bluuebunny/crossref_metadata_2025 huggingface dataset:
Prm2deficiency triggers a Reactive Oxygen Species (ROS)-mediated destruction cascade during epididymal sperm maturation in mice
Authors: Schneider Simon , Shakeri Farhad , Trötschel Christian , Arévalo Lena , Kruse Alexander , Buness Andreas , Poetsch Ansgar , Steger Klaus , Schorle Hubert
Published: May 2020

Protamines are the safeguards of the paternal sperm genome. They replace most of the histones during spermiogenesis, resulting in DNA hypercondensation, thereby protecting its genome from environmental noxa. Impaired protamination has been linked to male infertility in mice and humans in many studies. Apart from impaired DNA integrity, protamine-deficient human and murine sperm show multiple secondary effects, including decreased motility and aberrant head morphology. In this study, we use aPrm2-deficient mouse model in combination with label-free quantitative proteomics to decipher the underlying molecular processes of these effects. We show that loss of the sperm’s antioxidant capacity, indicated by downregulation of key proteins like SOD1 and PRDX5, ultimately initiates an oxidative stress-mediated destruction cascade during epididymal sperm maturation. This is confirmed by an increased level of 8-OHdG in epididymal sperm, a biomarker for oxidative stress-mediated DNA damage.Prm2-deficient testicular sperm are not affected and initiate the proper development of blastocyst stage preimplantation embryosin vitroupon intracytoplasmic sperm injection (ICSI) into oocytes. Our results provide new insight into the role ofPrm2and its downstream molecular effects on sperm function and present an important contribution to the investigation of new treatment regimens for infertile men with impaired protamination.

Significance statement

Sexual reproduction requires the successful fertilization of female eggs by male sperm. The generation of functional sperm is a complex, multi-step differentiation process known as spermatogenesis that takes places in the male testis. One important step for physiological sperm function is the incorporation of small proteins, known as protamines into the DNA. Defects within this process are common causes of male infertility. However, the underlying molecular mechanisms still remain largely unknown, thus preventing targeted therapies. Here, we identify the molecular cascade being initiated in protamine-deficient murine sperm that ultimately impedes fertilization. Our findings have broad implications for the development of new treatment options for infertile men with faulty protamination that seek medical advice.
Brain/MINDS Beyond Human Brain MRI Project: A Protocol for Multi-Site Harmonization across Brain Disorders Throughout the Lifespan
Authors: Koike Shinsuke , Tanaka Saori C , Okada Tomohisa , Aso Toshihiko , Asano Michiko , Maikusa Norihide , Morita Kentaro , Okada Naohiro , Fukunaga Masaki , Uematsu Akiko , Togo Hiroki , Miyazaki Atsushi , Murata Katsutoshi , Urushibata Yuta , Autio Joonas , Ose Takayuki , Yoshimoto Junichiro , Araki Toshiyuki , Glasser Matthew F , Van Essen David C , Maruyama Megumi , Sadato Norihiro , Kawato Mitsuo , Kasai Kiyoto , Okamoto Yasumasa , Hanakawa Takashi , Hayashi Takuya ,   Brain/MINDS Beyond Human Brain MRI Group
Published: May 2020

Psychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (FY2018 ∼ FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. The Harmonization protocol (HARP) was established for five high-quality 3T scanners to obtain multimodal brain images including T1 and T2-weighted, resting state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, providing high reproducibility and sensitivity to subject-specific connectome. A total of 75 TS, as well as patients with various psychiatric and neurological disorders, are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a rigorous, prospective harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.
Individuals with autism have no detectable deficit in neural markers of prediction error when presented with auditory rhythms of varied temporal complexity
Authors: Knight Emily J. , Oakes Leona A. , Hyman Susan L. , Freedman Edward G. , Foxe John J.
Published: May 2020

The brain’s ability to encode temporal patterns and predict upcoming events is critical for speech perception and other aspects of social communication. Deficits in predictive coding may contribute to difficulties with social communication and overreliance on repetitive predictable environments in individuals with autism spectrum disorder (ASD). Using a mismatch negativity (MMN) task involving rhythmic tone sequences of varying complexity, we tested the hypotheses that 1) individuals with ASD have reduced MMN response to auditory stimuli that deviate in presentation timing from expected patterns, particularly as pattern complexity increases and 2) amplitude of MMN signal is inversely correlated with level of impairment in social communication and repetitive behaviors. Electroencephalography was acquired as individuals (age 6-21years) listened to repeated five-rhythm tones that varied in the Shannon entropy of the rhythm across three conditions (zero, medium-1 bit) and high-2 bit entropy). The majority of the tones conformed to the established rhythm (standard tones); occasionally the 4thtone was temporally shifted relative to its expected time of occurrence (deviant tones). Social communication and repetitive behaviors were measured using the Social Responsiveness Scale and Repetitive Behavior Scale-Revised. Both neurotypical controls (n=19) and individuals with ASD (n=21) show stepwise decreases in MMN as a function of increasing entropy. Contrary to the result forecasted by a predictive coding hypothesis, individuals with ASD do not differ from controls in these neural mechanisms of prediction error to auditory rhythms of varied temporal complexity, and there is no relationship between these signals and social communication or repetitive behavior measures.

