bluuebunny/crossref_metadata_2025 huggingface dataset:
Anacapa Toolkit: an environmental DNA toolkit for processing multilocus metabarcode datasets
Authors: Curd Emily E. , Gold Zack , Kandlikar Gaurav S , Gomer Jesse , Ogden Max , O’Connell Taylor , Pipes Lenore , Schweizer Teia , Rabichow Laura , Lin Meixi , Shi Baochen , Barber Paul , Kraft Nathan , Wayne Robert , Meyer Rachel S.
Published: December 2018

1. Environmental DNA (eDNA) metabarcoding is a promising method to monitor species and community diversity that is rapid, affordable, and non-invasive. Longstanding needs of the eDNA community are modular informatics tools, comprehensive and customizable reference databases, flexibility across high-throughput sequencing platforms, fast multilocus metabarcode processing, and accurate taxonomic assignment. As bioinformatics tools continue to improve, addressing each of these demands within a single bioinformatics toolkit is becoming a reality.

2. We present the modular metabarcode sequence toolkit Anacapa (https://github.com/limey-bean/Anacapa/), which addresses the above needs, allowing users to build comprehensive reference databases and assign taxonomy to raw multilocus metabarcode sequence data A novel aspect of Anacapa is our database building module, Creating Reference libraries Using eXisting tools (CRUX), which generates comprehensive reference databases for specific user-defined metabarcode loci. The Quality Control and Dereplication module sorts and processes multiple metabarcode loci and processes merged, unmerged and unpaired reads maximizing recovered diversity. Followed by amplicon sequence variants (ASVs) detection using DADA2. The Anacapa Classifier module aligns these ASVs to CRUX-generated reference databases using Bowtie2. Taxonomy is assigned to ASVs with confidence scores using a Bayesian Lowest Common Ancestor (BLCA) method. The Anacapa Toolkit also includes an R package, ranacapa, for automated results exploration through standard biodiversity statistical analysis.

3. We performed a series of benchmarking tests to verify that the Anacapa Toolkit generates comprehensive reference databases that capture wide taxonomic diversity and that it can assign high-quality taxonomy to both MiSeq-length and Hi-Seq length sequence data. We demonstrate the value of the Anacapa Toolkit to assigning taxonomy to eDNA sequences from seawater samples from southern California including capability of this tool kit to process multilocus metabarcoding data.

4. The Anacapa Toolkit broadens the exploration of eDNA and assists in biodiversity assessment and management by generating metabarcode specific databases, processing multilocus data, retaining all read types, and expanding non-traditional eDNA targets. Anacapa software and source code are open and available in a virtual container to ease installation.
Molecular convergence and positive selection associated with the evolution of symbiont transmission mode in stony corals
Authors: Dixon Groves B , Kenkel Carly D
Published: December 2018

Heritable symbioses are thought to be important for the maintenance of mutually beneficial relationships (1), and for facilitating major transitions in individuality, such as the evolution of the eukaryotic cell (2, 3). In stony corals, vertical transmission has evolved repeatedly (4), providing a unique opportunity to investigate the genomic basis of this complex trait. We conducted a comparative analysis of 25 coral transcriptomes to identify orthologous genes exhibiting both signatures of positive selection and convergent amino acid substitutions in vertically transmitting lineages. The frequency of convergence events tends to be higher among vertically transmitting lineages, consistent with the proposed role of natural selection in driving the evolution of convergent transmission mode phenotypes (5). Of the 10,774 total orthologous genes identified, 403 exhibited at least one molecular convergence event and evidence of positive selection in at least one vertically transmitting lineage. Functional enrichments among these top candidate genes include processes previously implicated in mediating the coral-Symbiodiniaceae symbiosis including endocytosis, immune response, cytoskeletal protein binding and cytoplasmic membrane-bounded vesicles (6). We also identified 100 genes showing evidence of positive selection at the particular convergence event. Among these, we identified several novel candidate genes, highlighting the value of our approach for generating new insight into the mechanistic basis of the coral symbiosis, in addition to uncovering host mechanisms associated with the evolution of heritable symbioses.
Counter-stimuli Inhibit GRPR Neurons via GABAergic Signaling in the Spinal Cord
Authors: Bardoni Rita , Barry Devin M. , Li Hui , Shen Kai-Feng , Jeffry Joseph , Yang Qianyi , Comitato Antonella , Li Yun-Qing , Chen Zhou-Feng
Published: December 2018

A myriad of counter-stimuli, including algogens and cooling, could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Optical or chemogenetic activation of GRPR neurons evokes itch behavior that is partly dependent on NK1R activation. Importantly, we show that noxious or cooling counter-stimuli inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which could evoke a mix of itch and pain sensations, could exert both excitatory and inhibitory effects on GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby counter-stimuli inhibit itch by suppressing the function of GRPR neurons.

