bluuebunny/crossref_metadata_2025 huggingface dataset:
Understorey succession after burial by tephra from Mount St. Helens
Authors: Fischer Dylan G. , Antos Joseph A. , Biswas Abir , Zobel Donald B.
Published: July 2018

Successional change following disturbance is a fundamental ecological process that remains central to understanding patterns in plant ecology. Although succession has been studied for well over a century, understanding of the patterns and processes of change is still inadequate, partly because of the dearth of long‐term studies.

Here, we use, as a model system, a volcanic disturbance that is widespread and of global relevance. We examine succession in old‐growth conifer forest understories following burial by tephra (aerially transported volcanic ejecta) in the 1980 eruption of Mount St. Helens. Using four sites with different initial conditions and amounts of disturbance (tephra burial), we sampled plant communities at years 1, 20, and 36 since the eruption using permanent plots representing two treatments: undisturbed tephra and control plots from which tephra was experimentally removed. By using this long‐term data, we were able to gauge change through time and differences between tephra‐disturbed and control plots.

In tephra‐impacted plots, cover reached preeruption levels by year 36 except for bryophytes at three sites and shrubs at one site. Cover in control plots also increased significantly for all growth forms except bryophytes, remaining above that on tephra plots at the same site in most situations. Sites generally increased in species richness first, and then gradually increased in evenness and Shannon’s diversity; after 36 years, differences between control and tephra‐impacted plots remained at only one site. Community composition was stable in one site and shifted gradually through time at the two other sites, and differences between plot types persisted at one site. Communities change over 36 years could relate to various endogenic and abiotic factors.

Synthesis. These data suggest that, while recovery to the predisturbance status occurs in some cases, recovery is site‐specific. Understorey communities can be dynamic, even in old‐growth forests, and may still be responding to disturbance over three decades later. Long‐term experimental studies are key to understanding succession patterns and generalizations about the importance of initial conditions, disturbance intensity, and the complexity of interactions that determine vegetation change.
Seed size regulates plant dispersal distances in flowing water
Authors: de Jager Monique , Kaphingst Bettina , Janse Erik L. , Buisman Robert , Rinzema Sibrand G. T. , Soons Merel B.
Published: July 2018

Dispersal is an essential component of plant life, especially under the current threats of anthropogenic habitat fragmentation and climate change. For many wetland species, water is a key dispersal vector, as it can presumably disperse seeds long distances and towards suitable sites for establishment. Seed dispersal distance is affected by stream characteristics and seed traits. Yet, the effect of relevant seed traits, such as size, remains largely unknown.

Here, we report on an experimental field study examining the effect of seed size on dispersal distance in lowland streams. We released cork seed mimics of different sizes in four Dutch lowland streams in restored and channelized sections. After 24 hr, we recorded their entrapment location, entrapment mechanism, and the vegetation type in which they were caught.

Large seeds generally dispersed over longer distances than smaller seeds. This effect of seed size is likely caused by the different entrapment mechanisms—net trapping, surface tension, and wake trapping—which were highly correlated with seed size. Especially net trapping was responsible for the capture of a large proportion of small seed mimics in vegetation such as aquatic and riparian grasses, starwort, and reed. Due to the prevalent occurrence of these vegetation types in lowland streams, particularly during summer, smaller seeds are more likely to become entrapped and, hence, disperse less far. Our analysis on existing seed data reveals that water‐dispersed riparian plants have relatively large seeds and are thereby evolutionarily adapted to long‐distance dispersal. Furthermore, our results indicate that median dispersal distances are 0.02–1.8 km (99‐percentile <8.5 km) in lowland streams in summer. In winter, less vegetation is present in and surrounding the streams, which leads to median dispersal distances of 0.12–14.2 km (99‐percentile <65 km).

Synthesis. This study demonstrates that (a) large seeds generally disperse further than smaller seeds in lowland steams and (b) distances depend strongly on stream vegetation. This information should inform future restoration, for instance, by planning efforts to coincide with times or conditions of open water which are more favourable for the dispersal of target plant species—especially those with small seeds (<10 mm).
Effects of long‐term variation in pollinator abundance and diversity on reproduction of a generalist plant
Authors: Thomson Diane M.
Published: July 2018

Quantifying the benefits of pollinator abundance and diversity for plant reproduction is a critical challenge, especially given recent pollinator declines. Many studies test for pollen limitation (PL), but huge gaps remain in our understanding of how often and why plants experience PL. Most studies are limited to a few sites or years. Little existing research mechanistically links pollinator visitation with plant reproduction. Also, buffering against variability in visitation is a key but largely untested potential benefit of pollinator diversity. Long‐term studies pairing visitation data with PL experiments are essential to addressing these gaps, but extremely rare.

I measured pollinator visitation, responses to pollen supplementation, and fruit weights in the generalist plant Scrophularia californica across multiple sites for 8 years. I determined how often S. californica experienced significant PL and tested mechanistic models predicting PL and fruit (capsule) weight from visitation. I then used those models to simulate pollinator loss and evaluate the relative effects of changes in visit quantity and quality. I explored the stabilizing benefits of visitor diversity by quantifying both covariation among pollinators and effects of simulated species loss on variation in PL and capsule weights.