Lay Summary

We tested the idea that the brain’s ability to use previous experience to influence processing of sounds is weaker in individuals with autism spectrum disorder (ASD) than in neurotypical individuals. We found no difference between individuals with ASD and neurotypical controls in brain wave responses to sounds that occurred earlier than expected in either simple or complex rhythms. There was also no relationship between these brain waves and social communication or repetitive behavior scores.
A convolutional neural network for estimating synaptic connectivity from spike trains
Authors: Endo Daisuke , Kobayashi Ryota , Bartolo Ramon , Averbeck Bruno B. , Sugase-Miyamoto Yasuko , Hayashi Kazuko , Kawano Kenji , Richmond Barry J. , Shinomoto Shigeru
Published: May 2020

The recent increase in reliable, simultaneous high channel count extracellular recordings is exciting for physiologists and theoreticians because it offers the possibility of reconstructing the underlying neuronal circuits. We recently presented a method of inferring this circuit connectivity from neuronal spike trains by applying the generalized linear model to cross-correlograms. Although the algorithm can do a good job of circuit reconstruction, the parameters need to be carefully tuned for each individual dataset. Here we present another method using a Convolutional Neural Network for Estimating synaptic Connectivity from spike trains (CoNNECT). After adaptation to huge amounts of simulated data, this method robustly captures the specific feature of monosynaptic impact in a noisy cross-correlogram. There are no user-adjustable parameters. With this new method, we have constructed diagrams of neuronal circuits recorded in several cortical areas of monkeys.
Clusterin secretion is attenuated by pro-inflammatory cytokines in culture models of cartilage degradation
Authors: Matta Csaba , Fellows Christopher R. , Quasnichka Helen , Williams Adam , Jeremiasse Bernadette , Allaway David , Mobasheri Ali
Published: May 2020

Proteomic studies have implicated clusterin as a potential biomarker of osteoarthritis (OA). However, there are two isoforms of clusterin with opposing functions, and their roles in OA have not previously been clarified. The secreted form of clusterin (sCLU) is a cytoprotective extracellular chaperone which prevents protein aggregation and enhances cell proliferation and viability, whereas nuclear clusterin (nCLU) acts as a pro-death signal. In this study, we focused on the role of sCLU and used established, pathophysiologically relevant,in vitroculture models to validate this potential biomarker of cartilage degradation. The secretome of equine cartilage explants, osteochondral biopsies and chondrocytes was analysed by western blotting for released sCLU, cartilage oligomeric protein (COMP) and matrix metalloproteinases (MMP) 3 and 13, following treatment with or without pro-inflammatory cytokines interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α). The amount of sulphated glycosaminoglycans (sGAG) released into the medium was determined by dimethylmethylene blue (DMMB) analysis. Clusterin mRNA expression was quantified by real-time PCR. MMP-3, MMP-13, COMP and sGAG released from explants and osteochondral biopsies was elevated with cytokine treatment, confirming cartilage degradation in these models. Release of sCLU was attenuated with cytokine treatment in all threein vitromodels. Expression of clusterin mRNA in cartilage explants and chondrocytes was down-regulated 7-days post cytokine stimulation. Cytokine stimulation attenuated expression and secretion of sCLU, therefore potentially limiting the cytoprotection which sCLU provides. These observations further implicate sCLU as having a role in OA, and diagnostic value as a potential biomarker for cartilage degradation.
Differential levels of dermatan sulfate generate distinct Collagen I gel architectures
Authors: M Jyothsna K , Sarkar Purba , Jha Keshav Kumar , Raghunathan Varun , Bhat Ramray
Published: May 2020

Collagen I is the most abundant extracellular matrix (ECM) protein in vertebrate tissues. As an endogenously synthesized fibrillar biopolymer or as a synthetic hydrogel, it provides mechanical durability to tissue microenvironments and regulates cell function. Predominant regulators of its fibrillogenesis are dermatan sulfate proteoglycans (DSPGs), proteins conjugated with iduronic acid containing DS glycosaminoglycans (GAGs). Although DS is known to regulate tissue function through its modulation of Collagen I architecture, a precise quantifiable understanding of the latter remains elusive. We investigate this problem by visualizing the pattern of structural elements within fixed Collagen I gels polymerized in the presence of varying concentrations of DS (50-, 200- and 400- μg/mL) using second harmonic generation microscopy (SHG). Measuring four independent imaging parameters: fibril density, mean SHG signal (which estimates the ordering of the fibrils), surface occupancy (which estimates the space occupied by fibrils), and the fibril width allows us to construct an informative model of the effects of DS on Collagen I element architecture. Supported by confocal microscopy, our observations indicate that the effect on collagen fibril pattern of DS is contextual upon its concentrations. Lower levels of DS result in more numerous disorganized fibrils; higher levels restore organization, but at lower fibril densities. Such Collagen I gel pattern-tuning of DS is likely of relevance for understanding its functions in disease progression and biomaterial applications.
Social recognition in rats and mice requires integration of olfactory, somatosensory and auditory cues
Authors: de la Zerda Shani Haskal , Netser Shai , Magalnik Hen , Briller Mayan , Marzan Dan , Glatt Sigal , Wagner Shlomo
Published: May 2020

In humans, discrimination between individuals, also termed social recognition, can rely on a single sensory modality, such as vision. By analogy, social recognition in rodents is thought to be based upon olfaction. Here, we hypothesized that social recognition in rodents relies upon integration of olfactory, auditory and somatosensory cues, hence requiring active behavior of social stimuli. Using distinct social recognition tests, we demonstrated that adult male rats and mice do not recognize familiar stimuli or learn the identity of novel stimuli that are inactive due to anesthesia. We further revealed that impairing the olfactory, somatosensory or auditory systems prevents recognition of familiar stimuli. Finally, we found that familiar and novel stimuli generate distinct movement patterns during social discrimination and that subjects react differentially to the movement of these stimuli. Thus, unlike what occurs in humans, social recognition in rats and mice relies on integration of information from several sensory modalities.
A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia
Authors: Ala-Kurikka Tommi , Pospelov Alexey , Summanen Milla , Alafuzoff Aleksander , Kurki Samu , Voipio Juha , Kaila Kai
Published: May 2020

Birth asphyxia (BA) is often associated with seizures which emerge during the recovery and may exacerbate the ensuing hypoxic-ischemic encephalopathy. In rodent models of BA, exposure to hypoxia is used to evoke seizures, which commence already during the insult. Here, we introduce a term-equivalent model of BA, in which seizures are triggered after, not during, brain hypoxia. Postnatal day 11-12 rat pups were exposed either to steady asphyxia (15 min; 5 % O2+ 20 % CO2) or to intermittent asphyxia (30 min; three 5+5 min cycles of 9 % and 5 % O2at constant 20 % CO2). Cortical activity and seizures were recorded in freely-behaving animals. Simultaneous electrode measurements of cortical local field potentials (LFP) and intracortical pH andPo2were made under urethane-anesthesia. Both protocols decreased blood pH to <7.0 and base excess by 20 mmol/l, and evoked an increase in plasma copeptin (0.2 to 5 nM). Clonic and tonic convulsions were triggered after intermittent but not steady asphyxia, and they were tightly associated with electrographic seizures. During intermittent asphyxia LFP activity was suppressed as brain pH decreased from 7.3 to 6.7. BrainPo2fell below detection level in 5 % ambient O2but returned to the baseline level during steps to 9 % O2. Neuronal hyperexcitability and seizures were suppressed in all types of experiments when the post-asphyxia brain pH recovery was slowed down by 5 % CO2. Our data suggest that the recurring hypoxic episodes during intermittent asphyxia promote neuronal excitability, which becomes established as hyperexcitability and seizures only after the suppressing effect of the hypercapnic acidosis is relieved. The present rodent model of BA is to our knowledge the first one in which, consistent with clinical BA, robust behavioral and electrographic seizures are triggered after and not during the BA-mimicking insult.
Very high extinction risk for Welwitschia mirabilis in the northern Namib Desert
Authors: Bombi Pierluigi , Salvi Daniele , Shuuya Titus , Vignoli Leonardo , Wassenaar Theo
Published: May 2020

One of the most recognisable icon of the Namib Desert is the endemic gymnosperm Welwitschia mirabilis. Recent studies indicated that climate change may seriously affect populations in the northern Namibia subrange (Kunene region) but their extinction risk has not yet been assessed. In this study, we apply IUCN criteria to define the extinction risk of welwitschia populations in northern Namibia and assign them to a red list category. We collected field data in the field to estimate relevant parameters for this assessment. We observed 1330 plants clustered in 12 small and isolated stands. The extent of occurrence has a surface of 214.2 km2 (i.e. < 5000 km2) and the area of occupancy a surface of 56.0 km2 (i.e. < 500 km2). The quality of habitat is expected to face a reduction of 69.47 % (i.e. > 50 %) as a consequence of climate change predicted in the area. These data indicate a very high extinction risk for welwitschia in northern Kunene and classify these populations as endangered (EN) according to IUCN criteria. Similar assessments for other subranges are prevented by the lack of relevant data, an issue that deserves further research attention. Our results advocate the necessity of a management plan for the species, including measures for mitigating the impact of climate change on isolated populations across its fragmented range.
The Basolateral amygdala → Nucleus Accumbens core circuit mediates the conditioned reinforcing effects of cocaine-paired cues on cocaine seeking
Authors: Puaud Mickaël , Higuera-Matas Alejandro , Brunault Paul , Everitt Barry J. , Belin David
Published: May 2020

Individuals addicted to cocaine spend much of their time foraging for the drug. Pavlovian drug-associated conditioned stimuli exert a major influence on the initiation and maintenance of drug seeking often long into abstinence, especially when presented response-contingently, acting as conditioned reinforcers that bridge delays to drug use. The acquisition of cue-controlled cocaine seeking has been shown to depend on functional interactions between the basolateral amygdala (BLA) and the core of the nucleus accumbens (NAcC). However, the precise neuronal circuits underlying the acquisition of cue-controlled cocaine seeking behaviour have not been elucidated. Here we used a projection-specific Cre-dependent DREADD-mediated causal approach to test the hypothesis that the direct projections from the BLA to the NAcC are required for the acquisition of cue-controlled cocaine seeking behaviour. In Sprague Dawley rats with cre-mediated expression of the inhibitory DREADD Hm4Di in the NAcC projecting BLA neurons, treatment with CNO, but not vehicle, selectively prevented the impact of cocaine-associated conditioned reinforcement on cocaine seeking under a second-order schedule of reinforcement. This effect was attributable to the chemogenetic inhibition of the NAcC projecting BLA neurons as it was reversible, and absent in CNO-treated rats expressing an empty control virus. In contrast, chemogenetic inhibition of the anterior insula, which receives collateral projections from NAcC projecting BLA neurons, was without effect. These data demonstrate that the acquisition of cue-controlled cocaine seeking that depends on the conditioned reinforcing effects of cocaine cues require activity in the direct projections from the basolateral amygdala to the nucleus accumbens core.
A semi-supervised Bayesian approach for simultaneous protein sub-cellular localisation assignment and novelty detection
Authors: Crook Oliver M. , Geladaki Aikaterini , Nightingale Daniel J.H. , Vennard Owen , Lilley Kathryn S. , Gatto Laurent , Kirk Paul D.W.
Published: May 2020

The cell is compartmentalised into complex micro-environments allowing an array of specialised biological processes to be carried out in synchrony. Determining a protein’s sub-cellular localisation to one or more of these compartments can therefore be a first step in determining its function. High-throughput and high-accuracy mass spectrometry-based sub-cellular proteomic methods can now shed light on the localisation of thousands of proteins at once. Machine learning algorithms are then typically employed to make protein-organelle assignments. However, these algorithms are limited by insufficient and incomplete annotation. We propose a semi-supervised Bayesian approach to novelty detection, allowing the discovery of additional, previously unannotated sub-cellular niches. Inference in our model is performed in a Bayesian framework, allowing us to quantify uncertainty in the allocation of proteins to new sub-cellular niches, as well as in the number of newly discovered compartments. We apply our approach across 10 mass spectrometry based spatial proteomic datasets, representing a diverse range of experimental protocols. Application of our approach tohyperLOPIT datasets validates its utility by recovering enrichment with chromatin-associated proteins without annotation and uncovers sub-nuclear compartmentalisation which was not identified in the original analysis. Moreover, using sub-cellular proteomics data fromSaccharomyces cerevisiae, we uncover a novel group of proteins trafficking from the ER to the early Golgi apparatus. Overall, we demonstrate the potential for novelty detection to yield biologically relevant niches that are missed by current approaches.
Type I and III interferons disrupt lung epithelial repair during recovery from viral infection
Authors: Major J. , Crotta S. , Llorian M. , McCabe T. M. , Gad H. H. , Hartmann R. , Wack A.
Published: May 2020

Excessive cytokine signalling frequently exacerbates lung tissue damage during respiratory viral infection. Type I and III interferons (IFN-α/β and IFN-λ) are host-produced antiviral cytokines and currently considered as COVID-19 therapy. Prolonged IFN-α/β responses can lead to harmful proinflammatory effects, whereas IFN-λ mainly signals in epithelia, inducing localised antiviral immunity. Here we show that IFN signalling interferes with lung repair during influenza recovery, with IFN-λ driving these effects most potently. IFN-induced p53 directly reduces epithelial proliferation and differentiation, increasing disease severity and susceptibility to bacterial superinfections. Hence, excessive or prolonged IFN-production aggravates viral infection by impairing lung epithelial regeneration. Therefore, timing and duration are critical parameters of endogenous IFN action, and should be considered carefully for IFN therapeutic strategies against viral infections like influenza and COVID-19.

One Sentence Summary

A novel IFN-mediated mechanism of immunopathology during respiratory virus infection by interference with lung tissue repair.
Novel strategies of Raman imaging for monitoring intracellular retinoid metabolism in cancer cells
Authors: Abramczyk Halina , Imiela Anna , Surmacki Jakub
Published: May 2020

We developed a label-free Raman method for whole-cell biochemical imaging to detect molecular processes that occur in normal and cancer brain cells due to retinol transport in human cancers at the level of isolated organelles. Our approach allows to create biochemical maps of retinoids localization in lipid droplets, mitochondria and nuclei in single cells. The maps were capable of discriminating triglycerides (TAG) from retinoids (RE) in lipid droplets (LD), and mitochondria providing an excellent tool to monitor intracellular retinoid metabolism. We detected spectral changes that arose in proteins and lipids due to retinoid metabolism in human cell lines of normal astrocytes and high-grade cancer cells of glioblastoma as well as in human medulloblastoma and glioblastoma tissue. Raman imaging is an effective tool for monitoring retinoids and retinol binding proteins involved in carcinogenesis by detecting unique spectral signatures of vibrations. We found two functionally distinct lipid droplets: TAG-LD, for energy storage, and RE-LD, for regulating mechanisms of signal transduction. Raman polarization measurements revealed the occurrence of conformational changes affecting discrete regions of proteins associated with retinol binding. Aberrant expression of retinoids and retinol binding proteins in human tumours were localized in lipid droplets, and mitochondria.
Clinical and Genetic Characteristics of Covid-19 Patients from UK Biobank
Authors: Kolin David A. , Kulm Scott , Elemento Olivier
Published: May 2020

Objective

To explore both clinical and genetic risk factors for Covid-19 in a cohort from the United Kingdom.

Design

Prospective cohort study.

Participants

669 positive Covid-19 patients within a cohort of 502,536 UK Biobank participants, recruited between 2006 and 2010.

Main Outcome Measures

The main outcome measure was Covid-19 positive status, determined by the presence of any positive test for a single individual. We also assessed risk factors for inpatient and outpatient status for Covid-19 positive individuals.

Results

We found that black participants were at over three times increased risk of testing positive for Covid-19, relative to white participants, even after adjusting for confounders (adjusted relative risk [ARR] 3.14, 95% confidence interval [CI] 2.28 to 4.31). Asian participants were also at higher risk of Covid-19 (ARR 2.03, 95% CI 1.40 to 2.95). Next, we analyzed the association of comorbidities with Covid-19. We found that participants were at increased risk of Covid-19 if they had chronic obstructive pulmonary disease (ARR 1.54, 95% CI 1.02 to 2.31) or ischemic heart disease (ARR 1.56, 95% CI 1.18 to 2.07). However, there was no evidence that either angiotensin converting enzyme inhibitors (ARR 1.32, 95% CI 0.95 to 1.84) or angiotensin II receptor blockers (ARR 1.37, 95% CI 0.94 to 1.98) increased the risk of Covid-19. We confirmed that blood type A was associated with Covid-19 relative to blood type O individuals, and we also found that the HLA variant DQA1_509 was enriched in Covid-19 positive cases, even after Bonferroni correction (P = 1.0 x 10−5).

Conclusions

In this study, we found that black and Asian participants were at increased risk of Covid-19, even after adjusting for confounders. We also identified a novel genetic association with the HLA variant DQA1_509. Further investigations of genetic associations with Covid-19 may lead to important discoveries of genetic drivers of severe disease.
Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience
Authors: Miller Cecelia R. , Lee Kristy , Pfau Ruthann B. , Reshmi Shalini C. , Corsmeier Donald J. , Hashimoto Sayaka , Dave-Wala Ashita , Jayaraman Vijayakumar , Koboldt Daniel , Matthews Theodora , Mouhlas Danielle , Stein Maggie , McKinney Aimee , Grossman Tom , Kelly Benjamin J. , White Peter , Magrini Vincent , Wilson Richard K. , Mardis Elaine R. , Cottrell Catherine E.
Published: May 2020

Exome sequencing (ES) has become an important tool in pediatric genomic medicine, improving identification of disease-associated variation due to assay breadth. Depth is also afforded by ES, enabling detection of lower-frequency mosaic variation compared to Sanger sequencing in the studied tissue, thus enhancing diagnostic yield. Within a pediatric tertiary-care hospital, we report two years of clinical ES data from probands evaluated for genetic disease to assess diagnostic yield, characteristics of causal variants, and prevalence of mosaicism among disease-causing variants. Exome-derived, phenotype-driven variant data from 357 probands was analyzed concurrent with parental ES data, when available. Blood was the source of nucleic acid. Sequence read alignments were manually reviewed for all assessed variants. Sanger sequencing was used for suspected de novo or mosaic variation. Clinical provider notes were reviewed to determine concordance between laboratory-reported data and the ordering provider's interpretation of variant-associated disease causality. Laboratory-derived diagnostic yield and provider-substantiated diagnoses had 91.4% concordance. The cohort returned 117 provider-substantiated diagnoses among 115 probands for a diagnostic yield of 32.2%. De novo variants represented 64.9% of disease-associated variation within trio analyses. Among the 115 probands, five harbored disease-associated somatic mosaic variation. Two additional probands were observed to inherit a disease-associated variant from an unaffected mosaic parent. Among inheritance patterns, de novo variation was the most frequent disease etiology. Somatic mosaicism is increasingly recognized as a significant contributor to genetic disease, particularly with increased sequence depth attainable from ES. This report highlights the potential and importance of detecting mosaicism in ES.
Calculation of total scattering from a crystalline structural model based on experimental optics parameters
Authors: Hiroi Satoshi , Ohara Koji , Ohuchi Satoru , Umetani Yukihiro , Kozaki Takashi , Igaki Emiko , Sakata Osami
Published: May 2020

Total scattering measurements enable understanding of the structural disorder in crystalline materials by Fourier transformation of the total structure factor, S(Q), where Q is the magnitude of the scattering vector. In this work, the direct calculation of total scattering from a crystalline structural model is proposed. To calculate the total scattering intensity, a suitable Q-broadening function for the diffraction profile is needed because the intensity and the width depend on the optical parameters of the diffraction apparatus, such as the X-ray energy resolution and divergence, and the intrinsic parameters. X-ray total scattering measurements for CeO2 powder were performed at beamline BL04B2 of the SPring-8 synchrotron radiation facility in Japan for comparison with the calculated S(Q) under various optical conditions. The evaluated Q-broadening function was comparable to the full width at half-maximum of the Bragg peaks in the experimental total scattering pattern. The proposed calculation method correctly accounts for parameters with Q dependence such as the atomic form factor and resolution function, enables estimation of the total scattering factor, and facilitates determination of the reduced pair distribution function for both crystalline and amorphous materials.
Crystal structure and Hirshfeld surface analysis of 1,3-diethynyladamantane
Authors: Domasevitch Kostiantyn V. , Degtyarenko Anna S.
Published: May 2020

The title compound, C14H16, exhibits exceptionally weak intermolecular C—H...π hydrogen bonding of the ethynyl groups, with the corresponding H...π separations [2.91 (2) and 3.12 (2) Å] exceeding normal vdW distances. This bonding complements distal contacts of the CH (aliphatic)...π type [H...π = 3.12 (2)–3.14 (2) Å] to sustain supramolecular layers. Hirshfeld surface analysis of the title compound suggests a relatively limited significance of the C...H/H...C contacts to the crystal packing (24.6%) and a major contribution from H...H contacts accounting 74.9% to the entire surface.
Problems encountered by elders in residential care services in Hong Kong
Authors: Lam Gigi
Published: May 2020

Purpose

Hong Kong implements a policy for the aging population involving the core themes of “aging in place as the core,” “institutional care as backup” and “continuum of care.” Encouraging elders to live independently at home is a top priority, and elders who are not able to live at home independently are provided with various residential care services, namely Hostels for the Elderly, Homes for the Aged, Care and Attention (C&A) Homes for the Elderly and Nursing Homes (NHs). The purpose of this paper is to analyze the adoption of the publicly funded model of providing residential care services of elderly in Hong Kong.

Design/methodology/approach

The paper analyzes the current conundrum encountered by elders in residential care services and makes recommendations. A comprehensive literature review was conducted covering relevant government reports, academics' journal papers and nongovernmental organizations’ reports concerning residential care service of elderly from 1965 to present.

Findings

Subsidized residential care homes for the elderly (RCHEs) clearly outperform private RCHEs in terms of space and staff provisions, but the supply of subsidized RCHEs cannot meet the demand. Hence, between 2007 and 2018, the average waiting time was 33 months for NHs and that for C&A homes was 23 months. Several viable measures to meet the demand are purchasing Enhanced Bought Place Schemes (EBPSs) from private RCHEs, subsidizing elders who opt for living in private RCHEs by providing them with Comprehensive Social Security Assistance (CSSA) and residential care service voucher (RCSV) and subsidizing elderly applicants who opt for living in RCHEs in Guangdong. However, these viable measures are problematic because of the inadequate quality of EBPSs and private RCHEs, which is attributed to the costing arrangement of public and private RCHEs that were established in the colonial period. The brief history of RCHEs also indicates a deviation from the original policy aim, namely aging in place, which was introduced in the Green Paper on Services for the Elderly in 1977.

Practical implications

The supply and quality of community and home care services should be thoroughly examined; effective community and home care services can prevent and even delay unnecessary institutionalization. Another complementary solution is to devise a long-term plan for residential care services. To address disparities in quality standards in different RCHEs, adopting the combination of punitive and compliance models such as conducting frequent inspections and implementing an accreditation system for private RCHEs is imperative.

Originality/value

Although the principle of “aging in place” originated in 1977, the institutionalization rate 6.8% of elders was unexpectedly high in Hong Kong and even surpassed the Asian counterparts. It necessities to rethink how to implement policy concerning long-term care services of elders.
Who are farm animal welfare conscious consumers?
Authors: Boaitey Albert , Minegishi Kota
Published: May 2020

Purpose

This paper aims to synthesize the literature on consumer preferences for farm animal welfare (FAW), with an emphasis on characterizing consumers based on their FAW preferences. The objective is to provide insights into the salient characteristics associated with animal welfare conscious consumers.

Design/methodology/approach

The authors conduct a systematic review of the results of published research on consumer preferences for FAW. Approximately 350 papers were reviewed, and 52 were included in the analysis.

Findings

The authors’ review suggests that consumers are not homogenous in their preferences for FAW. The authors identify seven themes that enabled them to characterize consumers with higher FAW preferences. These themes (i.e. age, education and income, gender, country and cross-cultural differences, attitudes and consumer and citizen functions) are grouped under four main headings (socio-demographics, ethics and attitudes, product characteristics and public roles).

Research limitations/implications

The authors’ synthesis reflects the findings reported in the literature to this date; the identified characteristics may change with time as new evidence becomes available.

Practical implications

The information collected in this article would be useful to farmers and food and non-food retailers interested in effective product differentiation and marketing strategies regarding FAW standards. It can also inform policymakers about the state of consumer concerns for FAW.

Originality/value

To the best of authors' knowledge, this is the first study that attempts to develop a systematic profile of consumers based on their FAW preferences.
The potential problem of picky eating: a pilot study among university students of food and nutrition
Authors: Kim So-young , Lee EunJu
Published: May 2020

Purpose

This pilot study is aimed to explore the potential problem of picky eating (PE) among university students majoring in food and nutrition as prospective nutrition professionals.

Design/methodology/approach

The current pilot study included a total of 87 South Korean students majoring in food and nutrition. The self-designed Food Bridge program was applied to identify the underlying causes of PE and examine the possibility of overcoming it. The program included planning and practicing stepwise exposures to target foods that were the subject of PE. Descriptive statistics were calculated, and distributive differences between the success and failure groups in the program were analyzed using a chi-squared test.

Findings

Vegetables were the most commonly disliked foods (74.7%). About 46% of all students mentioned negative experiences as a reason for food dislikes. Almost half (45%) of these negative experiences were due to external coercion: forced eating (30.0%) and vomiting after forced eating (15.0%). About 66% of the students achieved relatively positive results in overcoming PE. The proportion of failures tended to be higher when the reasons for food dislike included negative experiences.

Originality/value

As the current study implied, students majoring in food and nutrition can be subject to PE. Despite study limitations, this study is meaningful in that it raises concerns over the potential problem of PE and its treatment among prospective nutrition professionals. This study is also expected to serve as a basis for further research on adult PE.
The evolution of MNCs' R&D foreign units: the case of Swedish MNCs in India
Authors: Schweizer Roger , Lagerström Katarina , Jakobsson Johan
Published: May 2020

Purpose

The article aims to explain how the drivers of subsidiary evolution influence a multinational company's (MNC) research and development (R&D) subsidiary's evolution over time.

Design/methodology/approach

The article draws on insights from a longitudinal comparative case study of three Swedish MNCs' Indian R&D units.

Findings

The study shows that the evolution of R&D units is a triangular showdown among headquarter assignments, local market constraints, and opportunities, and that subsidiary choice is an important driver of both mandated extension and stagnation. We summarize our findings in various propositions that emphasize different drivers over time and that highlight the strong impact of a subsidiary's understanding of the corporate immune system on the evolution of that subsidiary's R&D mandate.

Research limitations/implications

Drawing on the common limitations of a case study approach, further research is needed to test the suggested propositions with larger samples, ideally with subsidiaries in other emerging and developed markets.

Practical implications

The study illustrates the risks involved for subsidiary managers when pushing an R&D mandate-related initiative too far and provoking the corporate immune system. For headquarters management, the study highlights the importance of understanding that the development of R&D competence and capability at a subsidiary cannot be guided solely by headquarter assignments and local market characteristics; rather, the subsidiary's initiatives also need to be considered.

Originality/value

The study contributes to the literature on R&D internationalization by showing how the drivers of subsidiary evolution influence a subsidiary's R&D mandates over time and that subsidiary choice is an important driver of both mandated extension and stagnation.
Understanding and visualizing schedule deviations in construction projects using fault tree analysis
Authors: Hsu Pei-Yuan , Aurisicchio Marco , Angeloudis Panagiotis , Whyte Jennifer
Published: May 2020

Purpose

Delays in construction projects are both disruptive and expensive. Thus, potential causes of schedule deviation need to be identified and mitigated. In previous research, delay factors were predominantly identified through surveys administered to stakeholders in construction projects. Such delay factors are typically considered individually and presented at the same level without explicitly examining their sequence of occurrence and inter-relationships. In reality, owing to the complex structure of construction projects and long execution time, non-conformance to schedule occurs by a chain of cascading events. An understanding of these linkages is important not only for minimising the delays but also for revealing the liability of stakeholders. To explicitly illustrate the cause–effect and logical relationship between delay factors and further identify the primary factors which possess the highest significance toward the overall project schedule delay, the fault tree analysis (FTA) method, a widely implemented approach to root cause problems in safety-critical systems, has been systematically and rigorously executed.

Design/methodology/approach

Using a case study, the in-depth analysis for identifying the most fundamental delay factors has been fulfilled through FTA's tree structure. The logical deduction for mapping and visualising the chronological and cause–effect relationships between various delay factors has been conducted through the logical gate functions of FTA based on the data collected from the site event log, pre-fabricated structural component manufacturing log and face-to-face interview with project stakeholders.

Findings

The analysis identified multiple delay factors and showed how they are linked logically and chronologically from the primary causes to the ultimate undesired event in a rigorous manner. A comparison was performed between the proposed FTA model and the conventional investigation method for revealing the responsibility employed in the construction industry, consisting of event logs and problem reports. The results indicate that the FTA model provides richer information and a clearer picture of the network of delay factors. Importantly, the ability of FTA in revealing the causal connection between the events leading to the undesired delays and in comprehending their prominence in the real-world construction project has been clearly displayed.

Originality/ value

This study demonstrates a new application of FTA in the construction sector allowing the delay factors to be understood and visualised from a new perspective. The new approach has practical use in finding and removing root causes of the delay, as well as clarifying the attribution of responsibility that causes the delay.
The roles of captains in megaproject innovation ecosystems: the case of the Hong Kong‐Zhuhai‐Macau Bridge
Authors: Chen Hongquan , Jin Zhizhou , Su Quanke , Yue Gaoyu
Published: May 2020

Purpose

The megaproject is a vital innovation ecosystem for participants engaging in technological adoption and integration to achieve project goals. The purpose of this paper is to examine how ecosystem captains build and operate a megaproject innovation ecosystem (MIE). To be more specific, we conducted an in-depth case study to identify the roles played by ecosystem captains in establishing and managing a megaproject innovation ecosystem.

Design/methodology/approach

Based on the Hong Kong-Zhuhai-Macau Bridge project, the data we collected range from 2010 to 2019 and include semi-structured interviews, informal conversations, and archival documents. We employed an inductive theory building approach to address our research question and analyzed our data using the coding process and Atlas.ti software.

Findings

We find that the ecosystem captains themselves are client organizations that have evolved with the ecosystem during four distinct yet inter-related phases. In addition, we find that the captains’ roles of the client organizations include two typical activities: ecosystem establishment and ecosystem collaboration. The ecosystem captains first frame problems, plan innovative activities, set rules, and select participants for the establishment of the ecosystem, and then orchestrate resources, buffer conflicts, incorporate innovative networks, and cultivate an innovation culture to create a collaborative ecosystem.

Originality/value

This study proposes a theoretical framework showing how ecosystem captains engage in MIE to manage innovative activities during different stages. It highlights the importance of captainship roles in client organizations in a megaproject.
Mitigating the legal challenges of imposing disincentives on nonperforming transportation projects
Authors: Alleman Douglas , Lee Eul-Bum
Published: May 2020

Purpose

The publication presents an analysis of the cost and schedule performance of incentive/disincentive projects and case studies toward developing a systematic disincentive valuation process, with Construction Analysis for Pavement Rehabilitation Strategies (CA4PRS) software integration that aids agencies in minimizing the likelihood of court challenges of disincentives.

Design/methodology/approach

From a California transportation database, the authors performed cost and schedule analyses of 43 incentive/disincentive (I/D) projects and case studies on four of those I/D projects. Interviewees included subject matter experts from transportation organizations to ensure applicability and maximum value-adding, and the process was implemented on ten California transportation projects and monitored for performance.

Findings

The presented process mitigates the contractor's ability to claim disincentives as penalties in a court of law through the following: (1) all calculations are performed using project-specific bases, backed by estimations of actual incurred costs; (2) the CA4PRS software allows for estimation transparency and (3) the clarity of cost inclusions reduces any chances of “double-dipping” between disincentives and liquidated damages.

Practical implications

Transportation agencies have historically faced legal challenges to their enforcements of disincentives. As agencies continue to apply disincentives on more megaprojects, contractors will likely attempt to pursue legal challenges more frequently. The presented process mitigates the likelihood of these challenges going to court and increases the accuracy and efficiency of disincentives.

Originality/value

While there have been publications that discuss the legal challenges of imposing disincentives, they mainly provide guidelines and lack applicable processes. Existing literature that does present incentive/disincentive valuation process focuses on incentive valuations and neglects the disincentives' legal challenges. The following publication fills this gap by presenting an applicable disincentive valuation process for transportation projects which incorporates the guidelines for legal mitigation.