Highlights

Activation of GRPR neurons evokes itch and is dependent upon NK1R activation

GRPR neurons receive both direct and indirect inputs from C/Aδ fibers

Counter-stimuli inhibit GRPR neurons via GABAergic signaling

Increased excitability of GRPR neurons in chronic itch condition
Accelerated Bayesian inference of gene expression models from snapshots of single-cell transcripts
Authors: Lin Yen Ting , Buchler Nicolas E.
Published: December 2018

Understanding how stochastic gene expression is regulated in biological systems using snapshots of single-cell transcripts requires state-of-the-art methods of computational analysis and statistical inference. A Bayesian approach to statistical inference is the most complete method for model selection and uncertainty quantification of kinetic parameters from single-cell data. This approach is impractical because current numerical algorithms are too slow to handle typical models of gene expression. To solve this problem, we first show that time-dependent mRNA distributions of discrete-state models of gene expression are dynamic Poisson mixtures, whose mixing kernels are characterized by a piece-wise deterministic Markov process. We combined this analytical result with a kinetic Monte Carlo algorithm to create a hybrid numerical method that accelerates the calculation of time-dependent mRNA distributions by 1000-fold compared to current methods. We then integrated the hybrid algorithm into an existing Monte Carlo sampler to estimate the Bayesian posterior distribution of many different, competing models in a reasonable amount of time. We validated our method of accelerated Bayesian inference on several synthetic data sets. Our results show that kinetic parameters can be reasonably constrained for modestly sampled data sets, if the model is known a priori. If the model is unknown,the Bayesian evidence can be used to rigorously quantify the likelihood of a model relative to other models from the data. We demonstrate that Bayesian evidence selects the true model and outperforms approximate metrics, e.g., Bayesian Information Criterion (BIC) or Akaike Information Criterion (AIC), often used for model selection.
Glycolipid composition of the heterocyst envelope of Anabaena sp. PCC 7120 is crucial for diazotrophic growth and relies on the UDP-galactose 4-epimerase HgdA
Authors: Shvarev Dmitry , Nishi Carolina N. , Maldener Iris
Published: December 2018

The nitrogenase complex in the heterocysts of the filamentous freshwater cyanobacterium Anabaena sp. PCC 7120 fixes atmospheric nitrogen to allow diazotrophic growth. The heterocyst cell envelope protects the nitrogenase from oxygen and consists of a polysaccharide and a glycolipid layer that are formed by a complex process involving the recruitment of different proteins. Here we studied the function of the putative nucleoside-diphosphate-sugar epimerase HgdA, which along with HgdB and HgdC is essential for deposition of the glycolipid layer and growth without a combined nitrogen source. Using site-directed mutagenesis and single homologous recombination approach, we performed a thoroughly functional characterization of HgdA and confirmed that the glycolipid layer of the hgdA mutant heterocyst is aberrant as shown by transmission electron microscopy and chemical analysis. The hgdA gene was expressed during late stages of the heterocyst differentiation. GFP-tagged HgdA protein localized inside the heterocysts. The purified HgdA protein had UDP-galactose 4-epimerase activity in vitro. This enzyme could be responsible for synthesis of heterocyst-specific glycolipid precursors, which could be transported over the cell wall by the ABC transporter components HgdB/HgdC.
Analysis of Epichloë festucae small secreted proteins in the interaction with Lolium perenne
Authors: Scott Barry , Hassing Berit , Winter David , Mesarich Carl , Eaton Carla , Becker Yvonne
Published: December 2018

Epichloë festucae is an endophyte of the agriculturally important perennial ryegrass. This species systemically colonises the aerial tissues of this host where its growth is tightly regulated thereby maintaining a mutualistic symbiotic interaction. Recent studies have suggested that small secreted proteins, termed effectors, play a vital role in the suppression of host defence responses. To date only a few effectors with important roles in mutualistic interactions have been described. Here we make use of the fully assembled E. festucae genome and EffectorP to generate a suite of 141 effector candidates. These were analysed with respect to their genome location and expression profiles in planta and in several symbiosis-defective mutants. We found an association between effector candidates and a class of transposable elements known as MITEs, but no correlation with other dynamic features of the E. festucae genome, such as transposable element-rich regions. Three effector candidates and a small GPI-anchored protein were chosen for functional analysis based on their high expression in planta compared to in culture and their differential regulation in symbiosis defective E. festucae mutants. All three candidate effector proteins were shown to possess a functional signal peptide and two could be detected in the extracellular medium by western blotting. Localization of the effector candidates in planta suggests that they are not translocated into the plant cell, but rather, are localized in the apoplastic space or are attached to the cell wall. Deletion and overexpression of the effector candidates, as well as the putative GPI-anchored protein, did not affect the plant growth phenotype or restrict growth of E. festucae mutants in planta. These results indicate that these proteins are either not required for the interaction at the observed life stages or that there is redundancy between effectors expressed by E. festucae.
Developing a conceptual framework of knowledge management
Authors: Farooq Rayees
Published: December 2018

Purpose

Knowledge management is a function of learning orientation, knowledge sharing, organizational memory and knowledge reuse. This paper aims to endeavor to explore a link between knowledge management and value creation which seem to be fragmented in the literature due to various conceptualizations and meanings. The study hypothesized a moderating role of social capital on the relationship between knowledge management and value creation.