Scrophularia showed significant PL in only 26.9% of patch/year combinations tested. Visitation by the most abundant (Apis mellifera) and effective (Vespula pensylvanica) pollinators strongly predicted PL and capsule weights. Both response curves were highly nonlinear, but PL saturated more with increased visitation. Pollinator loss simulations predicted substantially increased PL and reduced capsule weights, mostly because of lower visit numbers rather than changes in visit quality. Visitation rates of individual pollinators varied substantially and without correlation. Simulated pollinator loss increased the spatial and temporal skew in visitation, resulting in higher predicted coefficients of variation for PL and capsule weights.

Synthesis. Previous work predicts a nonlinear relationship between pollinator visitation and plant reproduction, but this is the first long‐term study I am aware of that quantifies such a pattern. The analysis of covariance in pollinator visitation combined with my simulation results provide novel empirical support for another important hypothesis, that multiple pollinators can provide stabilizing benefits for plant reproduction.
Enoch Powell and the Conservative Party: Reflections on an Ambiguous Legacy
Authors: Peele Gillian
Published: July 2018

This article examines Enoch Powell's ‘Rivers of Blood’ speech in relation to the Conservative party. Powell's speech created an additional challenge to a Conservative party already weakened by the loss of the 1964 and 1966 elections and by the failure of the newly elected leader, Edward Heath, to impress his authority decisively on the party. Powell had some parliamentary support but his real following was concentrated in the Conservative grass roots. Powell lost the support of the liberal‐minded Shadow Cabinet; but after 1968 the Conservatives nevertheless moved to the right on the issue, especially after Mrs. Thatcher became leader in 1975. His speech has cast a long shadow as the party has sought to modernise in more recent times and to appeal to a more racially diverse electorate.
Detecting the molecular basis of phenotypic convergence
Authors: Chabrol Olivier , Royer‐Carenzi Manuela , Pontarotti Pierre , Didier Gilles
Published: July 2018

Convergence is the process by which several species independently develop similar traits. This evolutionary process is not only strongly related to fundamental questions such as the predictability of evolution and the role of adaptation, its study also may provide new insights about genes involved in the convergent phenotype. We focus on this latter question and aim to detect the molecular basis of a given phenotypic convergence.

After pointing out a number of concerns with current detection methods based on ancestral reconstruction, we propose a novel approach combining an original measure, called convergence index, which associates to any proteic site a quantity reflecting the extent to which it supports a phenotypic convergence, with a statistical framework for selecting genes from the convergence indices of all their sites.

First, our measure of the “convergence level” outperforms two previous ones in distinguishing simulated convergent sites from nonconvergent ones. Second, by applying our detection approach to the well‐studied case of convergent echolocation between dolphins and bats, we identified a set of genes which is very significantly annotated with audition‐related GO terms.

This result constitutes an indirect evidence that genes involved in a phenotypic convergence can be identified with a genome‐wide approach, a point which was highly debated, notably in the echolocation case. Our approach paves the way to systematic studies of numerous examples of convergent evolution in order to link convergent phenotypes to genotypes.
Effects of the Opioid System Modulator, Samidorphan, on Measures of Alcohol Consumption and Patient‐Reported Outcomes in Adults with Alcohol Dependence
Authors: O'Malley Stephanie S. , Todtenkopf Mark S. , Du Yangchun , Ehrich Elliot , Silverman Bernard L.
Published: July 2018

Background

Demonstrating clinically meaningful benefits of alcohol use disorder treatments is challenging.

Methods

We report findings from a 12‐week, phase 2, randomized, double‐blind, placebo‐controlled study of samidorphan (1, 2.5, or 10 mg/d) in adults with alcohol use disorder (NCT00981617). The primary end point was percentage of subjects with no heavy drinking days (PSNHDD) during weeks 5 to 12; secondary end points included alcohol consumption measures, craving, and patient‐rated outcomes.

Results

Altogether, 406 patients were included in the full analysis set (101, 104, 100, and 101 in the placebo, samidorphan 1, 2.5, and 10 mg treatment groups, respectively). There was no statistical difference between samidorphan and placebo groups on PSNHDD during weeks 5 to 12. However, dose‐dependent reductions in cumulative rate of heavy drinking days were observed (−41%, p < 0.001 for samidorphan 10 mg/d vs. placebo; −30 and −32% for samidorphan 2.5 and 1 mg, p < 0.05 for both). A higher percentage of samidorphan‐ than placebo‐treated patients had a ≥2‐category downshift in World Health Organization (WHO) risk levels of drinking. There were significant reductions from baseline with samidorphan versus placebo in alcohol craving (for samidorphan 10 mg: −38.2 [standard error: 2.9] vs. placebo: −30.2 [2.8]; p = 0.044). On a Patient Global Assessment of Response to Therapy (PGART), samidorphan 10 mg was superior to placebo at 4, 8, and 12 weeks (p < 0.001, p < 0.001, p < 0.01, respectively). Improvement in PGART correlated with a reduction in craving and a decrease in WHO risk level.

