bluuebunny/crossref_metadata_2025 huggingface dataset:
Imaging atelectrauma in Ventilator-Induced Lung Injury using 4D X-ray microscopy
Authors: Fardin Luca , Broche Ludovic , Lovric Goran , Mittone Alberto , Stephanov Olivier , Larsson Anders , Bravin Alberto , Bayat Sam
Published: February 2021

Mechanical ventilation can damage the lungs, a condition called Ventilator-Induced Lung Injury (VILI). However, the mechanisms leading to VILI at the microscopic scale remain poorly understood. Here we investigated the within-tidal dynamics of cyclic recruitment/derecruitment (R/D) using synchrotron radiation phase-contrast imaging (PCI), and the relation between R/D and cell infiltration, in a model of Acute Respiratory Distress Syndrome in 6 anaesthetized and mechanically ventilated New-Zealand White rabbits. Dynamic PCI was performed at 22.6 µm voxel size, under protective mechanical ventilation [tidal volume: 6 ml/kg; positive end-expiratory pressure (PEEP): 5 cmH2O]. Videos and quantitative maps of within-tidal R/D showed that injury propagated outwards from non-aerated regions towards adjacent regions where cyclic R/D was present. R/D of peripheral airspaces was both pressure and time-dependent, occurring throughout the respiratory cycle with significant scatter of opening/closing pressures. There was a significant association between R/D and regional lung cellular infiltration (p = 0.04) suggesting that tidal R/D of the lung parenchyma may contribute to regional lung inflammation or capillary-alveolar barrier dysfunction and to the progression of lung injury. PEEP may not fully mitigate this phenomenon even at high levels. Ventilation strategies utilizing the time-dependence of R/D may be helpful in reducing R/D and associated injury.
Uncovering the superior corrosion resistance of iron made via ancient Indian iron-making practice
Authors: Dwivedi Deepak , Mata Jitendra P. , Salvemini Filomena , Rowles Matthew R. , Becker Thomas , Lepková Kateřina
Published: February 2021

Ancient Indian iron artefacts have always fascinated researchers due to their excellent corrosion resistance, but the scientific explanation of this feature remains to be elucidated. We have investigated corrosion resistance of iron manufactured according to traditional metallurgical processes by the Indian tribes called ‘Agaria’. Iron samples were recovered from central India (Aamadandh, Korba district, Chhattisgarh). Iron artefacts are investigated using a range of correlative microscopic, spectroscopic, diffraction and tomographic techniques to postulate the hidden mechanisms of superlative corrosion resistance. The importance of manufacturing steps, ingredients involved in Agaria’s iron making process, and post-metal treatment using metal-working operation called hot hammering (forging) is highlighted. This study also hypothesizes the probable protective mechanisms of corrosion resistance of iron. Findings are expected to have a broad impact across multiple disciplines such as archaeology, metallurgy and materials science.
Modified conditioning regimen with idarubicin followed by autologous hematopoietic stem cell transplantation for invasive B-cell non-Hodgkin’s lymphoma patients
Authors: Tian Chen , Li Yueyang , Liu Su , Chen Zehui , Zhang Yizhuo , Yu Yong , Yang Hongliang , Zhao Haifeng , Zhao Zhigang , Yuan Tian , Wang Yafei
Published: February 2021

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) is still a consolidation treatment choice for relapsed/refractory B-cell non-Hodgkin’s lymphoma (NHL) patients and some aggressive B-cell NHL as frontline therapy. Due to the shortage of carmustine, we switched to idarubicin-substituted BEAC (IEAC) conditioning regimen. We retrospectively compared the outcomes of 72 aggressive B-cell NHL patients treated with IEAC or BEAC regimens followed by ASCT as upfront consolidative treatment. The median time to neutrophil and platelet reconstitution showed no difference between IEAC and BEAC groups. IEAC regimen was well tolerated without increase of adverse events. Transplant-related mortality didn’t occur. The overall survival (OS) and progression-free survival (PFS) of IEAC group (33 and 23 months) were a little longer than that of BEAC group (30 and 18 months). However, due to the small sample numbers, there’s no significant difference in OS and PFS between IEAC and BEAC group with DLBCL or MCL. Multivariate analysis showed that AnnArbor staging, IPI score, lactate dehydrogenase level, remission of disease, modified regimen were related with PFS and OS. In conclusion, IEAC regimen was well tolerated and replacement with idarubicin could be an alternative when carmustine was not available.
Biogeography of the cosmopolitan terrestrial diatom Hantzschia amphioxys sensu lato based on molecular and morphological data
Authors: Maltsev Yevhen , Maltseva Svetlana , Kociolek John Patrick , Jahn Regine , Kulikovskiy Maxim
Published: February 2021