Design/methodology/approach

The study was approached from the theoretical perspective. Study thoroughly reviews and analyzes the literature by developing a link between knowledge management and value creation. The studies were explored from selected databases including “Google scholar”, “Emerald” and “ProQuest” using the keyword search, namely, “Knowledge Sharing”, “Learning Orientation”, “Organizational Memory”, “Knowledge Re-use”, “Knowledge Management”, “Knowledge-based View”, “Competitive Advantage”, “Value Creation” and “Social Capital” to reduce the interpretation bias.

Findings

Knowledge management is an important predictor of value creation which can be strengthened by developing strong interpersonal relationships with all stakeholders. Organizations can create competitive advantage by managing social capital through knowledge management processes including learning orientation, knowledge sharing, organizational memory and knowledge reuse.

Research limitations/implications

The study is based on a theoretical model and an apparent limitation is the non-existence here of contributions and discussions that have been based on empirical data. Future study may use other moderating and mediating variables such as industry type, market orientation, human capital and organizational climate to know whether knowledge management directly affects the value creation or indirectly through these variables. The hypotheses emerged from the model can be operationalized by generating the items from the review of the literature.

Originality/value

The study contributes to the knowledge management literature by developing a theoretical model of knowledge management based on underlying dimensions of learning orientation, knowledge sharing, organizational memory and knowledge re-use.
An improved kinematic model for serial robot calibration based on local POE formula using position measurement
Authors: Liu Hua , Zhu Weidong , Dong Huiyue , Ke Yinglin
Published: December 2018

Purpose

This paper aims to propose a calibration model for kinematic parameters identification of serial robot to improve its positioning accuracy, which only requires position measurement of the end-effector.

Design/methodology/approach

The proposed model is established based on local frame representation of the product of exponentials (local POE) formula, which integrates all kinematic errors into the twist coordinates errors; then they are identified with the tool frame’ position deviations simultaneously by an iterative least squares algorithm.

Findings

To verify the effectiveness of the proposed method, extensive simulations and calibration experiments have been conducted on a 4DOF SCARA robot and a 5DOF drilling machine, respectively. The results indicate that the proposed model outperforms the existing model in convergence, accuracy, robustness and efficiency; fewer measurements are needed to gain an acceptable identification result.

Practical implications

This calibration method has been applied to a variable-radius circumferential drilling machine. The machine’s positioning accuracy can be significantly improved from 11.153 initially to 0.301 mm, which is well in the tolerance (±0.5 mm) for fastener hole drilling in aircraft assembly.

Originality/value

An accurate and efficient kinematic calibration model has been proposed, which satisfies the completeness, continuity and minimality requirements. Due to generality, this model can be widely used for serial robot kinematic calibration with any combination of revolute and prismatic joints.
Seismic damage of gravity abutment in liquefied ground
Authors: Wang Haitao , Shen Jiayu , Gao Da
Published: December 2018

Purpose

Abutment damage in liquefied ground is an important form of seismic damage of bridge structure. This paper aims to further research the effect of beam restriction on seismic damage mode of abutment in liquefied ground.

Design/methodology/approach

Based on the investigation of the seismic damage of Shengli Bridge in Tangshan earthquake, the finite element software dynamic effective stress analysis for ground (UWLC) is used to simulate the seismic damage of Shengli Bridge, and the results were compared with the actual seismic damage results. Then, the influences of the horizontal binding force of the beam, the liquefaction layer thickness, the top weight of the abutment, the peak acceleration, the liquefaction layer buried depth and the type of the foundation soil on the abutment seismic damage model are studied.

Findings

The results show that numerical simulation results are consistent with the actual seismic damage, and it is feasible to use UWLC software to simulate seismic damage. The results show that the seismic failure mode of the gravity abutment in liquefied ground is slip–rotation coupling type, not single slip type or rotation type. The large deformation of abutment bottom layer, horizontal binding force of the beam and post-stage soil pressure are the main reasons for abutment rotation or even destruction.

Research limitations/implications

A series of basic assumptions are used in the calculation process in this paper. The gravity abutment is defined as the elastic body and neglects its local deformation. The soil layer is a homogeneous isotropic. The consolidation process and the drainage boundary problem are not considered in the calculation process. Therefore, the paper may have some limitations.

Originality/value

To further research the seismic damage mode and influencing factors of abutment in liquefied ground, in this paper, based on the investigation of the seismic damage of Shengli Bridge in Tangshan earthquake, the finite element software UWLC is used to simulate the seismic damage of Shengli Bridge, and the results were compared with the actual seismic damage results. The seismic damage mode and influencing factors of gravity abutment in liquefied ground have been studied.
Re-imagining the country-of-origin effect: a promulgation approach
Authors: Andéhn Mikael , L’espoir Decosta Jean-Noel Patrick
Published: December 2018

Purpose

The country-of-origin effect (COO) has, as a research domain, suffered from several theoretical and methodological problems and tendencies including an incomplete conceptualization of its constituent components. The purpose of this study is to first problematize the concept in extant literature and to consequently propose a reconceptualization of the concept.