Conclusions

Results for the primary outcome measure PSNHDD were negative, but at variance with other measures and patient treatment perceptions that may be relevant for interventional studies. These findings highlight the importance of understanding the most relevant outcomes to patients and incorporating and prioritizing patient‐centered outcomes when assessing interventions for alcohol use disorder.
Sexually transmitted infections and preterm birth among Indigenous women of the Northern Territory, Australia: A case–control study
Authors: Burton Alice E. , Thomas Sujatha
Published: July 2018

Background

The incidence of both sexually transmitted infection (STI) and preterm birth is high among Indigenous women in the Northern Territory, Australia. It was hypothesised that these factors are linked.

Aims

To analyse whether antenatal STI is associated with preterm birth among Northern Territory Indigenous women.

Materials and Methods

A retrospective case–control study was conducted at a tertiary maternity hospital in the Northern Territory. Rates of STI among pregnant Indigenous women were compared between cases (singleton births at <37 weeks gestation) and controls (singleton births at 37 or greater weeks gestation). The association between the composite of any STI (chlamydia, gonorrhoea, trichomonas or syphilis) and preterm birth was evaluated by logistic regression analysis, adjusting for confounders. Secondary endpoints were the associations between each of these infections and preterm birth.

Results

There were 380 cases and 380 controls. Diagnosis of any sexually transmitted infection (composite) in pregnancy was not associated with preterm birth (adjusted odds ratio (aOR) 0.9, 95%CI 0.58–1.39). Women were at increased risk of preterm birth if they had gonorrhoea in pregnancy (aOR 2.92, 95%CI 1.07–7.97); there was no association with chlamydia (aOR 1.38, 95%CI 0.63–3.04) or trichomonas (aOR 0.66, 95%CI 0.39–1.12). There were three syphilis diagnoses among controls and none among cases.

Conclusions

Sexually transmitted infection (considered overall) in pregnancy did not affect preterm birth risk among Northern Territory Indigenous women. An association with preterm birth was observed for gonorrhoea in pregnancy but not with chlamydia, trichomonas or syphilis.
Meta‐analysis and trial sequential analysis of local vs. general anaesthesia for carotid endarterectomy
Authors: Hajibandeh S. , Hajibandeh S. , Antoniou S. A. , Torella F. , Antoniou G. A.
Published: July 2018

Controversy exists regarding the best choice of anaesthesia for carotid endarterectomy. We aimed to evaluate the peri‐operative outcomes of local vs. general anaesthesia for carotid endarterectomy. We conducted a systematic search of electronic information sources and applied a combination of free text and controlled vocabulary searches adapted to thesaurus headings, search operators and limits in each of the electronic databases. We defined peri‐operative stroke, transient ischaemic attack, mortality and myocardial infarction as the primary outcome measures. We identified 12 randomised controlled trials and 21 observational studies reporting a total of 58,212 patients undergoing carotid endarterectomy under local or general anaesthesia. Analysis of observational studies demonstrated that local anaesthesia was associated with a significantly lower incidence of stroke (odds ratio (OR (95% CI) 0.66 (0.55–0.80), p < 0.0001), transient ischaemic attack (0.52 (0.38–0.70), p < 0.0001), myocardial infarction (0.55 (0.41–0.75), p = 0.0002) and mortality (0.72 (0.56–0.94), p = 0.01) compared with general anaesthesia. Analysis of randomised controlled trials did not find a significant difference in the risk of stroke (0.92 (0.67–1.28), p = 0.63), transient ischaemic attack (2.20 (0.48–10.03), p = 0.31), myocardial infarction (1.25 (0.57–2.72), p = 0.58) or mortality (0.61 (0.35–1.05), p = 0.07) between local and general anaesthesia. On trial sequential analysis of the randomised trials, the Z‐curve did not cross the α‐spending boundaries or futility boundaries for stroke, mortality and transient ischaemic attack, suggesting that more trials are needed to reach conclusive results. Our meta‐analysis of observational studies suggests that local anaesthesia for carotid endarterectomy may be associated with lower peri‐operative morbidity and mortality compared with general anaesthesia. Although randomised studies have not confirmed any advantage for local anaesthesia, this may be due to a lack of pooled statistical power in these trials.
Safety, efficacy and compliance of extended thromboprophylaxis in hepatobiliary and upper gastrointestinal surgery
Authors: Marley Leah , Navadgi Suresh , Banting Simon , Fox Adrian , Hii Michael , Knowles Brett
Published: July 2018

Background

Extended venothromboprophylaxis (eVTP) after abdominal surgery for hepatobiliary (HPB) and upper gastrointestinal (UGI) malignancies is recommended. Safety, efficacy and compliance within this group of surgical patients are not well described. The primary aim was to assess safety and compliance of post‐operative administration of eVTP with low molecular weight heparin. Secondary aim was to assess barriers to treatment and monitor the rate of post‐operative venous thromboembolism.

Methods

A prospective observational cohort study of patients undergoing abdominal surgery for HPB or UGI malignancies was undertaken from January 2014 to June 2016. All patients were assessed for eVTP. Demographics, clinical outcomes and clinical questionnaires on discharge and at follow‐up 6 weeks post their initial surgery were used to assess the safety, compliance and efficacy of eVTP.