Until now, the reported diversity of representatives from the genus Hantzschia inhabiting soils from different parts of Eurasia was limited to the few species H. amphioxys, H. elongata and H. vivax and some of their infraspecific taxa. We have studied the morphology, ultrastructure and phylogeny of 25 soil diatom strains, which according to published description would be assigned to “H. amphioxys sensu lato” using 18S rDNA, 28S rDNA and rbcL. We show that strains are made up of seven different species of Hantzschia, including five new for science. Five strains were identified as H. abundans. This species has a slight curvature of the raphe near its external proximal ends. Four of the examined strains were represented by different populations of H. amphioxys and their morphological characteristics fully correspond with its isolectotype and epitype. The main specific features of this species include 21–25 striae in 10 μm, 6–11 fibulae in 10 μm, 40–50 areolae in 10 μm and internal proximal raphe endings bent in opposite directions. H. attractiva sp. nov., H. belgica sp. nov., H. parva sp. nov., H. pseudomongolica sp. nov. and H. stepposa sp. nov. were described based on differences in the shape of the valves, significant differences in dimensions, a lower number of striae and areolae in 10 μm and the degree and direction of deflection of the internal central raphe endings. Based on the study of the morphological variability and phylogeny of soil Hantzschia-species from different geographical locations we conclude that while some species such as H. amphioxys are truly cosmopolitan in their distributions, some sympatric populations of pseudocryptic taxa exist in the Holarctic.
Dogs (Canis familiaris) recognize their own body as a physical obstacle
Authors: Lenkei Rita , Faragó Tamás , Zsilák Borbála , Pongrácz Péter
Published: February 2021

Mental representations of one’s own body provide useful reference when negotiating physical environmental challenges. Body-awareness is a neuro-ontogenetic precursor for higher order self-representation, but there is a lack of an ecologically valid experimental approach to it among nonhuman species. We tested dogs (N = 32) in the ‘body as an obstacle’ task. They had to pick up and give an object to their owner, whilst standing on a small mat. In the test condition we attached the object to the mat, thus the dogs had to leave the mat because otherwise they could not lift the object. Dogs came off the mat more frequently and sooner in the test condition, than in the main control condition, where the object was attached to the ground. This is the first convincing evidence of body awareness through the understanding of the consequence of own actions in a species where previously no higher-order self-representation capacity was found. We urge for an ecologically valid approach, and following of bottom-up methods, in studying modularly constructed self-representation.
Multipronged dental analyses reveal dietary differences in last foragers and first farmers at Grotta Continenza, central Italy (15,500–7000 BP)
Authors: Nava Alessia , Fiorin Elena , Zupancich Andrea , Carra Marialetizia , Ottoni Claudio , Di Carlo Gabriele , Vozza Iole , Brugnoletti Orlando , Alhaique Francesca , Cremonesi Renata Grifoni , Coppa Alfredo , Bondioli Luca , Borić Dušan , Cristiani Emanuela
Published: February 2021

This paper provides results from a suite of analyses made on human dental material from the Late Palaeolithic to Neolithic strata of the cave site of Grotta Continenza situated in the Fucino Basin of the Abruzzo region of central Italy. The available human remains from this site provide a unique possibility to study ways in which forager versus farmer lifeways affected human odonto-skeletal remains. The main aim of our study is to understand palaeodietary patterns and their changes over time as reflected in teeth. These analyses involve a review of metrics and oral pathologies, micro-fossils preserved in the mineralized dental plaque, macrowear, and buccal microwear. Our results suggest that these complementary approaches support the assumption about a critical change in dental conditions and status with the introduction of Neolithic foodstuff and habits. However, we warn that different methodologies applied here provide data at different scales of resolution for detecting such changes and a multipronged approach to the study of dental collections is needed for a more comprehensive and nuanced understanding of diachronic changes.
Severe acute malnutrition morphological patterns in children under five
Authors: Medialdea Laura , Bogin Barry , Thiam Mbeugue , Vargas Antonio , Marrodán María D. , Dossou Nicole I.
Published: February 2021

Current methods for infant and child nutritional assessment rely on anthropometric measurements, whose implementation faces technical challenges in low- and middle-income countries. Anthropometry is also limited to linear measurements, ignoring important body shape information related to health. This work proposes the use of 2D geometric morphometric techniques applied to a sample of Senegalese participants aged 6–59 months with an optimal nutritional condition or with severe acute malnutrition to address morphometric variations due to nutritional status. Significant differences in shape and size body changes were described according to nutritional status, resulting age, sex and allometric effect crucial factors to establish nutritional morphological patterns. The constructed discriminant functions exhibited the best classification rates in the left arm. A landmark-based template registering body shape could be useful to both assess acute malnutrition and better understand the morphological patterns that nutritional status promotes in children during their first 5 years of growth and development.
A meta-analysis uncovers the first sequence variant conferring risk of Bell’s palsy
Authors: Skuladottir Astros Th. , Bjornsdottir Gyda , Thorleifsson Gudmar , Walters G. Bragi , Nawaz Muhammad Sulaman , Moore Kristjan Helgi Swerford , Olason Pall I. , Thorgeirsson Thorgeir E. , Sigurpalsdottir Brynja , Sveinbjornsson Gardar , Eggertsson Hannes P. , Magnusson Sigurdur H. , Oddsson Asmundur , Bjornsdottir Anna , Vikingsson Arnor , Sveinsson Olafur A. , Hrafnsdottir Maria G. , Sigurdardottir Gudrun R. , Halldorsson Bjarni V. , Hansen Thomas Folkmann , Paarup Helene , Erikstrup Christian , Nielsen Kaspar , Klokker Mads , Bruun Mie Topholm , Sorensen Erik , Banasik Karina , Burgdorf Kristoffer S. , Pedersen Ole Birger , Ullum Henrik , Jonsdottir Ingileif , Stefansson Hreinn , Stefansson Kari
Published: February 2021

Bell’s palsy is the most common cause of unilateral facial paralysis and is defined as an idiopathic and acute inability to control movements of the facial muscles on the affected side. While the pathogenesis remains unknown, previous studies have implicated post-viral inflammation and resulting compression of the facial nerve. Reported heritability estimates of 4–14% suggest a genetic component in the etiology and an autosomal dominant inheritance has been proposed. Here, we report findings from a meta-analysis of genome-wide association studies uncovering the first unequivocal association with Bell’s palsy (rs9357446-A; P = 6.79 × 10−23, OR = 1.23; Ncases = 4714, Ncontrols = 1,011,520). The variant also confers risk of intervertebral disc disorders (P = 2.99 × 10−11, OR = 1.04) suggesting a common pathogenesis in part or a true pleiotropy.
Flexibility and mobility of SARS-CoV-2-related protein structures
Authors: Römer Rudolf A. , Römer Navodya S. , Wallis A. Katrine
Published: February 2021

The worldwide CoVid-19 pandemic has led to an unprecedented push across the whole of the scientific community to develop a potent antiviral drug and vaccine as soon as possible. Existing academic, governmental and industrial institutions and companies have engaged in large-scale screening of existing drugs, in vitro, in vivo and in silico. Here, we are using in silico modelling of possible SARS-CoV-2 drug targets, as deposited on the Protein Databank (PDB), and ascertain their dynamics, flexibility and rigidity. For example, for the SARS-CoV-2 spike protein—using its complete homo-trimer configuration with 2905 residues—our method identifies a large-scale opening and closing of the S1 subunit through movement of the S$${}^\text{B}$$

B

domain. We compute the full structural information of this process, allowing for docking studies with possible drug structures. In a dedicated database, we present similarly detailed results for the further, nearly 300, thus far resolved SARS-CoV-2-related protein structures in the PDB.
Timescale of hole closure during plasma membrane repair estimated by calcium imaging and numerical modeling
Authors: Klenow Martin Berg , Heitmann Anne Sofie Busk , Nylandsted Jesper , Simonsen Adam Cohen
Published: February 2021

Plasma membrane repair is essential for eukaryotic cell life and is triggered by the influx of calcium through membrane wounds. Repair consists of sequential steps, with closure of the membrane hole being the key event that allows the cell to recover, thus identifying the kinetics of hole closure as important for clarifying repair mechanisms and as a quantitative handle on repair efficiency. We implement calcium imaging in MCF7 breast carcinoma cells subject to laser damage, coupled with a model describing the spatio-temporal calcium distribution. The model identifies the time point of hole closure as the time of maximum calcium signal. Analysis of cell data estimates the closure time as: $$\langle t_c \rangle =5.45\pm 2.25$$

⟨

t
c

⟩
=
5.45
±
2.25

s and $$\langle t_c \rangle =6.81\pm 4.69$$

⟨

t
c

⟩
=
6.81
±
4.69

s using GCaMP6s-CAAX and GCaMP6s probes respectively. The timescale was confirmed by independent time-lapse imaging of a hole during sealing. Moreover, the analysis estimates the characteristic time scale of calcium removal, the penetration depth of the calcium wave and the diffusion coefficient. Probing of hole closure times emerges as a strong universal tool for quantification of plasma membrane repair
Evolutionary development of the Homo antecessor scapulae (Gran Dolina site, Atapuerca) suggests a modern-like development for Lower Pleistocene Homo
Authors: García-Martínez Daniel , Green David J. , Bermúdez de Castro José María
Published: February 2021

Two well-preserved, subadult 800 ky scapulae from Gran Dolina belonging toHomo antecessor, provide a unique opportunity to investigate the ontogeny of shoulder morphology in Lower Pleistocene humans. We compared theH. antecessorscapulae with a sample of 98P. troglodytesand 108H. sapiensrepresentatives covering seven growth stages, as well as with the DIK-1-1 (Dikika;Australopithecus afarensis), KNM-WT 15000 (Nariokotome;H. ergaster), and MH2 (Malapa;A. sediba) specimens. We quantified 15 landmarks on each scapula and performed geometric morphometric analyses.H. sapiensscapulae are mediolaterally broader with laterally oriented glenoid fossae relative toPanand Dikika shoulder blades. Accordingly,H. antecessorscapulae shared more morphological affinities with modern humans, KNM-WT 15000, and even MH2. BothH. antecessorand modernHomoshowed significantly more positive scapular growth trajectories thanPan(slopes:P. troglodytes = 0.0012;H. sapiens = 0.0018;H. antecessor = 0.0020). Similarities in ontogenetic trajectories between theH. antecessorand modern human data suggest that Lower Pleistocene hominin scapular development was already modern human-like. At the same time, several morphological features distinguishH. antecessorscapulae from modern humans along the entire trajectory. Future studies should include additionalAustralopithecusspecimens for further comparative assessment of scapular growth trends.
Years of life lost to COVID-19 in 81 countries
Authors: Pifarré i Arolas Héctor , Acosta Enrique , López-Casasnovas Guillem , Lo Adeline , Nicodemo Catia , Riffe Tim , Myrskylä Mikko
Published: February 2021

Understanding the mortality impact of COVID-19 requires not only counting the dead, but analyzing how premature the deaths are. We calculate years of life lost (YLL) across 81 countries due to COVID-19 attributable deaths, and also conduct an analysis based on estimated excess deaths. We find that over 20.5 million years of life have been lost to COVID-19 globally. As of January 6, 2021, YLL in heavily affected countries are 2–9 times the average seasonal influenza; three quarters of the YLL result from deaths in ages below 75 and almost a third from deaths below 55; and men have lost 45% more life years than women. The results confirm the large mortality impact of COVID-19 among the elderly. They also call for heightened awareness in devising policies that protect vulnerable demographics losing the largest number of life-years.
The progression of chronic tinnitus over the years
Authors: Simões Jorge P. , Neff Patrick K. A. , Langguth Berthold , Schlee Winfried , Schecklmann Martin
Published: February 2021

Little is known about the trajectory of tinnitus over time. This study addressed (1) how often tinnitus remitted in patients with chronic tinnitus; (2) how subjective reported tinnitus characteristics, such as loudness, laterality, and type and measures of burden, such as tinnitus distress, depression, and quality of life, changes over time; (3) how often tinnitus-specific treatments were undertaken and the prevalence of comorbidities, (4) if the number of treatments and comorbidities were associated to changes in tinnitus distress over time. Data from 388 patients with chronic tinnitus who visited a tertiary tinnitus clinic between 2012 and 2017 were interrogated via a mail survey in 2018. Tinnitus characteristics were measured with the Tinnitus Sample Case History Questionnaire and numeric rating scales; tinnitus distress with Tinnitus Handicap Inventory (THI) and the Tinnitus Questionnaire (TQ), depression with the Major Depression Inventory and Quality of life with the World Health Organisation Quality of Life BREF at both time points and the clinical global impression scale. Comorbidities experienced and undertaken treatments were assessed with an in-house survey. Three participants (0.8% of the sample) reported tinnitus remission between both assessments. A decrease in the THI and TQ, and numeric ratings for tinnitus severity, annoyance, unpleasantness, and discomfort was observed, but no differences in tinnitus characteristics, depression, quality of life or overall health status. 64% presented at least one comorbidity, and 88% sought at least on tinnitus-specific treatment. Common comorbidities were psychological and sleeping problems, and the most common interventions were going to the dentist, taking medications, and wearing hearing aids. Our results suggest that full remission of tinnitus is a rare condition, that tinnitus distress on average decreases over time, and that tinnitus characteristics, quality of life, and depression tend to remain unaltered. The high number of interventions and comorbidities displayed minimal association to the changes in tinnitus distress, highlighting the substantial and durable burden of tinnitus sufferers.
Deep learning based automated diagnosis of bone metastases with SPECT thoracic bone images
Authors: Lin Qiang , Li Tongtong , Cao Chuangui , Cao Yongchun , Man Zhengxing , Wang Haijun
Published: February 2021

SPECT nuclear medicine imaging is widely used for treating, diagnosing, evaluating and preventing various serious diseases. The automated classification of medical images is becoming increasingly important in developing computer-aided diagnosis systems. Deep learning, particularly for the convolutional neural networks, has been widely applied to the classification of medical images. In order to reliably classify SPECT bone images for the automated diagnosis of metastasis on which the SPECT imaging solely focuses, in this paper, we present several deep classifiers based on the deep networks. Specifically, original SPECT images are cropped to extract the thoracic region, followed by a geometric transformation that contributes to augment the original data. We then construct deep classifiers based on the widely used deep networks including VGG, ResNet and DenseNet by fine-tuning their parameters and structures or self-defining new network structures. Experiments on a set of real-world SPECT bone images show that the proposed classifiers perform well in identifying bone metastasis with SPECT imaging. It achieves 0.9807, 0.9900, 0.9830, 0.9890, 0.9802 and 0.9933 for accuracy, precision, recall, specificity, F-1 score and AUC, respectively, on the test samples from the augmented dataset without normalization.
Defining the epitope of a blood–brain barrier crossing single domain antibody specific for the type 1 insulin-like growth factor receptor
Authors: Sheff Joey , Wang Ping , Xu Ping , Arbour Melanie , Masson Luke , van Faassen Henk , Hussack Greg , Kemmerich Kristin , Brunette Eric , Stanimirovic Danica , Hill Jennifer J. , Kelly John , Ni Feng
Published: February 2021

Ligand-activated signaling through the type 1 insulin-like growth factor receptor (IGF1R) is implicated in many physiological processes ranging from normal human growth to cancer proliferation and metastasis. IGF1R has also emerged as a target for receptor-mediated transcytosis, a transport phenomenon that can be exploited to shuttle biotherapeutics across the blood–brain barrier (BBB). We employed differential hydrogen–deuterium exchange mass spectrometry (HDX-MS) and nuclear magnetic resonance (NMR) to characterize the interactions of the IGF1R ectodomain with a recently discovered BBB-crossing single-domain antibody (sdAb), VHH-IR5, in comparison with IGF-1 binding. HDX-MS confirmed that IGF-1 induced global conformational shifts in the L1/FnIII-1/-2 domains and α-CT helix of IGF1R. In contrast, the VHH-IR5 sdAb-mediated changes in conformational dynamics were limited to the α-CT helix and its immediate vicinity (L1 domain). High-resolution NMR spectroscopy titration data and linear peptide scanning demonstrated that VHH-IR5 has high-affinity binding interactions with a peptide sequence around the C-terminal region of the α-CT helix. Taken together, these results define a core linear epitope for VHH-IR5 within the α-CT helix, overlapping the IGF-1 binding site, and suggest a potential role for the α-CT helix in sdAb-mediated transcytosis.
Multivariate spatio-temporal approach to identify vulnerable localities in dengue risk areas using Geographic Information System (GIS)
Authors: Withanage Gayan P. , Gunawardana Malika , Viswakula Sameera D. , Samaraweera Krishantha , Gunawardena Nilmini S. , Hapugoda Menaka D.
Published: February 2021

Dengue is one of the most important vector-borne infection in Sri Lanka currently leading to vast economic and social burden. Neither a vaccine nor drug is still not being practiced, vector controlling is the best approach to control disease transmission in the country. Therefore, early warning systems are imminent requirement. The aim of the study was to develop Geographic Information System (GIS)-based multivariate analysis model to detect risk hotspots of dengue in the Gampaha District, Sri Lanka to control diseases transmission. A risk model and spatial Poisson point process model were developed using separate layers for patient incidence locations, positive breeding containers, roads, total buildings, public places, land use maps and elevation in four high risk areas in the district. Spatial correlations of each study layer with patient incidences was identified using Kernel density and Euclidean distance functions with minimum allowed distance parameter. Output files of risk model indicate that high risk localities are in close proximity to roads and coincide with vegetation coverage while the Poisson model highlighted the proximity of high intensity localities to public places and possibility of artificial reservoirs of dengue. The latter model further indicate that clustering of dengue cases in a radius of approximately 150 m in high risk areas indicating areas need intensive attention in future vector surveillances.
Longitudinal analysis of safety and medication adherence of patients in the Fingolimod patient support program: a real-world observational study
Authors: Bourdin Aline , Schneider Marie Paule , Locatelli Isabella , Schluep Myriam , Bugnon Olivier , Berger Jérôme
Published: February 2021

The Fingolimod Patient Support Program (F-PSP) is an interprofessional specialty pharmacy service designed to ensure responsible use of fingolimod by promoting patient safety and medication adherence. This study aims to evaluate the safety and medication adherence of patients who joined the F-PSP between 2013 and 2016. Sociodemographic and medical characteristics, patient safety data (patient-reported symptoms, discontinuations due to adverse events (AEs), repeated first-dose monitoring), and medication adherence (implementation, persistence, reasons for discontinuation, influence of covariates, barriers and facilitators) were described. Sixty-seven patients joined the F-PSP. Patients reported a high frequency of symptoms. Due to AEs, 7 patients discontinued fingolimod, 3 took therapeutic breaks, and 1 reduced the regimen temporarily. Three patients repeated the first-dose monitoring. Patients had a high medication adherence over the 18-month analysis period: implementation decreased from 98.8 to 93.7%, and fingolimod persistence was 83.2% at 18 months. The patients’ level of education, professional situation, and living with child(ren) influenced implementation. Patients reported more facilitators of medication adherence than barriers. The F-PSP seems valuable for supporting individual patients (ensuring responsible use of fingolimod and inviting patients for shared-decision making) and public health (indirectly gathering real-world evidence).
HLA diversity in the Argentinian Umbilical Cord Blood Bank: frequencies according to donor’s reported ancestry and geographical distribution
Authors: Fernández Souto Daniela , Rosello Julieta , Lazo Laura , Veloso Florencia , Gamba Cecilia , Kuperman Silvina , Roca Valeria
Published: February 2021

Umbilical cord blood (UCB) is a suitable source for hematopoietic stem cell transplantation. The study of HLA genes by next generation sequencing is commonly used in transplants. Donor/patient HLA matching is often higher within groups of common ancestry, however “Hispanic” is a broad category that fails to represent Argentina’s complex genetic admixture. Our aim is to describe HLA diversity of banked UCB units collected across the country taking into consideration donor’s reported ancestral origins as well as geographic distribution. Our results showed an evenly distribution of units mainly for 2 groups: of European and of Native American descent, each associated to a defined geographic location pattern (Central vs. North regions). We observed differences in allele frequency distributions for some alleles previously described in Amerindian populations: for Class I (A*68:17, A*02:11:01G, A*02:22:01G, B*39:05:01, B*35:21, B*40:04, B*15:04:01G, B*35:04:01, B*51:13:01) and Class II (DRB1*04:11:01, DRB1*04:07:01G/03, DRB1*08:02:01, DRB1*08:07, DRB1*09:01:02G, DRB1*14:02:01, DRB1*16:02:01G). Our database expands the current knowledge of HLA diversity in Argentinian population. Although further studies are necessary to fully comprehend HLA heterogeneity, this report should prove useful to increase the possibility of finding compatible donors for successful allogeneic transplant and to improve recruitment strategies for UCB donors across the country.
MTBP phosphorylation controls DNA replication origin firing
Authors: Ferreira Pedro , Höfer Verena , Kronshage Nora , Marko Anika , Reusswig Karl-Uwe , Tetik Bilal , Dießel Christoph , Köhler Kerstin , Tschernoster Nikolai , Altmüller Janine , Schulze Nina , Pfander Boris , Boos Dominik
Published: February 2021

Faithful genome duplication requires regulation of origin firing to determine loci, timing and efficiency of replisome generation. Established kinase targets for eukaryotic origin firing regulation are the Mcm2-7 helicase, Sld3/Treslin/TICRR and Sld2/RecQL4. We report that metazoan Sld7, MTBP (Mdm2 binding protein), is targeted by at least three kinase pathways. MTBP was phosphorylated at CDK consensus sites by cell cycle cyclin-dependent kinases (CDK) and Cdk8/19-cyclin C. Phospho-mimetic MTBP CDK site mutants, but not non-phosphorylatable mutants, promoted origin firing in human cells. MTBP was also phosphorylated at DNA damage checkpoint kinase consensus sites. Phospho-mimetic mutations at these sites inhibited MTBP’s origin firing capability. Whilst expressing a non-phospho MTBP mutant was insufficient to relieve the suppression of origin firing upon DNA damage, the mutant induced a genome-wide increase of origin firing in unperturbed cells. Our work establishes MTBP as a regulation platform of metazoan origin firing.
Beta cell function, insulin resistance and vitamin D status among type 2 diabetes patients in Western Kenya
Authors: Said Jamil , Lagat David , Kimaina Allan , Oduor Chrispine
Published: February 2021

Serum vitamin D status exerts effects on glucose-insulin-homeostatic states underlying Diabetes-Mellitus, Type 2 (T2DM). This has been described in white and Asian population where low Vitamin D levels predicted future impairments in beta cell function and worsening of insulin resistance. This study aimed to examine the relationship between serum vitamin D, insulin resistance and beta cell function in a sub population of black Kenyan T2DM patients. The primary objective was to determine the levels of serum 25 hydroxy (25-OH) vitamin D, and estimate the insulin resistance, and beta cell function among T2DM patients at Moi Teaching and Referral Hospital (MTRH). This was a cross sectional study. 124 T2DM patients attending the MTRH Diabetes clinic between February and May 2016 were enrolled. Patients on insulin therapy and/or thiazolidinediones were excluded. Anthropometric, clinical and demographic data was obtained. Samples were drawn for estimation of serum 25-OH vitamin D, fasting insulin levels and fasting blood glucose levels. HOMA (Homeostatic model of assessment) model was used to estimate Beta cell secretion (HOMA-B) and insulin resistance (HOMA-IR); while the Disposition index {(DI) hyperbola product of insulin sensitivity (1/HOMA-IR) and beta cell secretion} was used to estimate the beta cell function. The relationships between serum vitamin D, insulin resistance and beta cell function were explored using a linear regression model. The study participants had a mean age of 56.2 (± 9.2) years, and a mean BMI of 26.9 kg/m2 (4.3). Forty nine percent (n = 61) were males. Vitamin D deficiency was present in 71.1% (n = 88) of the respondents. Relatively low levels of insulin resistance and higher levels of beta cell dysfunction were observed {median HOMA-IR of 2.3 (0.7, 6.5) and Disposition Index (DI) of 25.5 (14.3, 47.2)}. Vitamin D levels exhibited a low positive correlation with DI [r = 0.22 (95% CI: 0.03, 0.37)], but was not significantly correlated with HOMA-IR [r = 0.07(95% CI: − 0.11, 0.25)]. These results indicate that beta cell dysfunction rather than insulin resistance as the predominant defect among black T2DM patients seeking care at the MTRH diabetes clinic. Vitamin D deficiency is also prevalent among them and exhibits a low positive correlation with beta cell dysfunction. There was no correlation observed between Vitamin D deficiency and insulin resistance.
Quantifying the inundation impacts of earthquake-induced surface elevation change by hydrological and hydraulic modeling
Authors: Ouyang Mao , Ito Yuka , Tokunaga Tomochika
Published: February 2021

Current estimates of flood hazards are often based on the assumption that topography is static. When tectonic and/or anthropogenic processes change the land surface elevation, the spatial patterns of floods might also change. Here, we employ the hydrological and hydraulic modeling to simulate floods in the Kujukuri Plain, Japan, in the years 2004 and 2013, when two severe floods occurred. In between the two floods, land surface elevations were changed by the 2011 Tohoku-Oki earthquake. The effects of land surface elevation changes on inundation areas were quantified by changing input topographies. Our results showed that, without taking into account land surface elevation changes, around 10% of inundation areas were underestimated at the time of flood events in the year 2013. The spatial distribution of inundation locations varied with local topographical features, for example, the areas with backmarsh and valley fill deposits were sensitive to the extent of inundation by land surface elevation changes. The sub-watershed near the coastal shoreline having below-zero meter elevation areas showed that the earthquake-induced land surface elevation changes exacerbated an additional 22% inundation area. This study suggests that the inundation areas will increase in catchments suffering severe settlements, which highlights the necessity of taking into account the spatio-temporal changes of land surface elevations on the assessment of flood hazards.
Diabetic vascular hyperpermeability: optical coherence tomography angiography and functional loss assessments of relationships among retinal vasculature changes
Authors: Arima Mitsuru , Nakao Shintaro , Kaizu Yoshihiro , Wada Iori , Yamaguchi Muneo , Fujiwara Kohta , Akiyama Masato , Stitt Alan W. , Sonoda Koh-Hei
Published: February 2021

Our study assessed the influence of vascular permeability on vascular flow density (FD)-correlated retinal sensitivity (RS) in DR. In this cross-sectional, prospective, consecutive study, RS in the extrafoveal macula of DR patient was measured by microperimetry. FD was measured in the total, superficial, and deep capillary plexus layers (TCP, SCP, and DCP) by optical coherence tomography angiography. All measurement points were classified into four categories according to intensity of fluorescein leakage and FD, and the RS reduction was compared. A stratified analysis by retinal thickness (RT) was also performed. Fourteen eyes (14 patients) were enrolled. FDs at 207 RS measurement points were analyzable. For TCP, SCP and DCP, the leakage did not decrease RS at points where FD was maintained. The greater the leakage, the smaller the RS reduction at points with low FD in TCP (P = .020). Points with high leakage showed a significant smaller RS reduction than points with low leakage (P = .001 for TCP, P = .040 for SCP, and P = .046 for DCP) only in areas with low RT and low FD. Our results suggested that vascular hyperpermeability may inhibit the RS reduction in the non-edematous ischemic diabetic retina.
Zero-crossing patterns reveal subtle epileptiform discharges in the scalp EEG
Authors: Pyrzowski Jan , Le Douget Jean- Eudes , Fouad Amal , Siemiński Mariusz , Jędrzejczak Joanna , Le Van Quyen Michel
Published: February 2021

Clinical diagnosis of epilepsy depends heavily on the detection of interictal epileptiform discharges (IEDs) from scalp electroencephalographic (EEG) signals, which by purely visual means is far from straightforward. Here, we introduce a simple signal analysis procedure based on scalp EEG zero-crossing patterns which can extract the spatiotemporal structure of scalp voltage fluctuations. We analyzed simultaneous scalp and intracranial EEG recordings from patients with pharmacoresistant temporal lobe epilepsy. Our data show that a large proportion of intracranial IEDs manifest only as subtle, low-amplitude waveforms below scalp EEG background and could, therefore, not be detected visually. We found that scalp zero-crossing patterns allow detection of these intracranial IEDs on a single-trial level with millisecond temporal precision and including some mesial temporal discharges that do not propagate to the neocortex. Applied to an independent dataset, our method discriminated accurately between patients with epilepsy and normal subjects, confirming its practical applicability.
Tolerance engineering in Deinococcus geothermalis by heterologous efflux pumps
Authors: Boulant Erika , Cambon Emmanuelle , Vergalli Julia , Bernard Rémi , Neulat-Ripoll Fabienne , Nolent Flora , Gorgé Olivier , Girleanu Maria , Favier Anne-Laure , Leonetti Jean-Paul , Bolla Jean Michel
Published: February 2021

Producing industrially significant compounds with more environmentally friendly represents a challenging task. The large-scale production of an exogenous molecule in a host microfactory can quickly cause toxic effects, forcing the cell to inhibit production to survive. The key point to counter these toxic effects is to promote a gain of tolerance in the host, for instance, by inducing a constant flux of the neo-synthetized compound out of the producing cells. Efflux pumps are membrane proteins that constitute the most powerful mechanism to release molecules out of cells. We propose here a new biological model, Deinococcus geothermalis, organism known for its ability to survive hostile environment; with the aim of coupling the promising industrial potential of this species with that of heterologous efflux pumps to promote engineering tolerance. In this study, clones of D. geothermalis containing various genes encoding chromosomal heterologous efflux pumps were generated. Resistant recombinants were selected using antibiotic susceptibility tests to screen promising candidates. We then developed a method to determine the efflux efficiency of the best candidate, which contains the gene encoding the MdfA of Salmonella enterica serovar Choleraesuis. We observe 1.6 times more compound in the external medium of the hit recombinant than that of the WT at early incubation time. The data presented here will contribute to better understanding of the parameters required for efficient production in D. geothermalis.
Head-to-head comparison of clustering methods for heterogeneous data: a simulation-driven benchmark
Authors: Preud’homme Gregoire , Duarte Kevin , Dalleau Kevin , Lacomblez Claire , Bresso Emmanuel , Smaïl-Tabbone Malika , Couceiro Miguel , Devignes Marie-Dominique , Kobayashi Masatake , Huttin Olivier , Ferreira João Pedro , Zannad Faiez , Rossignol Patrick , Girerd Nicolas
Published: February 2021

The choice of the most appropriate unsupervised machine-learning method for “heterogeneous” or “mixed” data, i.e. with both continuous and categorical variables, can be challenging. Our aim was to examine the performance of various clustering strategies for mixed data using both simulated and real-life data. We conducted a benchmark analysis of “ready-to-use” tools in R comparing 4 model-based (Kamila algorithm, Latent Class Analysis, Latent Class Model [LCM] and Clustering by Mixture Modeling) and 5 distance/dissimilarity-based (Gower distance or Unsupervised Extra Trees dissimilarity followed by hierarchical clustering or Partitioning Around Medoids, K-prototypes) clustering methods. Clustering performances were assessed by Adjusted Rand Index (ARI) on 1000 generated virtual populations consisting of mixed variables using 7 scenarios with varying population sizes, number of clusters, number of continuous and categorical variables, proportions of relevant (non-noisy) variables and degree of variable relevance (low, mild, high). Clustering methods were then applied on the EPHESUS randomized clinical trial data (a heart failure trial evaluating the effect of eplerenone) allowing to illustrate the differences between different clustering techniques. The simulations revealed the dominance of K-prototypes, Kamila and LCM models over all other methods. Overall, methods using dissimilarity matrices in classical algorithms such as Partitioning Around Medoids and Hierarchical Clustering had a lower ARI compared to model-based methods in all scenarios. When applying clustering methods to a real-life clinical dataset, LCM showed promising results with regard to differences in (1) clinical profiles across clusters, (2) prognostic performance (highest C-index) and (3) identification of patient subgroups with substantial treatment benefit. The present findings suggest key differences in clustering performance between the tested algorithms (limited to tools readily available in R). In most of the tested scenarios, model-based methods (in particular the Kamila and LCM packages) and K-prototypes typically performed best in the setting of heterogeneous data.
Altered non-coding RNA expression profile in F1 progeny 1 year after parental irradiation is linked to adverse effects in zebrafish
Authors: Martín Leonardo , Kamstra Jorke H. , Hurem Selma , Lindeman Leif C. , Brede Dag A. , Aanes Håvard , Babiak Igor , Arenal Amilcar , Oughton Deborah , Salbu Brit , Lyche Jan Ludvig , Aleström Peter
Published: February 2021

Gamma radiation produces DNA instability and impaired phenotype. Previously, we observed negative effects on phenotype, DNA methylation, and gene expression profiles, in offspring of zebrafish exposed to gamma radiation during gametogenesis. We hypothesize that previously observed effects are accompanied with changes in the expression profile of non-coding RNAs, inherited by next generations. Non-coding RNA expression profile was analysed in F1 offspring (5.5 h post-fertilization) by high-throughput sequencing 1 year after parental irradiation (8.7 mGy/h, 5.2 Gy total dose). Using our previous F1-γ genome-wide gene expression data (GSE98539), hundreds of mRNAs were predicted as targets of differentially expressed (DE) miRNAs, involved in pathways such as insulin receptor, NFkB and PTEN signalling, linking to apoptosis and cancer. snRNAs belonging to the five major spliceosomal snRNAs were down-regulated in the F1-γ group, Indicating transcriptional and post-transcriptional alterations. In addition, DEpiRNA clusters were associated to 9 transposable elements (TEs) (LTR, LINE, and TIR) (p = 0.0024), probable as a response to the activation of these TEs. Moreover, the expression of the lincRNAs malat-1, and several others was altered in the offspring F1, in concordance with previously observed phenotypical alterations. In conclusion, our results demonstrate diverse gamma radiation-induced alterations in the ncRNA profiles of F1 offspring observable 1 year after parental irradiation.
Theory and experimental verification of configurable computing with stochastic memristors
Authors: Naous Rawan , Siemon Anne , Schulten Michael , Alahmadi Hamzah , Kindsmüller Andreas , Lübben Michael , Heittmann Arne , Waser Rainer , Salama Khaled Nabil , Menzel Stephan
Published: February 2021

The inevitable variability within electronic devices causes strict constraints on operation, reliability and scalability of the circuit design. However, when a compromise arises among the different performance metrics, area, time and energy, variability then loosens the tight requirements and allows for further savings in an alternative design scope. To that end, unconventional computing approaches are revived in the form of approximate computing, particularly tuned for resource-constrained mobile computing. In this paper, a proof-of-concept of the approximate computing paradigm using memristors is demonstrated. Stochastic memristors are used as the main building block of probabilistic logic gates. As will be shown in this paper, the stochasticity of memristors’ switching characteristics is tightly bound to the supply voltage and hence to power consumption. By scaling of the supply voltage to appropriate levels stochasticity gets increased. In order to guide the design process of approximate circuits based on memristors a realistic device model needs to be elaborated with explicit emphasis of the probabilistic switching behavior. Theoretical formulation, probabilistic analysis, and simulation of the underlying logic circuits and operations are introduced. Moreover, the expected output behavior is verified with the experimental measurements of valence change memory cells. Hence, it is shown how the precision of the output is varied for the sake of the attainable gains at different levels of available design metrics. This approach represents the first proposition along with physical verification and mapping to real devices that combines stochastic memristors into unconventional computing approaches.
Bioabsorbable nerve conduits three-dimensionally coated with human induced pluripotent stem cell-derived neural stem/progenitor cells promote peripheral nerve regeneration in rats
Authors: Onode Ema , Uemura Takuya , Takamatsu Kiyohito , Yokoi Takuya , Shintani Kosuke , Hama Shunpei , Miyashima Yusuke , