bluuebunny/crossref_metadata_2025 huggingface dataset:
Ndc80/Nuf2-like protein KKIP1 connects a stable kinetoplastid outer kinetochore complex to the inner kinetochore and responds to metaphase tension
Authors: Brusini Lorenzo , D’Archivio Simon , McDonald Jennifer , Wickstead Bill
Published: September 2019

Kinetochores perform an essential role in eukaryotes, coupling chromosomes to the mitotic spindle. In model organisms they are composed of a centromere-proximal inner kinetochore and an outer kinetochore network that binds to microtubules. In spite of its universal function, the composition of kinetochores in extant eukaryotes can differ greatly, and understanding how these different systems evolved and now function are important questions in cell biology. In trypanosomes and other Kinetoplastida, the kinetochores are extremely divergent, with most components showing no detectable similarity to proteins in other systems. They may also be very different functionally, potentially binding to the spindle directly via the inner kinetochore protein KKT4. However, we do not know the extent of the trypanosome kinetochore and proteins interacting with a highly divergent Ndc80/Nuf2-like protein, KKIP1, suggest the existence of more centromere-distal complexes. Here we use quantitative proteomics from multiple start-points to define a stable 9-protein kinetoplastid outer kinetochore (KOK) complex. Two of these core components were recruited from other nuclear processes, exemplifying the role of moonlighting proteins in kinetochore evolution. The complex is physically and biochemically distinct from KKT proteins, but KKIP1 links the inner and outer sets, with its C-terminus very close to the centromere and N-terminus at the outer kinetochore. Moreover, trypanosome kinetochores exhibit intra-kinetochore movement during metaphase, primarily by elongation of KKIP1, consistent with pulling at the outer kinetochores. Together, these data suggest that the KOK complex, KKIP5 and N-terminus of KKIP1 likely constitute the extent of the trypanosome outer kinetochore and that this assembly binds to the spindle with sufficient strength to stretch the kinetochore.
Segmenting nuclei in brightfield images with neural networks
Authors: Fishman Dmytro , Salumaa Sten-Oliver , Majoral Daniel , Peel Samantha , Wildenhain Jan , Schreiner Alexander , Palo Kaupo , Parts Leopold
Published: September 2019

Identifying nuclei is a standard first step to analysing cells in microscopy images. The traditional approach relies on signal from a DNA stain, or fluorescent transgene expression localised to the nucleus. However, imaging techniques that do not use fluorescence can also carry useful information. Here, we demonstrate that it is possible to accurately segment nuclei directly from brightfield images using deep learning. We confirmed that three convolutional neural network architectures can be adapted for this task, with U-Net achieving the best overall performance, Mask R-CNN providing an additional benefit of instance segmentation, and DeepCell proving too slow for practical application. We found that accurate segmentation is possible using as few as 16 training images and that models trained on images from similar cell lines can extrapolate well. Acquiring data from multiple focal planes further helps distinguish nuclei in the samples. Overall, our work liberates a fluorescence channel reserved for nuclear staining, thus providing more information from the specimen, and reducing reagents and time required for preparing imaging experiments.
Sequences of Intonation Units form a ~1 Hz rhythm
Authors: Inbar Maya , Grossman Eitan , Landau Ayelet N.
Published: September 2019

Studies of speech processing investigate the relationship between temporal structure in speech stimuli and neural activity. Despite clear evidence that the brain tracks speech at low frequencies (~1 Hz), it is not well understood what linguistic information gives rise to this rhythm. Here, we harness linguistic theory to draw attention to Intonation Units (IUs), a fundamental prosodic unit of human language, and characterize their temporal structure as captured in the speech envelope, an acoustic representation relevant to the neural processing of speech.

IUs are defined by a specific pattern of syllable delivery, together with resets in pitch and articulatory force. Linguistic studies of spontaneous speech indicate that this prosodic segmentation paces new information in language use across diverse languages. Therefore, IUs provide a universal structural cue for the cognitive dynamics of speech production and comprehension.

We study the relation between IUs and periodicities in the speech envelope, applying methods from investigations of neural synchronization. Our sample includes recordings from every-day speech contexts of over 100 speakers and six languages. We find that sequences of IUs form a consistent low-frequency rhythm and constitute a significant periodic cue within the speech envelope. Our findings allow to predict that IUs are utilized by the neural system when tracking speech, and the methods we introduce facilitate testing this prediction given physiological data.
Single-trial dynamics of competing reach plans in the human motor periphery
Authors: Selen Luc P. J. , Corneil Brian D. , Medendorp W. Pieter
Published: September 2019

Contemporary motor control theories propose competition between multiple motor plans before the winning command is executed. While most competitions are completed prior to movement onset, movements are often initiated before the competition has been resolved. An example of this is saccadic averaging, wherein the eyes land at an intermediate location between two visual targets. Behavioral and neurophysiological signatures of competing motor commands have also been reported for reaching movements, but debate remains about whether such signatures attest to an unresolved competition, arise from averaging across many trials, or reflect a strategy to optimize behavior given task constraints. Here, we recorded electromyographic activity from an upper limb muscle (m. pectoralis) while twelve (8 female) participants performed an immediate response reach task, freely choosing between one of two identical and suddenly presented visual targets. On each trial, muscle recruitment showed two distinct phases of directionally-tuned activity. In the first wave, time-locked ~100 ms of target presentation, muscle activity was clearly influenced by the non-chosen target, reflecting a competition between reach commands that was biased in favor of the ultimately chosen target. This resulted in an initial movement intermediate between the two targets. In contrast, the second wave, time-locked to voluntary reach onset, was not biased toward the non-chosen target, showing that the competition between targets was resolved. Instead, this wave of activity compensated for the averaging induced by the first wave. Thus, single-trial analysis reveals an evolution in how the non-chosen target differentially influences the first and second wave of muscle activity.