Results

A total of 100 patients were assessed for post‐operative eVTP. Of these, 80 patients were prescribed 28 days of low molecular weight heparin. Of 80 patients, 65 (85%) patients completed the full eVTP, 11 (13%) missed 1–5 injections and only four (6%) missed 6–15 injections. In the 80 eVTP patients, there were no episodes of significant bleeding or venous thromboembolism. A total of nine (11%) patients would be unwilling to undertake eVTP again for a variety of reasons, including ease of disposal of syringes and needle phobias.

Conclusion

The administration of eVTP in patients undergoing major HPB and UGI surgery is safe, with minimal morbidity and high compliance. The greatest barrier to administration is doctor prescription.
Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease
Authors: Demangel Caroline , High Stephen
Published: July 2018

Infection with Mycobacterium ulcerans results in a necrotising skin disease known as a Buruli ulcer, the pathology of which is directly linked to the bacterial production of the toxin mycolactone. Recent studies have identified the protein translocation machinery of the endoplasmic reticulum (ER) membrane as the primary cellular target of mycolactone, and shown that the toxin binds to the core subunit of the Sec61 complex. Mycolactone binding strongly inhibits the capacity of the Sec61 translocon to transport newly synthesised membrane and secretory proteins into and across the ER membrane. Since the ER acts as the entry point for the mammalian secretory pathway, and hence regulates initial access to the entire endomembrane system, mycolactone‐treated cells have a reduced ability to produce a range of proteins including secretory cytokines and plasma membrane receptors. The global effect of this molecular blockade of protein translocation at the ER is that the host is unable to mount an effective immune response to the underlying mycobacterial infection. Prolonged exposure to mycolactone is normally cytotoxic, since it triggers stress responses activating the transcription factor ATF4 and ultimately inducing apoptosis.
Flexible Use of Temporal and Spatial Reasoning for Fast and Scalable CPU Broad‐Phase Collision Detection Using KD‐Trees
Authors: Serpa Ygor Rebouças , Rodrigues Maria Andréia Formico
Published: July 2018

Realistic computer simulations of physical elements such as rigid and deformable bodies, particles and fractures are commonplace in the modern world. In these simulations, the broad‐phase collision detection plays an important role in ensuring that simulations can scale with the number of objects. In these applications, several degrees of motion coherency, distinct spatial distributions and different types of objects exist; however, few attempts have been made at a generally applicable solution for their broad phase. In this regard, this work presents a novel broad‐phase collision detection algorithm based upon a hybrid SIMD optimized KD‐Tree and sweep‐and‐prune, aimed at general applicability. Our solution is optimized for several objects distributions, degrees of motion coherence and varying object sizes. These features are made possible by an efficient and idempotent two‐step tree optimization algorithm and by selectively enabling coherency optimizations. We have tested our solution under varying scenario setups and compared it to other solutions available in the literature and industry, up to a million simulated objects. The results show that our solution is competitive, with average performance values two to three times better than those achieved by other state‐of‐the‐art AABB‐based CPU solutions.
Identifying conservation priorities for threatened Eastern Himalayan mammals
Authors: Dorji Sangay , Rajaratnam Rajanathan , Falconi Lorena , Williams Stephen E. , Sinha Priyakant , Vernes Karl
Published: July 2018

To augment mammal conservation in the Eastern Himalayan region, we assessed the resident 255 terrestrial mammal species and identified the 50 most threatened species based on conservation status, endemism, range size, and evolutionary distinctiveness. By using the spatial analysis package letsR and the complementarity core‐area method in the conservation planning software Zonation, we assessed the current efficacy of their protection and identified priority conservation areas by comparing protected areas (PAs), land cover, and global ecoregion 2017 maps at a 100 × 100 m spatial scale. The 50 species that were most threatened, geographically restricted, and evolutionarily distinct faced a greater extinction risk than globally nonthreatened and wide‐ranging species and species with several close relatives. Small, medium‐sized, and data‐deficient species faced extinction from inadequate protection in PAs relative to wide‐ranging charismatic species. There was a mismatch between current PA distribution and priority areas for conservation of the 50 most endangered species. To protect these species, the skewed regional PA distribution would require expansion. Where possible, new PAs and transboundary reserves in the 35 priority areas we identified should be established. There are adequate remaining natural areas in which to expand current Eastern Himalayan PAs. Consolidation and expansion of PAs in the EH requires strengthening national and regional transboundary collaboration, formulating comprehensive regional land‐use plans, diversifying conservation funding, and enhancing information sharing through a consolidated regional database.
Hunting for common ground between wildlife governance and commons scholarship
Authors: Smith Hillary , Marrocoli Sergio , Garcia Lozano Alejandro , Basurto Xavier
Published: July 2018

Wildlife hunting is essential to livelihoods and food security in many parts of the world, yet present rates of extraction may threaten ecosystems and human communities. Thus, governing sustainable wildlife use is a major social dilemma and conservation challenge. Commons scholarship is well positioned to contribute theoretical insights and analytic tools to better understand the interface of social and ecological dimensions of wildlife governance, yet the intersection of wildlife studies and commons scholarship is not well studied. We reviewed existing wildlife‐hunting scholarship, drawing on a database of 1,410 references, to examine the current overlap with commons scholarship through multiple methods, including social network analysis and deductive coding. We found that a very small proportion of wildlife scholarship incorporated commons theories and frameworks. The social network of wildlife scholarship was densely interconnected with several major publication clusters, whereas the wildlife commons scholarship was sparse and isolated. Despite the overarching gap between wildlife and commons scholarship, a few scholars are studying wildlife commons. The small body of scholarship that bridges these disconnected literatures provides valuable insights into the understudied relational dimensions of wildlife and other overlapping common‐pool resources. We suggest increased engagement among wildlife and commons scholars and practitioners to improve the state of knowledge and practice of wildlife governance across regions, particularly for bushmeat hunting in the tropics, which is presently understudied through a common‐pool resource lens. Our case study of the Republic of Congo showed how the historical context and interrelationships between hunting and forest rights are essential to understanding the current state of wildlife governance and potential for future interventions. A better understanding of the interconnections between wildlife and overlapping common‐pool resource systems may be key to understanding present wildlife governance challenges and advancing the common‐pool resource research agenda.
Awe as a Scientific Emotion
Authors: Gottlieb Sara , Keltner Dacher , Lombrozo Tania
Published: July 2018

Awe has traditionally been considered a religious or spiritual emotion, yet scientists often report that awe motivates them to answer questions about the natural world, and to do so in naturalistic terms. Indeed, awe may be closely related to scientific discovery and theoretical advance. Awe is typically triggered by something vast (either literally or metaphorically) and initiates processes of accommodation, in which existing mental schemas are revised to make sense of the awe‐inspiring stimuli. This process of accommodation is essential for the kind of belief revision that characterizes scientific reasoning and theory change. Across six studies, we find that the tendency to experience awe is positively associated with scientific thinking, and that this association is not shared by other positive emotions. Specifically, we show that the disposition to experience awe predicts a more accurate understanding of how science works, rejection of creationism, and rejection of unwarranted teleological explanations more broadly.
Cytology smears for DNA extraction: Practical approach for selecting the best slide
Authors: Gupta Neha , Brenkert Ryan , Lee Joong Won , Klein Melissa , Spitzer Silvia , Chau Karen , Das Kasturi
Published: July 2018

Background

Next generation sequencing (NGS) to detect actionable genetic abnormalities is standard of care in advanced stage lung adenocarcinoma. Many studies have shown that the molecular results obtained from fine needle aspiration cytology material are comparable to those obtained from formalin‐fixed tissue samples. We undertook this study to validate DNA extraction from cytology material for molecular studies and to find any correlation between DNA yield, pattern of tumour cells and tumour fraction.

Methods

DNA was extracted from 34 cytology slides of pulmonary adenocarcinoma cases with predetermined EGFR mutation status. Cytology slides were reviewed for pattern of tumour distribution and tumour fraction. NGS was performed on five slides with variable DNA and compared with original results.

Results

There were 14 alcohol‐fixed and 20 air‐dried smears. The mean DNA yield was 1.74 μg and median of 0.4 μg (range, 0.02‐21 μg). Tumour fractions varied from 10% to 90%. No correlation was found between tumour fraction and DNA yield (P = 0.14). The mean DNA yield was high in slides with tumour throughout the slide (sheets or scattered clusters) as compared to rare scattered clusters and/or single cells. EGFR mutation was found in four of the five cases sent for NGS lung panel while one case revealed BRAF mutation.

Conclusions

DNA with good quantity and quality can be extracted from the cytology slides for NGS irrespective of type of fixation. DNA yield has better correlation with distribution pattern of tumour cells on the slides rather than tumour fraction.
Unilateral orchidomegaly with precocious puberty: A challenging diagnosis
Authors: Gupta Parikshaa , Uppula Pavan , Bhansali Anil , Rajwanshi Arvind
Published: July 2018

Clinical diagnosis of testicular masses in presence of precocious puberty is often tricky. In such cases, the main differential diagnoses include testicular adrenal rest tumors (TARTs) and leydig cell tumors (LCTs). Tumor cells in both TART and LCT exhibit marked morphologic similarities, thereby amplifying the diagnostic difficulty. However, as in the present case, subtle clinical cues and an immunocytochemical panel can supplement cytomorphology in achieving an accurate pre‐operative diagnosis even in challenging cases.
Effective tax rates and firm size in Ethiopia
Authors: Mascagni Giulia , Mengistu Andualem
Published: July 2018

The literature on Effective Tax Rates (ETRs) focuses on high‐ and middle‐income countries, but there is very little evidence on low‐income countries. This article addresses this gap with new evidence from Ethiopia. We investigate corporate ETRs in Ethiopia and whether the distributional effects they have in practice are in line with the corporate tax policy design. We calculate ETRs in line with the literature in this field, using profit tax at the numerator and gross profit at the denominator. We then analyse ETRs not only using panel data, focusing particularly on their relation to firm size, but also including other explanatory variables. Our main result is that, despite a proportional tax rate, small firms face a higher effective tax burden than larger firms, while middle‐sized firms face the lowest burden of all. We highlight that tax systems can have practical implications that differ largely from their policy design, due to compliance costs and imperfect enforcement. Measures to reduce compliance costs for small firms are particularly recommended.
α‐Synuclein concentration increases over time in plasma supernatant of single donor platelets
Authors: Stefaniuk Catherine M. , Hong Hong , Harding Clifford V. , Maitta Robert W.
Published: July 2018

Objectives

In platelets, α‐synuclein is important in calcium‐dependent granule release. Notably, cells release α‐synuclein in setting of cell damage or death. Therefore, we investigated α‐synuclein levels in plasma of single donor platelet (SDP) units during storage.