Design/methodology/approach

As part of lateral promulgation, the authors use theoretical and methodological ideas from other disciplines such as psychology, ethnography and geography to problematize the present conceptualization of COO in extant literature to reveal research possibilities relevant to, but underrepresented or absent in, COO research.

Findings

This study identifies several central theoretical and methodological problems and reveals that (1) COO is not necessarily linear and alternative modes of engagement with consumption need to be considered; (2) many of these problems can be addressed by alternative methodologies; and (3) COO operates at the level of symbolic orders that require a further engagement with the role of place in human experience.

Research/limitations/implications

The findings suggest that in future research, field experiments be considered to resolve some of the methodological artefacts that have hampered past research; qualitative methods be applied to uncover unexpected uses of place association beyond being mere quality proxies; and alternative areas of relevance, such as macro-level trade and exports from emerging economies, be entertained.

Originality Value

The study’s approach to problematizing and refining extant knowledge enable it to promulgate new knowledge and research directions for a research area that has historically suffered from a tendency to be self-referential.
Intrathecal betamethasone for cancer pain: A study of its analgesic efficacy and safety
Authors: Taguchi Hitoshi , Oishi Keiko , Shingu Koh , Matsumoto Hideo , Masuzawa Munehiro
Published: December 2018

Background

A preliminary study has shown effective cancer pain relief by intrathecal betamethasone (ITB). However, further evidence is needed to support this new approach.

Methods

Cancer patients with opioid‐resistant pain received lumbar intrathecal administration of betamethasone 2 or 3 mg once a week for 28 days. Immediate and short‐term analgesia (using a percentage pain reduction scale and a numerical rating scale, NRS) and long‐term analgesia (using NRS) were assessed. Patients were classified into two groups according to the most painful site of metastasis: vertebral column and/or surrounding nerve plexus metastases (group A) and other metastases distal from the vertebral column (group B).

Results

A total of 104 patients received ITB. Pain relief was observed not only in the lower half but also in the upper half of the body. The proportion of group A patients who experienced immediate analgesia was 81% (47/58), which was significantly greater than that of group B (P < 0.001). A decrease in NRS scores 1 day after ITB administration was observed in significantly more patients in group A than in group B (P < 0.001). Long‐term analgesia was also recorded in a greater proportion of patients in group A than in group B in the 7‐day (59%, 38/64 vs 6%, 2/33) and 28‐day periods (71%, 40/56 vs 31%, 8/26) (P < 0.001). No adverse effects related to neurotoxicity were recorded.

Conclusion

Intrathecal injection of betamethasone produced analgesia for opioid‐resistant cancer pain, and may be a potent therapeutic option for intolerable pain from vertebral column and/or surrounding nerve plexus metastases.
The Fyn kinase inhibitor, AZD0530, suppresses mouse alcohol self‐administration and seeking
Authors: Morisot Nadege , Berger Anthony L. , Phamluong Khanhky , Cross Alan , Ron Dorit
Published: December 2018

Fyn is a member of the Src family of protein tyrosine kinases (PTKs) that plays an important role not only in normal synaptic functions but also in brain pathologies including alcohol use disorder. We previously reported that repeated cycles of binge drinking and withdrawal activate Fyn in the dorsomedial striatum (DMS) of rodents, and that Fyn signaling in the DMS contributes to rat alcohol intake and relapse. Here, we used AZD0530, a CNS penetrable inhibitor of Src PTKs developed for the treatment of Alzheimer disease and cancer and tested its efficacy to suppress alcohol‐dependent molecular and behavioral effects. We show that systemic administration of AZD0530 prevents alcohol‐induced Fyn activation and GluN2B phosphorylation in the DMS of mice. We further report that a single dose of AZD0530 reduces alcohol operant self‐administration and promotes extinction of alcohol self‐administration without altering basal and dopamine D1 receptor‐dependent locomotion. Together, our findings suggest that AZD0530, through its inhibitory actions on Fyn kinase, dampens alcohol seeking and drinking.
Association between semen parameters and chance of fatherhood ‐ a long‐term follow‐up study
Authors: Malm G. , Rylander L. , Giwercman A. , Haugen T. B.
Published: December 2018

Background

Evaluation of male fertility includes standard semen analysis; however, there is uncertainty about the value of sperm parameters in predicting fertility.

Objective

To evaluate the association between semen parameters and fatherhood during a long‐time period.

Materials and methods

Semen parameters (total sperm count, concentration, motility, and morphology) and sperm DNA fragmentation Index (DFI) assessed on samples collected from 195 Norwegian men from the general population in 2001/2002 were matched with information about fatherhood until 2015, obtained from the Medical Birth Register. The parameters were dichotomized as normal vs. abnormal according to the WHO reference values from 1999 and 2010. Cut‐offs at 20% and 30% were used for DFI.

