in the Chinese commodity futures market. Then VAR models are employed to predict the commodity indices’ returns and squared returns.

Findings

The symmetric VAR model failed to model the market returns since the asymmetric effects of positive and negative returns are not taken into account. By allowing asymmetric behavior among positive and negative variables, asymmetric VAR model is utilized to trace the leading effect of overnight returns to daytime trading returns. However, the symmetric VAR model outperforms the asymmetric model when evaluating the predictive power of squared returns during night trading hours. Two major results based on asymmetric model for the return are: There is a 6-day leading effect of nighttime return to daytime return in Chinese commodity futures market. It is risky to hold day trading position overnight.

Research limitations/implications

Asymmetric VAR model provides a new approach to forecasting the direction of price movement.

Practical implications

Investment managers are able to create a stable portfolio contains major market information. Day and night traders are likely to gain some suggestions to discover arbitrage opportunities.

Social implications

Since there is no commodity futures index in China, the method for creating indices for Chinese commodity futures is provided to market regulators.

Originality/value

Combining principal component analysis and asymmetric VAR model provides a stable and predictable model to obtain market information.
A typology of logistics at work in collaborative consumption
Authors: Carbone Valentina , Rouquet Aurélien , Roussat Christine
Published: May 2018

Purpose

The growth of collaborative consumption is beginning to stimulate management research on this phenomenon. However, so far, few scholars have studied the logistics aspects related to these developments. The purpose of this paper is to develop a conceptual approach to the logistics at work in collaborative consumption.

Design/methodology/approach

The authors adopt an inductive, exploratory research method, based on a content analysis involving 32 collaborative consumption initiatives screened through their websites and other secondary sources.

Findings

Based on the way logistics is organized in these initiatives, the authors identify and describe four types of logistics: peer to peer, business, crowd, and open logistics.

Practical implications

The paper makes recommendations for improving the management of collaborative consumption logistics.

Originality/value

Our results enrich the literature about crowd practices and collaborative consumption by conceptualizing alternative roles played by logistics and revealing its specific organizational forms.
Student team integrating aspects of sustainability in practical design education
Authors: Ueda Edilson Shindi
Published: May 2018

Purpose

The purpose of this paper is to describe and analyze the first experiences (activities, attitudes and inclinations) of an undergraduate student team with eco-design activities.

Design/methodology/approach

Undergraduate students of an industrial design course were invited to participate in the design project. The activities of students were carried out in the class titled in Japanese “Sogo Project” (Overall Project). The project is experimental learning based on pedagogical case studies that students propose practical designs with a sustainable approach.

Findings

According to the activities and attitudes of the student team, they showed interest in focusing on sustainable consumption and consequently leant towards a socio-cultural rather than a technological eco-design approach in their works. The barriers to design education for sustainable design were found, and the student team expressed that the available support tool during their design process was complex. They also expressed that the tool was not compatible with their academic skills and background.

Research limitations/implications

This paper has limited participants, resources, time and contextual scale. Few Japanese educators are skilled in eco-design, and eco-design modules are also poorly integrated into undergraduate and graduate industrial-design courses at Japanese universities.

Originality/value

The paper contributes to an initial discussion in the field of Japanese industrial-design education regarding the principles of and barriers to design education for sustainability.