SIGNIFICANCE STATEMENT

Contemporary theories of motor control suggest that multiple motor plans compete for selection before the winning command is executed. Evidence for this is found in intermediate reach movements towards two potential target locations, but recent findings have challenged this notion by arguing that intermediate reaching movements reflect an optimal response strategy. By examining upper limb muscle recruitment during a free-choice reach task, we show early recruitment of a sub-optimal averaged motor command to the two targets that subsequently transitions to a single motor command that compensates for the initially averaged motor command. Recording limb muscle activity permits single-trial resolution of the dynamic influence of the non-chosen target through time.
Revealing the structure of information flows discriminates similar animal social behaviors
Authors: Valentini Gabriele , Mizumoto Nobuaki , Pratt Stephen C. , Pavlic Theodore P. , Walker Sara Imari
Published: September 2019

Behavioral correlations stretching over time are an essential but often neglected aspect of interactions among animals. These correlations pose a challenge to current behavioral-analysis methods that lack effective means to analyze complex series of interactions. Here we show that non-invasive information-theoretic tools can be used to reveal communication protocols that guide complex social interactions by measuring simultaneous flows of different types of information between subjects. We demonstrate this approach by showing that the tandem-running behavior of the ant Temnothorax rugatulus and that of the termites Coptotermes formosanus and Reticulitermes speratus are governed by different communication protocols. Our discovery reconciles the diverse ultimate causes of tandem running across these two taxa with their apparently similar signaling mechanisms. We show that bidirectional flow of information is present only in ants and is consistent with the use of acknowledgement signals to regulate the flow of directional information.
The medial temporal lobe is critical for spatial relational perception
Authors: Ruiz Nicholas A. , Meager Michael R. , Agarwal Sachin , Aly Mariam
Published: September 2019

The medial temporal lobe (MTL) is traditionally considered to be a system that is specialized for long-term memory. Recent work has challenged this notion by demonstrating that this region can contribute to many domains of cognition beyond long-term memory, including perception and attention. One potential reason why the MTL (and hippocampus specifically) contributes broadly to cognition is that it contains relational representations — representations of multidimensional features of experience and their unique relationship to one another — that are useful in many different cognitive domains. Here, we explore the hypothesis that the hippocampus/MTL plays a critical role in attention and perception via relational representations. We compared human participants with MTL damage to healthy age- and education-matched individuals on attention tasks that varied in relational processing demands. On each trial, participants viewed two images (rooms with paintings). On ‘similar room’ trials, they judged whether the rooms had the same spatial layout from a different perspective. On ‘similar art’ trials, they judged whether the paintings could have been painted by the same artist. On ‘identical’ trials, participants simply had to detect identical paintings or rooms. Patients were significantly and selectively impaired on the similar room task. This work provides further evidence that the hippocampus/MTL plays a ubiquitous role in cognition by virtue of its relational and spatial representations, and highlights its important contributions to rapid perceptual processes that benefit from attention.
Co-option of the lineage-specificLAVAretrotransposon in the gibbon genome
Authors: Okhovat Mariam , Nevonen Kimberly A. , Davis Brett A. , Michener Pryce , Ward Samantha , Milhaven Mark , Harshman Lana , Sohota Ajuni , Fernandes Jason D. , Salama Sofie R. , O’Neill Rachel J. , Ahituv Nadav , Veeramah Krishna R. , Carbone Lucia
Published: September 2019

Co-option of transposable elements (TEs) to become part of existing or new enhancers is an important mechanism for evolution of gene regulation. However, contributions of lineage-specific TE insertions to recent regulatory adaptations remain poorly understood. Gibbons present a suitable model to study these contributions as they have evolved a lineage-specific TE calledLAVA,which is still active in the gibbon genome. The LAVA retrotransposon is thought to have played a role in the emergence of the unusually rearranged structure of the gibbon genome by disrupting transcription of cell cycle genes. In this study, we investigated whether LAVA may have also contributed to the evolution of gene regulation by adopting enhancer function. We characterized fixed and polymorphic LAVA insertions across multiple gibbons and found 96 LAVA elements overlapping enhancer chromatin states. Moreover, LAVA was enriched in multiple transcription factor binding motifs, was bound by an important transcription factor (PU.1), and was associated with higher levels of gene expression incis. We found gibbon-specific signatures of purifying/positive selection at 27 LAVA insertions. Two of these insertions were fixed in the gibbon lineage and overlapped with enhancer chromatin states, representing putative co-opted LAVA enhancers. These putative enhancers were located within genes encoding SETD2 and RAD9A, two proteins that facilitate accurate repair of DNA double-strand breaks and prevent chromosomal rearrangement mutations. Thus, LAVA’s co-option in these genes may have influenced regulation of processes that preserve genome integrity. Our findings highlight the importance of considering lineage-specific TEs in studying evolution of novel gene regulatory elements.
Spatial distribution of lamin A determines nuclear stiffness and stress-mediated deformation
Authors: Srivastava Luv Kishore , Ju Zhaoping , Ghagre Ajinkya , Ehrlicher Allen J.
Published: September 2019