Results

Among men who had no children before 2003, those with normal progressive sperm motility had more often become fathers (WHO 1999, cut‐off ≥50%, adjusted OR 2.8, 95% CI 1.3–6.1 and WHO 2010, cut‐off ≥32%; aOR 4.2, 95% CI 1.1–15). Based on the WHO 1999 reference value, men with normal sperm concentration (≥20 × 106/mL) had more often become fathers (aOR 3.1, 95% CI 1.1–8.6). Men with progressive sperm motility ≥50% and concentration ≥20 × 106/mL did more often achieve fatherhood (aOR 8.4, 95% CI 2.1–34). For DFI, there was a borderline significance at cut‐off 20% in the group of men who had ever been fathers (OR 2.7, 95% CI 1.0–7.0 p < 0.05).

Discussion

The results indicate that sperm progressive motility, sperm concentration, and DFI are associated with fatherhood during a longer time period, with sperm motility being most consistent. Although the sample size is relatively small and our results should be replicated in larger studies, they may be of clinical relevance.

Conclusion

Semen parameters may have a diagnostic value not only in a short time frame but also for predicting future fertility potential.
The sonic hedgehog pathway mediates Tongxinluo capsule‐induced protection against blood‐brain barrier disruption after ischaemic stroke in mice
Authors: Liu Shen , Chang Liping , Wei Cong
Published: December 2018

Tongxinluo capsule (TXL), a Chinese prescription, has been extensively used for treating ischaemic cerebrovascular diseases in China. Studies have demonstrated that TXL protects the blood‐brain barrier (BBB) after cerebral ischaemia. However, the underlying protective mechanisms are not fully elucidated. Enlightened by the critical role of sonic hedgehog (Shh) pathway in promoting BBB integrity through up‐regulating tight junction (TJ) proteins, we examined whether the Shh pathway could mediate TXL‐induced up‐regulation of TJ proteins and subsequent protection against BBB disruption after stroke. Ischaemic stroke was induced in adult male C57BL/6J mice by permanent middle cerebral artery occlusion (pMCAO). The mice were orally administered TXL (3.0 g/kg) at 1, 3 and 21 hours after stroke. Meanwhile, cyclopamine, a specific Shh pathway inhibitor, was intraperitoneally injected at 1 and 21 hours after stroke. The following parameters were measured at 6 and 24 hours after pMCAO: BBB permeability; TJ proteins including occludin, claudin‐5 and zonula occludens‐1 (ZO‐1); and Shh signalling molecules such as Shh, Patched, Smoothened (Smo) and Gli‐1. Our results showed that TXL protected against BBB disruption at 6 and 24 hours after pMCAO, and cyclopamine partly reversed the protective effect of TXL on BBB. Meanwhile, cyclopamine blocked the effect of TXL–up‐regulated expression of occludin, claudin‐5 and ZO‐1. Moreover, TXL up‐regulated the expression of Shh derived from astrocytes, Patched, Smo and Gli‐1, and thus activated the Shh pathway. And cyclopamine inhibited TXL‐induced activation of the Shh pathway. Thus, our study demonstrates that the Shh pathway mediates TXL‐induced protection against BBB disruption after ischaemic stroke.
Neoglacial transition of atmospheric circulation patterns over Fennoscandia recorded in Holocene Lake Torneträsk sediments
Authors: Thienemann Matthias , Kusch Stephanie , Vogel Hendrik , Ritter Benedikt , Schefuẞ Enno , Rethemeyer Janet
Published: December 2018

Atmospheric circulation over the North Atlantic has undergone significant fluctuations during the Holocene. To better constrain these changes and their impacts on the Fennoscandian subarctic, we investigated molecular and inorganic proxies as well as plant wax D/H isotopes (δDC28) in a Holocene sedimentary record from Lake Torneträsk (Sweden). These data indicate a thermal maximum c. 8100 to 6300 cal. a BP with reduced soil organic matter input, followed by a long‐term cooling trend with increasing soil erosion. δD data suggest a stable atmospheric circulation with predominance of westerly flow and North Atlantic moisture sourcing during the Early and Middle Holocene. A substantial depletion in δD followed by increased flood frequency starting at c. 5300 cal. a BP and intensifying c. 1500 cal. a BP suggests a reorganization of the atmospheric circulation from zonal towards meridional flow with predominantly Arctic Ocean and Baltic Sea moisture sourcing.
“I was Excited by the Idea of a Project that Focuses on those Unasked Questions” Co‐Producing Disability Research with Disabled Young People
Authors: Liddiard Kirsty , Runswick‐Cole Katherine , Goodley Dan , Whitney Sally , Vogelmann Emma , Watts MBE Lucy
Published: December 2018

In this article, we detail the politics and practicalities of co‐produced disability research with disabled young people with life‐limiting and life‐threatening impairments. We centre an ESRC‐funded arts‐informed co‐produced research project that has brought together a Co‐Researcher Collective of disabled young people. Co‐production is an established approach; however, our co‐researchers have led us to develop inclusive research practices that engage with online social research methods in innovative ways. As we detail our experiences, we aim to encourage disability studies researchers and others to adopt virtual environments when researching with and for the lives of disabled people.
Mitochondrial DNA mutation m.3243A>G is associated with altered mitochondrial function in peripheral blood mononuclear cells, with heteroplasmy levels and with clinical phenotypes
Authors: Geng X. , Zhang Y. , Yan J. , Chu C. , Gao F. , Jiang Z. , Zhang X. , Chen Y. , Wei X. , Feng Y. , Lu H. , Wang C. , Zeng F. , Jia W.
Published: December 2018

Aims

To investigate the associations among heteroplasmy levels (i.e. the proportions of mutant and wild‐type mitochondrial DNA in the same cell), mitochondrial function and clinical severity of the m.3243A>G mutation.