Methods

Aliquots were obtained from same SDP units for 7 days from day of donation. Additionally, randomly sampled SDP units at same storage time points were also assayed by enzyme‐linked immunosorbent assay.

Results

α‐Synuclein in SDP plasma increased continuously over time at each assayed time point. Significant increases were measured on day 3 (11.7 ± 9.6 ng/mL, P = 0.025), day 5 (15.3 ± 5.9 ng/mL, P = 0.002), and highest on day 7 (23.7 ± 5.6 ng/mL, P < 0.0001) compared to day 0 (1.1 ± 0.8 ng/mL). Similar significant results were obtained in randomly sampled SDP units at same corresponding time points. Flow cytometry showed that platelets had strong expression of α‐synuclein and lacked expression of other synucleins.

Conclusions

Increases of α‐synuclein during SDP storage is a steady and continuous process that increases with time. Our findings indicate that α‐synuclein may represent a biomarker of platelet biological state during storage. Further research will be needed to determine how α‐synuclein increases correlate with platelets’ function.
Aplastic anemia: Etiology, molecular pathogenesis, and emerging concepts
Authors: Shallis Rory M. , Ahmad Rami , Zeidan Amer M.
Published: July 2018

Aplastic anemia (AA) is rare disorder of bone marrow failure which if severe and not appropriately treated is highly fatal. AA is characterized by morphologic marrow features, namely hypocellularity, and resultant peripheral cytopenias. The molecular pathogenesis of AA is not fully understood, and a uniform process may not be the culprit across all cases. An antigen‐driven and likely autoimmune dysregulated T‐cell homeostasis is implicated in the hematopoietic stem cell injury which ultimately founds the pathologic features of the disease. Defective telomerase function and repair may also play a role in some cases as evidenced by recurring mutations in related telomerase complex genes such asTERTandTERC. In addition, recurring mutations inBCOR/BCORL, PIGA, DNMT3A,andASXL1as well as cytogenetic abnormalities, namely monosomy 7, trisomy 8, and uniparental disomy of the 6p arm seem to be intimately related to AA pathogenesis. The increased incidence of late clonal disease has also provided clues to accurately describe plausible predispositions to the development of AA. The emergence of newer genomic sequencing and other techniques is incrementally improving the understanding of the pathogenic mechanisms of AA, the detection of the disease, and ultimately offers the potential to improve patient outcomes. In this comprehensive review, we discuss the current understanding of the immunobiology, molecular pathogenesis, and future directions of such for AA.
Cholinergic modulation of spatial learning, memory and navigation
Authors: Solari Nicola , Hangya Balázs
Published: July 2018

Spatial learning, including encoding and retrieval of spatial memories as well as holding spatial information in working memory generally serving navigation under a broad range of circumstances, relies on a network of structures. While central to this network are medial temporal lobe structures with a widely appreciated crucial function of the hippocampus, neocortical areas such as the posterior parietal cortex and the retrosplenial cortex also play essential roles. Since the hippocampus receives its main subcortical input from the medial septum of the basal forebrain (BF) cholinergic system, it is not surprising that the potential role of the septo‐hippocampal pathway in spatial navigation has been investigated in many studies. Much less is known of the involvement in spatial cognition of the parallel projection system linking the posterior BF with neocortical areas. Here we review the current state of the art of the division of labour within this complex ‘navigation system’, with special focus on how subcortical cholinergic inputs may regulate various aspects of spatial learning, memory and navigation.
Micro‐computed tomography assessment of root dentin around fluoride‐releasing restorations after demineralization/remineralization
Authors: Zan Khine W. , Nakamura Keiki , Hamba Hidenori , Sadr Alireza , Nikaido Toru , Tagami Junji
Published: July 2018

Using micro‐computed tomography (micro‐CT), this study assessed the inhibitory effect of three different types of restorations on root‐caries formation under a cariogenic challenge. Bovine‐root dentin blocks with a cylindrical cavity were divided into three restoration groups: a fluoride‐free self‐etch adhesive and a resin composite (SE‐ES); a self‐etch adhesive and a resin composite with multi‐ion release (FL‐BF); and a glass ionomer cement (Fuji‐VII). After the restorative procedures, the specimens were stored in artificial saliva for 1 d, then subjected to a demineralization solution for 4 d and a remineralization solution for 28 d. Mineral density and mean mineral loss of dentin around the restorations were measured using micro‐CT. The mean mineral loss values of dentin around the restorations were highest among SE‐ES restorations and lowest among Fuji‐VII restorations. Fuji‐VII showed the highest mineral density and the lowest mineral loss after 28 d of remineralization. The observations made by scanning electron microscopy demonstrated that Fuji‐VII created the smallest outer lesion followed by FL‐BF and SE‐ES. Fuji‐VII has a larger inhibitory effect on root caries around the restorations and enhances remineralization more effectively than either FL‐BF or SE‐ES. Multi‐ion and fluoride release from the restorative materials may be beneficial for inhibition of root‐dentin caries around the restorations.
The chromatin remodeling protein INO80 contributes to the removal of H2A.Z at the p53‐binding site of the p21 gene in response to doxorubicin
Authors: Ding Jian , Yu Chao , Sui Yi , Wang Lingyao , Yang Yang , Wang Fei , Yao Hongjie , Xing Feiyang , Liu Hongshen , Li Yana , Shah Junaid Ali , Cai Yong , Jin Jingji
Published: July 2018