The nucleus is the largest organelle and information center of the cell; while diverse cellular components have been identified as mechanotransduction elements, the deformation of the nucleus itself is emerging as a critical mechanosensory mechanism, suggesting that the nuclear stiffness is essential in determining responses to intracellular and extracellular stresses. The nuclear membrane protein, lamin A, is known to be a dominant component in nuclear stiffening; however, the quantitative relationship between lamin A expression and nuclear deformation is still unclear. Here we measure the nuclear moduli as a function of lamin A expression and applied stress, revealing a linear dependence of bulk modulus on lamin A expression. We also find that the bulk modulus is anisotropic, with the vertical axis of the nucleus being more compliant than the minor and major axis. To examine how lamin A influences nuclear mechanics at the sub-micron scale we correlated the spatial distribution of lamin A with 3D nuclear envelope deformation, revealing that local areas of the nuclear envelope with higher expression levels of lamin A have correspondingly lower local deformations, and that increased lamin A expression levels result in a narrower distribution of smaller deformations. These findings describe the complex dispersion of nuclear deformations as a function of lamin A expression and distribution and implicate a role in mechanotransduction.
PARC: ultrafast and accurate clustering of phenotypic data of millions of single cells
Authors: Stassen Shobana V. , Siu Dickson M. D. , Lee Kelvin C. M. , Ho Joshua W. K. , So Hayden K. H. , Tsia Kevin K.
Published: September 2019

Motivation

New single-cell technologies continue to fuel the explosive growth in the scale of heterogeneous single-cell data. However, existing computational methods are inadequately scalable to large datasets and therefore cannot uncover the complex cellular heterogeneity.

Results

We introduce a highly scalable graph-based clustering algorithm PARC -phenotyping by accelerated refined community-partitioning –for ultralarge-scale, high-dimensional single-cell data (> 1 million cells). Using large single cell mass cytometry, RNA-seq and imaging-based biophysical data, we demonstrate that PARC consistently outperforms state-of-the-art clustering algorithms without sub-sampling of cells, including Phenograph, FlowSOM, and Flock, in terms of both speed and ability to robustly detect rare cell populations. For example, PARC can cluster a single cell data set of 1.1M cells within 13 minutes, compared to >2 hours to the next fastest graph-clustering algorithm, Phenograph. Our work presents a scalable algorithm to cope with increasingly large-scale single-cell analysis.

Availability and Implementation

https://github.com/ShobiStassen/PARC
Short-term effects on brain functional network caused by focused-attention meditation revealed by Tucker3 clustering on graph theoretical metrics
Authors: Miyoshi Takuma , Tanioka Kensuke , Yamamoto Shoko , Yadohisa Hiroshi , Hiroyasu Tomoyuki , Hiwa Satoru
Published: September 2019

This study examines the short-term effects of focused-attention meditation on functional brain state in novice meditators. There are a number of feature metrics for functional brain states, such as functional connectivity, graph theoretical metrics, and amplitude of low frequency fluctuation (ALFF). It is necessary to choose appropriate metrics and also to specify the region of interests (ROIs) from a number of brain regions. Here, we use a Tucker3 clustering method, which simultaneously selects the feature vectors (graph theoretical metrics and fractional ALFF) and the ROIs that can discriminate between resting and meditative states based on the characteristics of the given data. In this study, breath-counting meditation, one of the most popular forms of focused-attention meditation, was used and brain activities during resting and meditation states were measured by functional magnetic resonance imaging. The results indicated that the clustering coefficients of eight brain regions tended to increase through the meditation. Our results reveal that short-term effects of breath-counting meditation can be explained by network density changes in these eight brain regions.
Related party transactions disclosure and procedures: a critical analysis in business groups
Authors: Marchini Pier Luigi , Andrei Paolo , Medioli Alice
Published: September 2019

Purpose

In the light of the risks involved in related party transactions, transparent disclosure is particularly important. The impact of related party transactions is relevant for all types of company, but there is greater complexity in business groups where they can be easier to hide. Focusing on business groups, this study aims to analyze the accuracy and transparency of related party transaction information, its understandability, compliance with legislation and comparability. It also examines whether shareholders can be fully informed of all related party transactions by reading only the consolidated financial statement.

Design/methodology/approach

Three case studies are used. The units of analysis are three corporate groups in which the parent company is listed on the Milan Stock Exchange as of 1 July 2015. The authors use two different sets of information. The first is secondary data from company procedures, annual reports and other official documents. They analyzed the separate financial statement of each firm, including the separate financial statement of the parent company and compared all relevant information from the consolidated financial statement and the separate financial statement. The second set is primary data from face-to-face semi-structured interviews and observation.

Findings

This study underlines that there is no requirement for a specific classification of related party transactions disclosure, and as a consequence, it is not possible to compare information. An unambiguous framework for disclosure, established by regulation or legislation, for use by companies supplying related party transactions information would be useful.

Originality/value

The results offer possible recommendations for regulators to improve presentation of related party transaction information without increasing the amount of information required.
Online news recommendations based on topic modeling and online interest adjustment
Authors: Liu Duen-Ren , Liao Yu-Shan , Lu Jun-Yi
Published: September 2019

Purpose

Providing online news recommendations to users has become an important trend for online media platforms, enabling them to attract more users. The purpose of this paper is to propose an online news recommendation system for recommending news articles to users when browsing news on online media platforms.

Design/methodology/approach

A Collaborative Semantic Topic Modeling (CSTM) method and an ensemble model (EM) are proposed to predict user preferences based on the combination of matrix factorization with articles’ semantic latent topics derived from word embedding and latent topic modeling. The proposed EM further integrates an online interest adjustment (OIA) mechanism to adjust users’ online recommendation lists based on their current news browsing.

Findings

This study evaluated the proposed approach using offline experiments, as well as an online evaluation on an existing online media platform. The evaluation shows that the proposed method can improve the recommendation quality and achieve better performance than other recommendation methods can. The online evaluation also shows that integrating the proposed method with OIA can improve the click-through rate for online news recommendation.

Originality/value

The novel CSTM and EM combined with OIA are proposed for news recommendation. The proposed novel recommendation system can improve the click-through rate of online news recommendations, thus increasing online media platforms’ commercial value.
New ways of sports entrepreneurship in the university
Authors: Sánchez-Oliver Antonio Jesús , Gálvez-Ruiz Pablo , Grimaldi-Puyana Moisés , Fernández-Gavira Jesús , García-Fernández Jerónimo
Published: September 2019

Purpose

The purpose of this paper is to present a project called EmprendeSport, whose aim is to increase knowledge in entrepreneurship and sports in students, professors and professionals through seminars carried out from 2015 to 2018. This study summarises the experience and data extracted throughout these seminars with the purpose of helping to design policies that stimulate business activity of the universities that seek to promote entrepreneurial spirit within a higher educational context.

Design/methodology/approach

This is a descriptive paper of the experiences of the seminars done during four years, with a regularly assistance of 200 people. The profile of the assistants was, mainly males, studying a degree on sports or entrepreneurship and working.

Findings

There is a lack of knowledge and interest in entrepreneurship. The realisation of the seminar resulted to be a useful incentive for the public to develop new ideas to innovate in their daily lives, some of them also, because of the seminar through of creating their own business. From the organisation perspective, in order to increase the entrepreneurial culture between the females.

Originality/value

The main contribution of this document could be to help design policies that stimulate business activities of universities and, therefore, stimulate their contribution to the development of the modern knowledge economy.
Requirements for future digital visitor flow management
Authors: Huettermann Marcel , Thimm Tatjana , Hannich Frank , Bild Christine
Published: September 2019

Purpose

The purpose of this paper is to examine visitor management in the German-Swiss border area of the Lake Constance region. Taking a customer perspective, it determines the requirements for an application with the ability to optimize personal mobility.

Design/methodology/approach

A quantitative study and a survey of focus groups were conducted to identify movement patterns of different types of visitors and their requirements concerning the development of a visitor management application.

Findings

Visitors want an application that provides real-time forecasts of issues such as traffic, parking and queues and, at the same time, enables them to create a personal activity schedule based on this information.

Research limitations/implications

Not every subsample reached a sufficient number of cases to yield representative results.

Practical implications

The results may lead to an optimization and management separation of mobility flows in the research area and be helpful to municipal planners, destination marketing organizations and visitors.

Originality/value

The German border cities of Konstanz, Radolfzell and Singen in the Lake Constance region need improved visitor management, mainly because of a high level of shopping tourism by Swiss visitors to Germany. In the Summer months, Lake Constance is also a popular destination for leisure tourists, which causes overtourism. For the first time, the results of this research presented here offer possible solutions, in particular by showing how a mobile application for visitors could defuse the situation.
Experimental evidence that phosphorus fertilization and arbuscular mycorrhizal symbiosis can reduce the carbon cost of phosphorus uptake
Authors: Ven Arne , Verlinden Melanie S. , Verbruggen Erik , Vicca Sara
Published: September 2019

Plants allocate substantial amounts of carbon (C) below‐ground to obtain nutrients and other resources.

Increasing nutrient availability typically reduces the C investment in root growth and mycorrhizal fungi, hence reducing the C cost of nutrient acquisition. This C cost of nutrient acquisition, however, remains poorly quantified.

In a P fertilization experiment with Zea mays, we examined below‐ground C allocation and the C cost of phosphorus (P) uptake. In addition, we compared plants inoculated with arbuscular mycorrhizal fungi (AMF) to those growing in pasteurized soil to examine the same measures in the absence of AMF.

P fertilization tended to increase above‐ground plant growth more than it increased the total below‐ground C flux (TBCF; root growth plus rhizosphere respiration), suggesting a reduced investment in nutrient acquisition. This was confirmed by a negative fertilization effect on the TBCF‐to‐total plant P ratio (~25% reduction for high vs. low P fertilization). Soil pasteurization increased this proxy for the C cost of P uptake (~50% increase).

This novel quantification of the influence of P availability and mycorrhizal fungi on plant–soil C partitioning can guide the incorporation of these processes in vegetation models.

A free Plain Language Summary can be found within the Supporting Information of this article.
Past spatial structure of plant communities determines arbuscular mycorrhizal fungal community assembly
Authors: Bittebiere Anne‐Kristel , Vandenkoornhuyse Philippe , Maluenda Elodie , Gareil Agnès , Dheilly Alexandra , Coudouel Sophie , Bahin Mathieu , Mony Cendrine
Published: September 2019

Due to the importance of arbuscular mycorrhizal fungi (AMF) in ecosystem productivity, a key ecological question is how do their communities assemble? As plant spatial patterns constitute a mosaic of AM fungi habitats, we hypothesized that AM fungal community assembly is determined by plant community structure, both in space and time.

We tested our hypothesis by sampling individuals of two host‐plant species, Brachypodium pinnatum and Elytrigia repens, from experimental communities cultivated in mesocosms, and assessed their AM fungal root colonizers by mass sequencing. We related AM fungal community structure to the distribution of neighbouring plant species at different spatio‐temporal scales.

We demonstrated that AM fungal community assembly depends mostly on past plant spatial patterns at a small spatial scale (5 cm), indicating that plants growing at given locations leave a footprint on the AM fungi community. This spatial scale of response was also influenced by the host‐plant species, probably by its clonal propagation.

Synthesis. Overall, we highlighted that processes involved in Arbuscular mycorrhizal (AM) fungal community assembly do not operate at the rough scale of the overall plant community mosaic but are instead locally determined, delineating the AM fungal ‘eye‐view’ of the host‐plant community.
Does Monetary Policy Respond to Uncertainty? Evidence from Australia
Authors: Ponomareva Natalia , Sheen Jeffrey , Wang Ben Zhe
Published: September 2019

We construct a novel measure of uncertainty using expert monetary policy recommendation data for Australia. Our results suggest that the Reserve Bank of Australia (RBA) tends to lower the cash rate when expert uncertainty is high. This result is robust to using other uncertainty measures.
A possible solution to minimise scotta as a food waste: A sports beverage
Authors: Tirloni Erica , Vasconi Mauro , Cattaneo Patrizia , Moretti Vittorio , Bellagamba Federica , Bernardi Cristian , Stella Simone
Published: September 2019

A pilot study trial was performed on ready‐to‐drink beverages produced in a small‐scale dairy plant starting from Ricotta whey (scotta) with the addition of fruit puree and starter cultures. Microbiological shelf life was evaluated at 4 and 12 °C. At 4 °C, the product showed moderate total viable counts until the end of the trial (~5 log cfu/mL). Yeasts proved to be the specific spoilage microorganisms of the product. When applying a thermal abuse at 20 °C for 6 h, total viable count did not increase. The addition of fruit puree changed the volatile profile of the beverages compared to raw scotta.
The efficacy of immune checkpoint inhibitors in anaplastic lymphoma kinase‐positive non‐small cell lung cancer
Authors: Heo Ja Yoon , Park Changhee , Keam Bhumsuk , Ock Chan‐Young , Kim Miso , Kim Tae Min , Kim Dong‐Wan , Kim Se Hyun , Kim Yu Jung , Lee Jong Seok , Heo Dae Seog
Published: September 2019

Background

Despite recent advances in treating non‐small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs), their role in ALK‐positive NSCLC patients is unclear. We investigated the efficacy of ICIs in patients with ALK‐positive NSCLC.

Methods

Between 2011 and 2018, a total of 14 ALK‐positive NSCLC patients treated with ICIs were evaluated retrospectively. Clinicopathologic features including age, PD‐L1 expression, and treatment outcomes were analyzed. RNA expression level and cytolytic activity by ALK positivity were analyzed using The Cancer Genome Atlas (TCGA) and National Cancer Center Research Institute (NCCRI) data sets.

Results

A total of 13 patients (92.9%) received ALK inhibitors. Patients received a median of three (range 2–8) courses of therapy. The study included nine patients (64.3%) who were PD‐L1‐high (>50%) and four (28.6%) who were PD‐L1‐low (<50%). The objective response rate was 14.3% (2/14). The median progression‐free survival time was 2.18 months (95% confidence interval [CI] 1.13 months‐not reached [NR]). The median overall survival time was 5.67 months (95% CI 3.00 months‐NR). RNA expression levels of CD274 were similar between the ALK‐positive and negative groups in both TCGA and NCCRI datasets. RNA levels of CD8A in both TCGA and NCCRI data sets were nonsignificantly lower in the ALK‐positive group. Cytolytic activity scores including interferon‐γ‐related response were lower in the ALK‐positive group in the NCCRI but not TCGA dataset.

Conclusions

Despite high PD‐L1‐positive rates, ICIs show limited efficacy in ALK‐positive NSCLC. Decreased interferon‐γ‐related response may underlie these findings.
Dementia and CSF‐biomarkers for Alzheimer's disease predict mortality after acute hip fracture
Authors: Dutkiewicz Robert , Zetterberg Henrik , Andreasson Ulf , Blennow Kaj , Nellgård Bengt
Published: September 2019

Background

Mortality is high after an acute hip fracture (AHF) surgery. Are cognitive impairment and/or altered levels of Alzheimer's Disease (AD)‐biomarkers in cerebrospinal fluid (CSF) predictors of mortality in AHF‐patients, as retrospective studies indicate?

Methods

Prospective single‐center study including 373 AHF‐patients, operated in spinal anesthesia. Cognitive status was evaluated by clinical dementia rating (CDR); CSF was analyzed for AD‐biomarker concentrations (total tau (T‐tau), phosphorylated tau (P‐tau), amyloid beta ratio (Aβ42/Aβ40). CDR and biomarker levels were related to mortality up to one‐year post‐surgery, using univariate logistic regression analysis.

Results

Survival analyses showed that mortality was associated to the degree of dementia. In the entire patient cohort 30‐, 90‐, and 365‐day mortality rates were 7.2%, 15.5%, and 25.5%, respectively, but only 2.7%, 5.5%, and 12.6%, for cognitively intact vs 16.3%, 31.7%, and 42.3% for demented patients (OR = 2.2‐2.8 [CI = 1.6‐4.9]; P = .0001). High CSF T‐tau (OR = 1.19 [CI = 1.05‐1.33]; P = .004) and low Aβ42/Aβ40‐ratio (OR = 0.85 [CI = 0.74‐0.97]; P = .017) were associated with increased 90‐day mortality. Analysis of 4 subgroups (Cognitive impairment ± and Biomarkers ±) showed significant associations of dementia and CSF biomarker concentrations to mortality after an AHF. Even cognitively intact patients presenting with abnormal AD‐biomarkers showed an increased 90‐day mortality which, however, was statistically insignificant.

Conclusions

Cognitive impairment and altered CSF biomarker concentrations indicative of AD pathology can predict increased mortality in patients with an AHF, and so probably even before clinical dementia diagnosis by early biomarker analysis; a notion that may have substantial clinical implications by improving perioperative treatment and postoperative rehabilitation.
Incidental observation of pre‐eruptive intracoronal resorption after seven years
Authors: Currell SD , Cakar T
Published: September 2019

Pre‐eruptive intracoronal resorption (PIER) can be described by the presence of coronal radiolucency in a unerupted tooth. Upon eruption, the resorbed dentine might leave the occlusal layer of enamel unsupported and susceptible to fracture, potentially exposing the pulp chamber and root canals to the oral flora. With current case studies showing unfavourable endodontic and restorative consequences of PIER lesions when left untreated, this case report presents an unchanged lesion, 7 years following initial identification.
P40 polyester sheet plastination technique for brain and body slices: The vertical and horizontal flat chamber methods
Authors: Baptista Carlos A. C. , DeJong Kees , Latorre Rafael , Bittencourt Athelson S.
Published: September 2019

The P40 technique produces high‐quality brain and body slices and is the user‐friendliest of the polyester techniques. The P40 polyester technique follows the same classical steps for plastination. That is, preparation of the specimen, fixation (optional), dehydration by freeze substitution, forced impregnation and curing. Two methods used to prepare two different types of specimens, that is, brain slices and body slices are described. Each method has its own characteristics depending on the specimen type used. Brain slices were used to illustrate the vertical small chamber method while the body slices were used to illustrate the horizontal large chamber method. The brain slices obtained using P40 are of very good quality presenting good contrast between grey and white matter. The body slices are also of very good quality. The physical appearance of these slices makes them an exceptional instrument for diagnostic imaging and anatomical correlation. Body slices prepared with P40 retain the natural colour of the tissue and preserve the anatomical relationships.
Histological and ultrastructural studies on the coronary artery of adult domestic dog (Canis familiaris)
Authors: Kilany Maha S. , El Sayed Shafika A. , Salem Hoda F. , Beheiry Rasha R.
Published: September 2019

The objective of this work was to study the histological structure of the dog's coronary artery by light and transmission electron microscope (TEM). The coronary artery consisted of three tunics: tunica intima, tunica media and tunica adventitia. The tunica intima consisted of endothelium rested directly on internal elastic lamina without the subendothelial connective tissue layer. The tunica media were composed of smooth muscle fibres interspersed with few elastic and collagen fibres. The tunica adventitia consisted of collagen and elastic fibres intermingled with fibroblast cells; it had vasa vasorum and nervi vasorum. Some histomorphometric measurements were performed and compared statistically. The ultrastructural study showed that the endothelial cells were communicated through complex junctions and characterised by filiform cytoplasmic processes passed through the opening of the underlying internal elastic membrane. The smooth muscle fibres of tunica media communicated with each other through cytoplasmic processes. The tunica adventitia showed minute non‐myelinated nerve. This work revealed that the dog's coronary arteries are typical muscular arteries, which show little structural variations from that of other mammals.
Clinical predictors of small solitary hepatitis B virus‐related hepatocellular carcinoma microinvasion
Authors: Lu Wenping , Tang Haowen , Yang Zhanyu , Jiang Kai , Chen Yongliang , Lu Shichun
Published: September 2019

Background

Microinvasion serves as a reliable indicator of poor prognosis after hepatectomy or transplantation for hepatocellular carcinoma (HCC). However, microinvasion is difficult to detect with current imaging modalities and is usually diagnosed histopathologically. The aim of this study is to identify the preoperative clinical predictors of microinvasion of small solitary hepatitis B virus (HBV)‐related HCC.

Methods

From January 2000 to December 2009, 110 patients with HBV‐related small primary solitary HCC (tumour diameter ≤3.0 cm) who underwent hepatectomy at Chinese PLA General Hospital were enrolled. The independent predictors of microinvasion, such as microvascular invasion and microscopic satellite nodules, were analysed. The prognosis of patients with microinvasion was compared with that of patients without microinvasion.

Results

Of the 110 patients, 31 (28.2%) exhibited microinvasion. Among them, 16 (51.6%) had microvascular invasion with microscopic satellite nodules, five (16.1%) had microscopic satellite nodules without microvascular invasion and 10 (32.3%) had microvascular invasion without microscopic satellite nodules. Two independent predictors of microinvasion were identified: serum alpha‐fetoprotein >20 ng/mL and a viral load of >104 copies/mL. Patients without microinvasion exhibited a significantly better prognostic outcome compared with those with microinvasion.

Conclusion

Regarding HBV‐related small HCC, patients presenting with alpha‐fetoprotein levels >20 ng/mL and a high viral load (HBV‐DNA >104 copies/mL) are at substantial risk for microinvasion.
Prostate‐specific membrane antigen‐positron emission tomography/computed tomography (PSMA‐PET/CT)‐guided stereotactic ablative body radiotherapy for oligometastatic prostate cancer: a single‐institution experience and review of the published literature
Authors: Ong Wee Loon , Koh Tze Lui , Lim Joon Daryl , Chao Michael , Farrugia Briana , Lau Eddie , Khoo Vincent , Lawrentschuk Nathan , Bolton Damien , Foroudi Farshad
Published: September 2019

Objectives

To report the outcomes of stereotactic ablative body radiotherapy (SABR) in men with oligometastatic prostate cancer (PCa) diagnosed on prostate‐specific membrane antigen (PSMA)‐positron emission tomography/computed tomography (PET/CT), based on a single‐institution experience and the published literature.

Patients and Methods

This was a retrospective cohort study of the first 20 consecutive men with oligometastatic PCa, treated with SABR in a single institution, who had biochemical recurrence after previous curative treatment (surgery/radiotherapy), had no evidence of local recurrence, were not on palliative androgen deprivation therapy (ADT), and had PSMA‐PET/CT‐confirmed oligometastatic disease (≤3 lesions). These men were treated with SABR to a dose of 30 Gy in three fractions for bone metastases, and 35–40 Gy in five fractions for nodal metastases. The outcomes of interest were: PSA response; local progression‐free survival (LPFS); distant progression‐free survival (DPFS); and ADT‐free survival (ADTFS). A literature review was performed to identify published studies reporting on outcomes of PSMA‐PET/CT‐guided SABR.

Results

In our institutional cohort, 12 men (60%) had a decline in PSA post‐SABR. One man had local progression 9.6 months post‐SABR, with 12‐month LPFS of 93%. Ten men had distant progression outside of their SABR treatment field, confirmed on PSMA‐PET/CT, with 12‐month DPFS of 62%, of whom four were treated with palliative ADT, two received prostate bed radiotherapy for prostate bed progression (confirmed on magnetic resonance imaging), and four received a further course of SABR (of whom one had further progression and was treated with palliative ADT). At last follow‐up, six men (one with local progression and five with distant progression) had received palliative ADT. The 12‐month ADTFS was 70%. Men with longer intervals between local curative treatment and SABR had better DPFS (P = 0.03) and ADTFS (P = 0.005). Four additional studies reporting on PSMA‐PET/CT‐guided SABR for oligometastatic PCa were identified and included in the review, giving a total of 346 patients. PSA decline was reported in 60–70% of men post‐SABR. The 2‐year LPFS, DPFS and ADTFS rates were 76–100%, 27–52%, and 58–62%, respectively.

Conclusion

Our results showed that PSMA‐PET/CT could have an important role in identifying men with true oligometastatic PCa who would benefit the most from metastases‐directed therapy with SABR.
Pharmacological targeting of β2‐adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease
Authors: O'Neill Eoin , Yssel Justin D. , McNamara Caoimhe , Harkin Andrew
Published: September 2019

Background and Purpose

Chronic inflammation may play a role in the pathogenesis of Parkinson's disease (PD). Noradrenaline is an endogenous neurotransmitter with anti‐inflammatory properties. In the present investigation, we assessed the immunomodulatory and neuroprotective efficacy of pharmacologically targeting the CNS noradrenergic system in a rat model of PD.

Experimental Approach

The impact of treatment with the β2‐adrenoceptor agonists clenbuterol and formoterol was assessed in the intranigral LPS rat model of PD. The immunomodulatory potential of formoterol to influence the CNS response to systemic inflammation was also assessed.

Key Results

LPS‐induced deficits in motor function (akinesia and forelimb‐use asymmetry) and nigrostriatal dopamine loss were rescued by both agents. Treatment with the noradrenaline reuptake inhibitor atomoxetine reduced striatal dopamine loss and motor deficits following intranigral LPS injection. Co‐treatment with the β2‐adrenoceptor antagonist ICI 118,551 attenuated the protective effects of atomoxetine. Systemic LPS challenge exacerbated reactive microgliosis, IL‐1β production, dopamine cell loss in the substantia nigra, nerve terminal degeneration in the striatum, and associated motor impairments in animals that previously received intranigral LPS. This exacerbation was attenuated by formoterol treatment.

Conclusion and Implications

The results indicate that pharmacologically targeting β2‐adrenoceptors has the propensity to regulate the neuroinflammatory phenotype in vivo and may be a potential neuroprotective strategy where inflammation contributes to the progression of dopaminergic neurodegeneration. In accordance with this, clinical agents such as β2‐adrenoceptor agonists may prove useful as immunomodulatory agents in the treatment of neurodegenerative conditions associated with brain inflammation.
Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies
Authors: Najafi Arash , Caspar Sylvan M. , Meienberg Janine , Rohrbach Marianne , Steinmann Beat , Matyas Gabor
Published: September 2019

Genome‐scale high‐throughput sequencing enables the detection of unprecedented numbers of sequence variants. Variant filtering and interpretation are facilitated by mutation databases, in silico tools, and population‐based reference datasets such as ExAC/gnomAD, while variants are classified using the ACMG/AMP guidelines. These methods, however, pose clinically relevant challenges. We queried the gnomAD dataset for (likely) pathogenic variants in genes causing autosomal‐dominant disorders. Furthermore, focusing on the fibrillinopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), we screened 500 genomes of our patients for co‐occurring variants in FBN1 and FBN2. In gnomAD, we detected 2653 (likely) pathogenic variants in 253 genes associated with autosomal‐dominant disorders, enabling the estimation of variant‐filtering thresholds and disease predisposition/prevalence rates. In our database, we discovered two families with hitherto unreported co‐occurrence of FBN1/FBN2 variants causing phenotypes with mixed or modified MFS/CCA clinical features. We show that (likely) pathogenic gnomAD variants may be more frequent than expected and are challenging to classify according to the ACMG/AMP guidelines as well as that fibrillinopathies are likely underdiagnosed and may co‐occur. Consequently, selection of appropriate frequency cutoffs, recognition of digenic variants, and variant classification represent considerable challenges in variant interpretation. Neglecting these challenges may lead to incomplete or missed diagnoses.
Effect of platelet‐rich plasma on peri‐implant trabecular bone volume and architecture: A preclinical micro‐CT study in beagle dogs
Authors: Huang Yan , Li Zhaokai , Van Dessel Jeroen , Salmon Benjamin , Huang Bo , Lambrichts Ivo , Politis Constantinus , Jacobs Reinhilde
Published: September 2019

Objectives

To evaluate the peri‐implant trabecular bone volume and architecture changes with 6‐month follow‐up after local application of platelet‐rich plasma (PRP) and platelet‐poor plasma (PPP) using high‐resolution micro‐CT.

Material and methods

Seventy‐two dental implants were placed into healed mandibular sites of 9 beagle dogs. Implants were randomly divided into 4 groups following a split‐mouth design: control I; control II; PPP; and PRP. Primary and secondary stabilities were assessed using resonance frequency analyses. At 1, 3, and 6 months after implant loading, trabecular structural parameters were evaluated at 0.5, 1, and 1.5 mm away from implants using micro‐CT (voxel = 20 μm).

Results

Primary and secondary stabilities were equivalent in all conditions. PPP and PRP groups showed higher bone volume fraction (BV/TV) and trabecular thickness (Tb.Th) but lower trabecular separation (Tb.Sp) and total porosity percentage (Po (tot)) at all 3 time points. A significant decrease in BV/TV and Tb.Th was found for the control groups after 3 months of healing, while this was not observed in both the PPP and PRP groups. However, no distinct difference was found between the PRP and PPP groups over time. Moreover, as the investigated distance from the implant surface increased, BV/TV and Po (tot) within the same group and time point stayed the same, yet Tb.Th and Tb.Sp continued to increase.

Conclusions

Platelet‐rich plasma and PPP with conventional implant placement lead to similar primary and secondary implant stability, but improved peri‐implant bone volume and structural integration. The present research does not seem to suggest a different bone remodeling pattern when using PRP or PPP.
Living toward the end
Authors: Sponheim Paul R.
Published: September 2019

Human beings look to the end as terminus, a passing away when the individual's life story will be complete. Against a cultural tendency to deny death, Christians—claiming a Creator God who does not die—can accept their finitude in principle and aspire to a “high definition” ending. That hope is threatened by the devastating reality of dementia. But Kierkegaard reminds us that the “positive third” of selfhood is not to be identified with mentality and Whitehead stresses that the reception of the inrushing world does not depend on conscious mentality. Against the prevalent culture of individualism, a person of faith can recognize the constitutive role of community past and present. She can find in her terminus a telos, a passing on of life to the others as she steps aside. Is there more? The Newer Testament proclaims a new creation in which life's ending is transformed by the sense of end as beginning, end as advent. This omega as alpha entails both continuity and discontinuity. As to discontinuity, the Christian envisions a life “beyond Eden,” where the perilous gift of freedom is transformed in an integrating knowledge of self, world, and God—fulfilling the calling given to all as created in God's image. This sense of end does not function as an “escape to a transcendent elsewhere,” but motivates and empowers the believer to care for the suffering victims of this volatile and violent age.