Methods

A total of 17 participants carrying the m.3243A>G mutation and 17 sex‐ and age‐matched healthy controls were included in this study. Heteroplasmy levels of the m.3243A>G mutation in leukocytes, saliva and urine sediment were determined by pyrosequencing. The clinical evaluation included endocrinological, audiological and ophthalmological examinations. Mitochondrial function was determined in peripheral blood mononuclear cells isolated from participants.

Results

Heteroplasmy levels in urine sediment were higher than those in leukocytes and saliva. Reduced levels of adenosine triphosphate and mitochondrial membrane potential, and increased reactive oxygen species production were observed in mutant peripheral blood mononuclear cells (all P < 0.05). Linear regression analysis indicated that higher heteroplasmy levels in peripheral blood leukocytes were associated with increased levels of glycated albumin and HbA1c, and decreased total hip bone mineral density T‐score after adjustment for age and sex (all P < 0.05). Furthermore, mitochondrial membrane potential was independently associated with bone mineral density T‐score at the femoral neck (P < 0.05).

Conclusions

Heteroplasmy levels in peripheral blood leukocytes and mitochondrial membrane potential in peripheral blood mononuclear cells were closely associated with clinical manifestations and were valuable for evaluation of the clinical severity of the m.3243A>G mutation.
Dietary protein affects both the dose and pattern of insulin delivery required to achieve postprandial euglycaemia in Type 1 diabetes: a randomized trial
Authors: Evans M. , Smart C. E. M. , Paramalingam N. , Smith G. J. , Jones T. W. , King B. R. , Davis E. A.
Published: December 2018

Aim

To quantify the insulin requirement for a high‐protein meal compared with a low‐protein meal, controlling for carbohydrate and fat content.

Methods

In this crossover study, young people with Type 1 diabetes were randomized to consume a high‐ (60 g) or low‐protein meal (5 g), each containing 30 g carbohydrate and 8 g fat. A variation of the insulin clamp technique was used to determine the insulin requirements to maintain euglycaemia for the following 5 h.

Results

A total of 11 participants (mean ± sd age 16.5 ± 2.7 years, HbA1c 52 ± 8.7 mmol/mol [6.9 ± 0.8%], diabetes duration 6.9±5.1 years) completed the study. The mean insulin requirements for the high‐protein meal were higher than for the low‐protein meal [10.3 (CI 8.2, 12.57) vs 6.7 units (CI 4.7, 8.8); P=0.001], with inter‐individual requirements ranging from 0.9 to six times the low‐protein meal requirement. Approximately half the additional insulin [1.1 units/h (CI 0.5, 1.8; P=0.001)] was given in the first 2 h, compared with an additional 0.5 units/h (CI –0.2, 1.2; P=0.148) in the second 2 h and 0.1 units (CI –0.6, 0.8; P=0.769) in the final hour.

Conclusions

A high‐protein meal requires ~50% more insulin to maintain euglycaemia than a low‐protein meal that contains the same quantity of carbohydrate. The majority is required within the first 2 h. Inter‐individual differences exist in insulin requirements for dietary protein.
Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability
Authors: Snoeijen‐Schouwenaars Francesca M. , van Ool Jans S. , Verhoeven Judith S. , van Mierlo Petra , Braakman Hilde M. H. , Smeets Eric E. , Nicolai Joost , Schoots Jeroen , Teunissen Mariel W. A. , Rouhl Rob P. W. , Tan In Y. , Yntema Helger G. , Brunner Han G. , Pfundt Rolph , Stegmann Alexander P. , Kamsteeg Erik‐Jan , Schelhaas Helenius J. , Willemsen Marjolein H.
Published: December 2018

Objective

Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy.

Methods

One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so‐called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines.

Results

In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future.

Significance

This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield.
Cis‐trans proline isomers in the catalytic domain of calcineurin
Authors: Teixeira João M.C. , Guasch Alicia , Biçer Atilla , Aranguren‐Ibáñez Álvaro , Chashmniam Saeed , Paniagua Juan Carlos , Pérez‐Riba Mercè , Fita Ignacio , Pons Miquel
Published: December 2018

Calcineurin is an essential calcium‐activated serine/threonine phosphatase. The six NMR‐observable methionine methyl groups in the catalytic domain of human calcineurin Aα (CNA) were assigned and used as reporters of the presence of potential cis‐trans isomers in solution. Proline 84 is found in the cis conformation in most calcineurin X‐ray structures, and proline 309, which is part of a highly conserved motif in phosphoprotein phosphatases, was modeled with a cis peptide bond in one of the two molecules present in the asymmetric unit of CNA. We mutated each of the two prolines to alanine to force the trans conformation. Solution NMR shows that the P84A CNA mutant exists in two forms, compatible with cis‐trans isomers, while the P309A mutant is predominantly in the trans conformation.

