bluuebunny/crossref_metadata_2025_split huggingface dataset:
INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH
Authors: Hathazi Denisa , Cox Dan , D'Amico Adele , Tasca Giorgio , Charlton Richard , Carlier Robert-Yves , Baumann Jennifer , Kollipara Laxmikanth , Zahedi René P , Feldmann Ingo , Deleuze Jean-Francois , Torella Annalaura , Cohn Ronald , Robinson Emily , Ricci Francesco , Jungbluth Heinz , Fattori Fabiana , Boland Anne , O’Connor Emily , Horvath Rita , Barresi Rita , Lochmüller Hanns , Urtizberea Andoni , Jacquemont Marie-Line , Nelson Isabelle , Swan Laura , Bonne Gisèle , Roos Andreas 
Published: March 2021

Abstract
Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.
Cation leak underlies neuronal excitability in an HCN1 developmental and epileptic encephalopathy
Authors: Bleakley Lauren E , McKenzie Chaseley E , Soh Ming S , Forster Ian C , Pinares-Garcia Paulo , Sedo Alicia , Kathirvel Anirudh , Churilov Leonid , Jancovski Nikola , Maljevic Snezana , Berkovic Samuel F , Scheffer Ingrid E , Petrou Steven , Santoro Bina , Reid Christopher A 
Published: March 2021

Abstract
Pathogenic variants in HCN1 are associated with developmental and epileptic encephalopathies. The recurrent de novo HCN1 M305L pathogenic variant is associated with severe developmental impairment and drug-resistant epilepsy. We engineered the homologue Hcn1 M294L heterozygous knock-in (Hcn1M294L) mouse to explore the disease mechanism underlying an HCN1 developmental and epileptic encephalopathy. The Hcn1M294L mouse recapitulated the phenotypic features of patients with the HCN1 M305L variant, including spontaneous seizures and a learning deficit. Active epileptiform spiking on the electrocorticogram and morphological markers typical of rodent seizure models were observed in the Hcn1M294L mouse. Lamotrigine exacerbated seizures and increased spiking, whereas sodium valproate reduced spiking, mirroring drug responses reported in a patient with this variant. Functional analysis in Xenopus laevis oocytes and layer V somatosensory cortical pyramidal neurons in ex vivo tissue revealed a loss of voltage dependence for the disease variant resulting in a constitutively open channel that allowed for cation ‘leak’ at depolarized membrane potentials. Consequently, Hcn1M294L layer V somatosensory cortical pyramidal neurons were significantly depolarized at rest. These neurons adapted through a depolarizing shift in action potential threshold. Despite this compensation, layer V somatosensory cortical pyramidal neurons fired action potentials more readily from rest. A similar depolarized resting potential and left-shift in rheobase was observed for CA1 hippocampal pyramidal neurons. The Hcn1M294L mouse provides insight into the pathological mechanisms underlying hyperexcitability in HCN1 developmental and epileptic encephalopathy, as well as being a preclinical model with strong construct and face validity, on which potential treatments can be tested.
A phenomapping-derived tool to personalize the selection of anatomical vs. functional testing in evaluating chest pain (ASSIST)
Authors: Oikonomou Evangelos K , Van Dijk David , Parise Helen , Suchard Marc A , de Lemos James , Antoniades Charalambos , Velazquez Eric J , Miller Edward J , Khera Rohan 
Published: March 2021

Abstract

Aims
Coronary artery disease is frequently diagnosed following evaluation of stable chest pain with anatomical or functional testing. A more granular understanding of patient phenotypes that benefit from either strategy may enable personalized testing.

Methods and results
Using participant-level data from 9572 patients undergoing anatomical (n = 4734) vs. functional (n = 4838) testing in the PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) trial, we created a topological representation of the study population based on 57 pre-randomization variables. Within each patient’s 5% topological neighbourhood, Cox regression models provided individual patient-centred hazard ratios for major adverse cardiovascular events and revealed marked heterogeneity across the phenomap [median 1.11 (10th to 90th percentile: 0.52–2.61]), suggestive of distinct phenotypic neighbourhoods favouring anatomical or functional testing. Based on this risk phenomap, we employed an extreme gradient boosting algorithm in 80% of the PROMISE population to predict the personalized benefit of anatomical vs. functional testing using 12 model-derived, routinely collected variables and created a decision support tool named ASSIST (Anatomical vs. Stress teSting decIsion Support Tool). In both the remaining 20% of PROMISE and an external validation set consisting of patients from SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) undergoing anatomical-first vs. functional-first assessment, the testing strategy recommended by ASSIST was associated with a significantly lower incidence of each study's primary endpoint (P = 0.0024 and P = 0.0321 for interaction, respectively), as well as a harmonized endpoint of all-cause mortality or non-fatal myocardial infarction (P = 0.0309 and P &lt; 0.0001 for interaction, respectively).