Transcriptional activation of p21 (cyclin‐dependent kinase inhibitor 1A) due to DNA damage often alters the distribution of histone variant H2A.Z at the p21 gene. However, whether the human INO80 complex regulates changes in H2A.Z at the p21 promoter is unclear. We show here that activation of p21 expression by doxorubicin (Doxo) in U2OS cells is required for removal of H2A.Z by INO80 at the p53‐binding site proximal region (−2.2 kb) of the p21 promoter. A purified INO80 complex, but not the INO80E653Q mutant‐complex, which lost DNA‐sliding activity, is mainly responsible for removing H2A.Z from reconstituted nucleosomes in vitro. This activity was enhanced with MOF‐mediated histone acetylation, suggesting that INO80 more readily removes H2A.Z from loosened nucleosomes. Also, co‐occupancy of INO80 and H2A.Z −2.2 kb upstream of the p21 transcriptional start site (TSS) was observed. H2A.Z at this region was removed in a short time after Doxo treatment and activated p21 expression. However, p21 induction was inhibited by INO80 knockdown by delaying H2A.Z removal, indicating the need for INO80. Moreover, shMOF‐mediated histone acetylation reduced recruitment of INO80 −2.2 kb upstream of p21 TSS and inhibited the removal of H2A.Z in Doxo‐treated cells. These data provide new insights into the transcriptional regulation of p21 by the INO80 complex.
Structure‐based design and molecular profiling of Smac‐mimetics selective for cellular IAPs
Authors: Corti Alessandro , Milani Mario , Lecis Daniele , Seneci Pierfausto , de Rosa Matteo , Mastrangelo Eloise , Cossu Federica
Published: July 2018

Inhibitor of Apoptosis Proteins (IAPs) is highly conserved negative regulators of apoptosis overexpressed in many cancer cells. Based on their endogenous antagonist, Smac/DIABLO, mimic compounds (Smac‐mimetics, SMs) have been developed to inhibit IAPs prosurvival activity, showing promising effects in advanced phases of clinical trials. Since different IAP homologs play distinctive roles in cancer cell survival and immunomodulation, SM‐induced apoptosis proceeds through diverse mechanisms. After binding to their BIR3 domain, SMs have been shown to rapidly induce auto‐ubiquitylation and degradation of cellular IAPs (cIAPs), thus leading to cell death mainly by activation of the noncanonical NF‐κB pathway. For this reason, we started the BIR3‐driven design of compounds selective for cIAP1 and with reduced affinity for X‐linked IAP (XIAP), in order to focus SMs antitumor activity on cIAPs degradation. In this work, we describe the crystal structures of the BIR3 domains of cIAP1 and XIAP, each in complex with a cIAP1‐selective SM (SM130 and SM114, respectively). The two SMs displayed 23‐ and 32‐fold higher affinity for cIAP1‐BIR3 over XIAP‐BIR3 in molecular displacement experiments based on fluorescence polarization. In vitro cell‐based assays confirmed that both selective SMs triggered apoptosis in cancer cells with different efficiencies by inducing caspases‐3, ‐8, and ‐9‐independent cIAP1 degradation. The design of cIAPs‐selective compounds represents an innovative approach in the field of anticancer drugs development, being useful to elucidate different prosurvival mechanisms and to reduce the adverse effects of pan‐IAPs compounds in cancer therapy.

Database

Structural data are available in the Protein Data Bank database under the accession codes 6EXW (cIAP1‐BIR3/SM130 complex) and 6EY2 (XIAP‐BIR3/SM114 complex).
Targeted therapies don't work for a reason; the neglected tumor suppressor phosphatase PP2A strikes back
Authors: Westermarck Jukka
Published: July 2018

Therapies targeting tyrosine and serine/threonine kinases have raised enormous interest as potential cure for cancer patients in many common cancer types. However, except for the success story with BCR/ABL tyrosine kinase inhibitors in chronic myeloid leukemia (CML), critical review of results of a large number of clinical trials indicates that the clinical success with kinase inhibitors has been overall disappointing. These alarming results call for critical assessment of whether there is some fundamental flaw in the design of strategies to target phosphorylation‐dependent oncogenic signaling for cancer therapy. This viewpoint debates on one potential, but thus far largely neglected, molecular explanation why inhibition of protein kinases is not sufficient for cancer cure. We note that the phosphorylation status, and thus the oncogenic potential of any given protein, is not regulated only by kinases, but rather by an intimate balance between kinases and their antagonist phosphatases. We further review the supporting functional evidence that for oncogenic transformation of human cells it is not enough to activate kinase signaling by activated kinases, if a group of counteracting tumor suppressor phosphatases is not inactivated. Based on these considerations, and a very recently emerged role of oncogenic function of a group of phosphatase inhibitor proteins as human oncoproteins, we propose that in order to efficiently inhibit phosphorylation‐dependent signaling in cancer cells, and thus provide better therapeutic index, the kinase inhibitors should be combined with strategies to reactivate tumor suppressor phosphatases such as Protein Phosphatase 2A (PP2A).
Multimodel ensembles improve predictions of crop–environment–management interactions
Authors: Wallach Daniel , Martre Pierre , Liu Bing , Asseng Senthold , Ewert Frank , Thorburn Peter J. , van Ittersum Martin , Aggarwal Pramod K. , Ahmed Mukhtar , Basso Bruno , Biernath Christian , Cammarano Davide , Challinor Andrew J. , De Sanctis Giacomo , Dumont Benjamin , Eyshi Rezaei Ehsan , Fereres Elias , Fitzgerald Glenn J. , Gao Y. , Garcia‐Vila Margarita , Gayler Sebastian , Girousse Christine , Hoogenboom Gerrit , Horan Heidi , Izaurralde Roberto C. , Jones Curtis D. , Kassie Belay T. , Kersebaum Kurt C. , Klein Christian , Koehler Ann‐Kristin , Maiorano Andrea , Minoli Sara , Müller Christoph , Naresh Kumar Soora , Nendel Claas , O'Leary Garry J. , Palosuo Taru , Priesack Eckart , Ripoche Dominique , Rötter Reimund P. , Semenov Mikhail A. , Stöckle Claudio , Stratonovitch Pierre , Streck Thilo , Supit Iwan , Tao Fulu , Wolf Joost , Zhang Zhao
Published: July 2018

A recent innovation in assessment of climate change impact on agricultural production has been to use crop multimodel ensembles (MMEs). These studies usually find large variability between individual models but that the ensemble mean (e‐mean) and median (e‐median) often seem to predict quite well. However, few studies have specifically been concerned with the predictive quality of those ensemble predictors. We ask what is the predictive quality of e‐mean and e‐median, and how does that depend on the ensemble characteristics. Our empirical results are based on five MME studies applied to wheat, using different data sets but the same 25 crop models. We show that the ensemble predictors have quite high skill and are better than most and sometimes all individual models for most groups of environments and most response variables. Mean squared error of e‐mean decreases monotonically with the size of the ensemble if models are added at random, but has a minimum at usually 2–6 models if best‐fit models are added first. Our theoretical results describe the ensemble using four parameters: average bias, model effect variance, environment effect variance, and interaction variance. We show analytically that mean squared error of prediction (MSEP) of e‐mean will always be smaller than MSEP averaged over models and will be less than MSEP of the best model if squared bias is less than the interaction variance. If models are added to the ensemble at random, MSEP of e‐mean will decrease as the inverse of ensemble size, with a minimum equal to squared bias plus interaction variance. This minimum value is not necessarily small, and so it is important to evaluate the predictive quality of e‐mean for each target population of environments. These results provide new information on the advantages of ensemble predictors, but also show their limitations.
Acupuncture is clinically but not yet cost‐effective in the treatment of symptomatic idiopathic detrusor overactivity
Authors: Jenks Julie , Kavia Rajesh , Pakzad Mahreen H. , Hamid Rizwan , Ockrim Jeremy L. , Greenwell Tamsin J.
Published: July 2018

Is acupuncture clinically and cost‐effective in the treatment of symptomatic idiopathic detrusor overactivity (IDO)? To assess the symptomatic outcome of patients having acupuncture for IDO and to assess and compare costs with other common IDO treatments. Acupuncture is well‐tolerated and produces a significant short‐term reduction in frequency and urgency in patients with overactive bladder (OAB). Repeat treatments are required for continued benefit. Thirty patients having acupuncture for symptomatic IDO were prospectively evaluated using objective (frequency/volume chart) and subjective (EurQol 5 dimension 3 level (EQ5D‐3L), International consultation on incontinence questionnaire on overactive bladder (ICIQ‐OAB), pain scores) measures. Outcome measures were assessed at baseline and post‐treatment, and compared for responders and non‐responders. A cost analysis was performed comparing acupuncture with mono and duel drug pharmacotherapies commonly used in OAB and conservative management methods. Statistical analysis was by Student's paired t test for parametric and Mann‐Whitney U test for non‐parametric data. Of the 30 patients 27 (90%) patients completed treatment with no reported adverse effects. OAB symptoms were “cured” in 14.8%, significantly improved in 59.3% and unchanged in 25.9%. Responders had a significantly lower mean pretreatment functional capacity compared with non‐responders and had a significant increase in this capacity following treatment. Acupuncture carried a higher cost burden at 6 months (£2267/$2990/€2560) compared to pharmacotherapy (mono = £477/$590/€539) or (duel = £681/$898/€769) and conservative methods (£749/$988/€846). Acupuncture is a well‐tolerated and effective treatment for IDO and should be part of the clinical armamentarium in a comprehensive continence service. It is more costly than maximal pharmacotherapy and conservative methods but has excellent compliance.