Database

PDB depositions mentioned PDB 5C1V and 2JOG.
Primary liver carcinoma with sarcomatous changes: Analysis of 10 cases
Authors: Ohya Kazuki , Saitoh Satoshi , Fujiyama Shunichiro , Kawamura Yusuke , Sezaki Hitomi , Hosaka Tetsuya , Akuta Norio , Kobayashi Masahiro , Kobayashi Mariko , Suzuki Fumitaka , Suzuki Yoshiyuki , Arase Yasuji , Ikeda Kenji , Kinowaki Keiichi , Fujii Takeshi , Kondo Fukuo , Kumada Hiromitsu
Published: December 2018

Primary liver carcinoma with sarcomatous change is a rare malignancy associated with high aggressiveness and poor prognosis. However, the characteristics of these types of tumors are still unknown. The aim of this study was to assess the imaging features, prognostic significance, and clinicopathological characteristics of patients with these tumors. Of 1070 patients who underwent surgical resection of primary liver carcinoma at Toranomon Hospital (Tokyo, Japan) from 2003 to 2017, 10 patients were diagnosed with primary liver carcinoma containing sarcomatous component. This study included all 10 patients. We evaluated the percentage of the sarcomatous component in each tumor. Patients were classified into two groups: the low percentage group (area of sarcomatous changes ≤30%) and high percentage group (area sarcomatous component ≥70%). We also divided patients into two groups based on the combination of the percentage of sarcomatous tissue and tumor size (≥40 mm or <40 mm). The overall survival rate of patients with ≥70% sarcomatous component and ≥40 mm tumor was significantly worse than that of patients with ≤30% sarcomatous tissue or <40 mm tumor size (P = 0.0059). The results confirmed the poor prognosis of patients with sarcomatous changes in primary liver carcinoma, especially those with large sarcomatous component and large tumor size. Radical resection in the early stage is recommended to improve prognosis.
The meanings of place and space in forensic psychiatric care – A qualitative study reflecting patients’ point of view
Authors: Olausson Sepideh , Danielson Ella , Berglund Johansson Inger , Wijk Helle
Published: December 2018

The outcome of care for patients sentenced to forensic psychiatric care is of importance not only for the patient but also for society, in preventing new crimes. In recent years, a person‐centered perspective is influencing the care, recognizing the design of the physical environment as a therapeutic resource. To capture the complexity of patients’ experience of the physical environment, a qualitative approach is needed. The aim of this study was to investigate the meanings of the patient room as a place and space in forensic psychiatric in‐patient care from the patients’ perspective. An explorative qualitative design was chosen, data were collected by photovoice; a combination of photographs, taken by the patients, followed by interviews. Eleven (N = 11) patients were interviewed. The interviews were analysed by a thematic analysis method. Four themes emerged from the data revealing the meanings of the patient room as a place and space: (i) striving towards normality; (ii) being anchored and protected; (iii) being at‐home and homeness; and (iv) being in communion and meaningfulness. The findings show that the physical environment has a say in patients’ basic needs and a role in maintaining normality. Substandard reveals a lack of respect and dignity towards this patient group. Involving patients in the design process of new facilities can be a way to make progress.
Complex Contingency Tables Treated by the Partition of χ2
Authors: Lancaster H. O.
Published: December 2018

The partition of χ2 can be used to investigate the interactions of all orders in the higher contingency tables. The χ2, obtained by partition, in the case of the 2 × 2 × 2 table for the second order interaction is asymptotically equal to that obtained by Bartlett (1935).

Difficulties arise when an attempt is made to find an exact solution. The method of obtaining matrices for orthogonal transformations of variables arranged in hierarchical order is explained. The orthogonal transformation in the case of the 2 × 2 × 2 table is given in full.
Inversions and Rank Correlation Coefficients
Authors: Durbin J. , Stuart A.
Published: December 2018

A relation is developed between Spearman’s coefficient of rank correlation rs and the inversions in the two rankings. This leads to an expression for the mean value of rs in samples from a finite population, and to the improvement of Daniels’ inequality relating rs and Kendall’s coefficient t.
On Queueing Processes with Bulk Service
Authors: Bailey Norman T. J.
Published: December 2018