Conclusion
We propose a novel phenomapping-derived decision support tool to standardize the selection of anatomical vs. functional testing in the evaluation of stable chest pain, validated in two large and geographically diverse clinical trial populations.
Appendicitis in children with acute abdominal pain in primary care, a retrospective cohort study
Authors: Blok Guus C G H , Veenstra Laura M M , van der Lei Johan , Berger Marjolein Y , Holtman Gea A 
Published: March 2021

Abstract

Background
General practitioners (GPs) face a diagnostic challenge when assessing acute abdominal pain in children. However, no information is available on the current diagnostic process or the diagnostic accuracy of history and physical examination in primary care settings.

Objective
To describe the diagnostic process for acute abdominal pain among children in primary care, focusing on appendicitis, and to assess the diagnostic accuracy of individual clinical features.

Methods
A retrospective cohort study in Dutch primary care, using the Integrated Primary Care Information database. Children aged 4–18 years were included if they had no history of appendicitis and presented with acute abdominal pain during 2010–2016. We evaluated GP management and the diagnostic accuracy of clinical features for appendicitis. Pre- and post-test probabilities were calculated for each clinical feature and compared with the probability of appendicitis after GP assessment.

Results
Out of 5691 children, 944 (16.6%) were referred and 291 (5.1%) had appendicitis, of whom 55 (18.9%) were initially misdiagnosed. The pre-test probability (i.e. of appendicitis in evaluated children) varied from 3% (rigidity) to 28% (migratory pain). Concerning post-test probabilities, positive values for rebound pain (32.1%) and guarding (35.8%) and the negative value for right lower quadrant tenderness (0.6%) were superior to overall GP assessment (29.6% and 1.1%, respectively).

Conclusions
GP assessment will miss almost one-fifth of children with appendicitis at their first presentation, and about two-third of GP referrals will be negative. The presence of specific signs can increase or decrease the likelihood of appendicitis, emphasising the importance of a physical examination.
Cyber offense in NATO: challenges and opportunities
Authors: Jacobsen Jeppe T 
Published: March 2021

Abstract
As a response to the Russian invasion of Crimea, NATO returned to the core military concepts of deterrence and collective defence. This NATO adaption has recently come to include attempts to integrate offensive cyber effects into NATO force structure and response doctrine. The article argues—counter to what is publicly declared—that such an integration does little to strengthen NATO's deterrence posture and is unlikely to deter non-military, hybrid cyber activity below the threshold of collective defence. The article identifies several practical challenges to the current integration effort, which include the temporal dimension of developing exploits, battle damage assessment and deconfliction. With these challenges in mind, the article suggests that deploying minor and less resourceful cyber effects that cause persistent ‘cyber annoyances’ holds an unappreciated potential as they can drain opponent resources, disturb vital IT-systems and complicate decision-making. The article ends by arguing that NATO should not adapt its collective defence clause to cyberspace. A more active NATO in cyberspace risks undermining the cyber-intelligence norm that so far has prevented escalation and thereby increasing the likelihood that Russia misinterprets intelligence and active cyber defence activities as military preparation, armament or an attack in the making.
The development of a sustainability assessment indicator and its response to management changes as derived from salmon lice dispersal modelling
Authors: Sandvik Anne D , Bui Samantha , Huserbråten Mats , Karlsen Ørjan , Myksvoll Mari S , Ådlandsvik Bjørn , Johnsen Ingrid A 
Published: March 2021

Abstract
Aquaculture is providing an increasingly larger proportion of the world’s protein for human consumption; however, its environmental impact is a bottleneck for sustainable expansion. In Norway, the government has enacted a framework where salmon lice-induced mortality in wild salmonid populations is used for assessing the environmental sustainability in production zones. Direct measurements of the level of lice-induced mortality on wild salmonids are difficult to acquire, thus comprehensive sustainability assessments are based on a set of evidence-based proxies. One such proxy is the infestation pressure from a bio-hydrodynamic model, from which we develop an index that summarize the sustainability of aquaculture in terms of lice infestation. This index is based on the proportion of areas with elevated lice loads, and is a novel approach used to investigate how sustainability could be achieved through scenario testing of different management strategies. The analyses identified a mismatch between legal and sustainable lice levels, but also a beneficial effect of reducing lice levels on farms. This study’s approach demonstrated how bio-hydrodynamic models might be used to assess sustainability and to predict the necessary reduction of lice larvae from farms to classify the entire Norwegian aquaculture industry as environmentally sustainable.
Multi-fleet state-space assessment model strengthens confidence in single-fleet SAM and provides fleet-specific forecast options
Authors: Nielsen Anders , Hintzen Niels T , Mosegaard Henrik , Trijoulet Vanessa , Berg Casper W 
Published: March 2021