A mathematical investigation has been made of a simple queueing process in which customers arrive at random, form a single queue in order of arrival, and are served in batches, the size of each batch having a fixed maximum. In most of the results obtained the time intervals between successive occasions of service are assumed to be independently distributed in χ2 distributions with an even number of degrees of freedom (including the special cases of a random distribution and a constant service interval). The equilibrium distribution of queue length has been studied by the imbedded Markov chain method, and ergodicity established when the average demand is less than the average supply available. Expressions for the mean and variance of queue length, and the mean waiting-time are given. A useful inequality for the latter is also available in the special case of a constant service interval. An immediate application can be made to hospital out-patient departments, with possible extensions to lifts, buses and so on.
On Minimizing a Convex Function Subject to Linear Inequalities
Authors: Beale E. M. L.
Published: December 2018

The minimization of a convex function of variables subject to linear inequalities is discussed briefly in general terms. Dantzig’s Simplex Method is extended to yield finite algorithms for minimizing either a convex quadratic function or the sum of the t largest of a set of linear functions, and the solution of a generalization of the latter problem is indicated. In the last two sections a form of linear programming with random variables as coefficients is described, and shown to involve the minimization of a convex function.
Waiting Time in Bulk Service Queues
Authors: Downton F.
Published: December 2018

The queuing process considered is that in which customers arrive at random and form a single queue in order of arrival. They are served in batches, the size of the batch being either a fixed number or the size of the queue, whichever is the smaller. Assuming that the queue is in equilibrium, the Laplace transform of the waiting time distribution is derived from the probability generating function of the queue length distribution. Expressions are obtained for the mean and variance of the waiting time, and a brief discussion is included of the computation of these quantities when the time intervals between successive epochs of service are independently distributed in a χ2 distribution with an even number of degrees of freedom. A short table of numerical results is given.
On the Weighted Combination of Significance Tests
Authors: Good I. J.
Published: December 2018

The distribution of Q=P1λ1P2λ2…Pnλn is obtained where p  1, p  2 … pn are independent tail-area probabilities arising from n continuous distributions.
New Tables of Behrens’ Test of Significance
Authors: Fisher R. A. , Healy M. J. R.
Published: December 2018

The Tables for using Behren’s test of significance of the difference between the means of two Normal samples are already available to reasonable accuracy for all cases save those involving very small samples (Statistical Tables, Tables VI, V2). In some experimental work, however, such small samples occur in conditions in which only Behren’s test is appropriate. The calculation of values for such cases is greatly facilitated by the explicit expressions developed in this note for the probability integral, when the numbers of degrees of freedom are both odd.
Curve and Periodogram Smoothing
Authors: Whittle P.
Published: December 2018

The difficulty in constructing smoothing formulae is to express quantitatively the type of smoothness one expects of the curve one is estimating. An argument is given in Sections 1 and 3 for formulating this “smoothness hypothesis” in terms of the properties of a population of curves of which the curve being estimated is a member. In equation (20) we obtain a solution for the matrix of optimum weighting coefficients in terms of certain “population moments” of the ordinates of the curve. Explicit formulae based on special assumptions are deduced in equations (34), (56)–(58). General information is gained on the way the optimum smoothing function and the variance of the smoothed estimate vary with the sample size and with the assumed degree of smoothness of the parent curve.
Distributions Associated with Random Walk and Recurrent Events
Authors: Skellam J. G. , Shenton L. R.
Published: December 2018

The main results in both the discrete and continuous cases are summarized side by side in Tables 8a and 8b.
Sampling Without Replacement with Probability Proportional to Size
Authors: Stevens W. L.
Published: December 2018

It is shown that sampling without replacement with probability proportional to size can be achieved if the units are grouped with reference to size. When the same unit is chosen a second time, it is substituted by another unit of the same size chosen at random. The estimate of the population total is formally the same as when sampling is done with replacement. The estimate of variance differs in that from the sum of squares of deviations of the ratio, r, we subtract, for each group chosen t (> 1) times, the quantity tS/N, where S is the sum of squares of deviations within the group and N the number in the group.
Multivariate Quantal Analysis
Authors: Claringbold P. J.
Published: December 2018

The canonical analysis of quantal data is described and a practical example given.
On Selecting the Largest of k Normal Population Means
Authors: Dunnett C. W.
Published: December 2018

Consider a k-variate normal distribution with unknown means μ  1, …, μk and with equal variances and equal covariances whose values are known; the problem is to select the variate associated with μ  max using a single-sample procedure of size n, and, in particular, to determine the required value of n. Previous work is reviewed. New results are given assuming that the population means μ  1, …, μk have a joint a priori normal distribution with means U  1, …, Uk known up to an additive constant, and with equal variances and equal covariances whose values are known.

Results are given first for the probability of correct selection, then for that probability taken conditionally on the largest μ exceeding the other μ’s by at least a specified amount, and for the probability of the selected mean being within a specified amount of the largest, the latter formulation being equivalent to considering a certain zero-one loss function. Next a loss function is assumed linear in the difference between μ  max and the selected μ and an experimentation cost proportional to n. The choice of k and n is considered and the relation with the plant-selection problem pointed out. The minimax solution and the concept of the “largest admissible” value of n are also discussed.

In an appendix an expression is given for the expected value of the maximum of k equally correlated normal variates with equal variances but unequal means.