Abstract
The state-space assessment model (SAM) is increasingly used to assess fish stocks in International Council for the Exploration of the Sea. One unique feature of the SAM class is that it allows the fishing selectivity to vary over time, and the degree to which it varies is not subjectively assigned, but estimated within the model. Selection may vary over time due to changes in the spatial pattern of the fish stock or fishing fleet, but a direct cause of selectivity change can be changed in fishing technology or other measures that target specific segments of the fish stocks. If the relative catches from fishing fleets which target different age or size classes of a species are changing over time, then the overall selectivity will also change—even if the selectivity within each fleet is fairly constant. A recent extension of the SAM model allows multiple fleets to be defined. It has been applied to two herring stocks to allow more detailed and fleet-specific management options in forecasts. For both stocks, the assessment from the multi-fleet models was consistent with the results from the single-fleet models, which strengthens confidence in the estimated time-varying selectivity for these and other stocks.
H∞ Optimal control of jump systems over multiple lossy communication channels
Authors: Mazumdar Abhijit , Krishnaswamy Srinivasan , Majhi Somanath 
Published: March 2021

Abstract
In this paper, the $H_{\infty }$ optimal control problem for a Markovian jump linear system (MJLS) over multiple lossy communication channels is considered. It is assumed that the controller communicates with each actuator through a different communication channel. We solve the $H_{\infty }$ optimization problem for the system with a Transmission Control Protocol (TCP) using the theory of dynamic games and obtain a state feedback controller. The infinite horizon $H_{\infty }$ optimization problem is analysed as a limiting case of the finite horizon optimization problem. Then, we obtain the corresponding state feedback controller and show that it stabilizes the closed-loop system in the face of random packet dropouts. A novel and relaxed condition for stability of the closed-loop system with the saddle-point policy is also presented. Further, we show that a weaker notion of observability is sufficient to establish our results.
Lipoblastoma as a cause of secondary omental torsion in children: report of the first case
Authors: Boscarelli Alessandro , Guida Edoardo , Ceschiutti Giulia , Bossini Benedetta , Olenik Damiana , Barbi Egidio , Schleef Jürgen 
Published: March 2021

Abstract
Acute abdominal pain remains a major diagnostic challenge to date. Omental torsion is an infrequent cause of abdominal pain in children, which usually presents with non-specific symptoms. Herein, we report a case of persistent abdominal pain after a minor abdominal trauma. A solid mass was found in the lower abdomen at ultrasound imaging evaluation. Surgical exploration demonstrated an omental torsion secondary to a rare neoplasm of childhood.
Super-eddington emission from accreting, highly magnetized neutron stars with a multipolar magnetic field
Authors: Brice Nabil , Zane Silvia , Turolla Roberto , Wu Kinwah 
Published: March 2021

ABSTRACT
Pulsating ultraluminous X-ray sources (PULXs) are characterized by an extremely large luminosity (&gt;1040 erg s−1). While there is a general consensus that they host an accreting, magnetized neutron star (NS), the problem of how to produce luminosities &gt;100 times the Eddington limit, LE, of a solar mass object is still debated. A promising explanation relies on the reduction of the opacities in the presence of a strong magnetic field, which allows for the local flux to be much larger than the Eddington flux. However, avoiding the onset of the propeller effect may be a serious problem. Here, we reconsider the problem of column accretion on to a highly magnetized NS, extending previously published calculations by relaxing the assumption of a pure dipolar field and allowing for more complex magnetic field topologies. We find that the maximum luminosity is determined primarily by the magnetic field strength near the NS surface. We also investigate other factors determining the accretion column geometry and the emergent luminosity, such as the assumptions on the parameters governing the accretion flow at the disc–magnetosphere boundary. We conclude that a strongly magnetized NS with a dipole component of ∼1013 G, octupole component of ∼1014 G, and spin period ∼1 s can produce a luminosity of ∼1041 erg s−1 while avoiding the propeller regime. We apply our model to two PULXs, NGC 5907 ULX-1, and NGC 7793 P13, and discuss how their luminosity and spin period rate can be explained in terms of different configurations, either with or without multipolar magnetic components.
Electron-impact rotational excitation cross-sections and rate coefficients of molecular ion: HCO+
Authors: Singh Jasmeet 
Published: March 2021

ABSTRACT
HCO+ is one of the most abundant polyatomic ion in the Universe, also its presence in the planetary atmospheres and interstellar medium (ISM) makes it an interesting case to study. Low energy e−-HCO+ collisions result in rotational excitation and other molecular processes. In this study, the cross-sections for rotational transitions in HCO+ are evaluated for four rotational levels (j = 0, 1, 2, and 3) using the UK R-matrix method and the multichannel quantum defect theory (MQDT). The UK R-matrix method used to generate scattering matrices, through which cross-sections are computed. In past two decades, after developments and implementations of different theoretical approaches, the improved channel elimination procedure applied here is more promising to evaluate more accurate results near rotational thresholds important for the analysis of intensities of microwave region in plasma modelling. The rate coefficients are deduced from the computed cross-sections and studied over a wide electron temperature range.
Rare instances of haploid inducer DNA in potato dihaploids and ploidy-dependent genome instability
Authors: Amundson Kirk R. , Ordoñez Benny , Santayana Monica , Nganga Mwaura Livingstone , Henry Isabelle M. , Bonierbale Merideth , Khan Awais , Tan Ek Han , Comai Luca 
Published: March 2021

Abstract
In cultivated tetraploid potato (Solanum tuberosum), reduction to diploidy (dihaploidy) allows for hybridization to diploids and introgression breeding and may facilitate the production of inbreds. Pollination with haploid inducers (HIs) yields maternal dihaploids, as well as triploid and tetraploid hybrids. Dihaploids may result from parthenogenesis, entailing the development of embryos from unfertilized eggs, or genome elimination, entailing missegregation and the loss of paternal chromosomes. A sign of genome elimination is the occasional persistence of HI DNA in some dihaploids. We characterized the genomes of 919 putative dihaploids and 134 hybrids produced by pollinating tetraploid clones with three HIs: IVP35, IVP101, and PL-4. Whole-chromosome or segmental aneuploidy was observed in 76 dihaploids, with karyotypes ranging from 2n = 2x − 1 = 23 to 2n = 2x + 3 = 27. Of the additional chromosomes in 74 aneuploids, 66 were from the non-inducer parent and 8 from the inducer parent. Overall, we detected full or partial chromosomes from the HI parent in 0.87% of the dihaploids, irrespective of parental genotypes. Chromosomal breaks commonly affected the paternal genome in the dihaploid and tetraploid progeny, but not in the triploid progeny, correlating instability to sperm ploidy and to haploid induction. The residual HI DNA discovered in the progeny is consistent with genome elimination as the mechanism of haploid induction.
Stabilization Exercises Versus Flexion Exercises in Degenerative Spondylolisthesis: A Randomized Controlled Trial
Authors: Nava-Bringas Tania Inés , Romero-Fierro Lizbeth Olivia , Trani-Chagoya Yessica Patricia , Macías-Hernández Salvador Israel , García-Guerrero Eduardo , Hernández-López Mario , Roberto Coronado-Zarco 
Published: March 2021

Abstract

Objective
Exercise is the mainstay of treatment in individuals with low back pain and the first-line option in degenerative spondylolisthesis (DS); however, there is still no consensus surrounding the superiority of any specific exercise program. Thus, the primary aim of this study was to compare the effectiveness of lumbar stabilization exercises and flexion exercises for pain control and improvements of disability in individuals with chronic low back pain (CLBP) and DS.

Methods
A randomized controlled trial was conducted in a tertiary public hospital and included 92 individuals over the age of 50 years who were randomly allocated to lumbar stabilization exercises or flexion exercises. Participants received 6 sessions of physical therapy (monthly appointments) and were instructed to execute exercises daily at home during the 6 months of the study. The primary outcome (measured at baseline, 1 month, 3 months, and 6 months) was pain intensity (visual analog scale, 0–100 mm) and disability (Oswestry Disability Index, from 0% to 100%). Secondary outcomes were disability (Roland-Morris Disability Questionnaire, from 0 to 24 points), changes in body mass index, and flexibility (fingertip to floor, in centimeters) at baseline and 6 months, and also the total of days of analgesic use at 6-month follow-up.

Results
Mean differences between groups were not significant (for lumbar pain: 0.56 [95% CI = −11.48 to 12.61]; for radicular pain: −1.23 [95% CI = −14.11 to 11.64]; for Oswestry Disability Index: −0.61 [95% CI = −6.92 to 5.69]; for Roland-Morris Disability Questionnaire: 0.53 [95% CI = −1.69 to 2.76]).

Conclusion
The findings from the present study reveal that flexion exercises are not inferior to and offer a similar response to stabilization exercises for the control of pain and improvements of disability in individuals with CLBP and DS.

Impact
Exercise is the mainstay of treatment in individuals with CLBP and DS; however, there is still no consensus surrounding the superiority of any specific exercise program. This study finds that flexion exercises are not inferior to and offer a similar response to stabilization exercises.

Lay Summary
Exercise is the mainstay of treatment in individuals with CLBP and DS, but there is no consensus on the superiority of any specific exercise program. If you have DS, flexion exercises may provide similar effects to stabilization exercises.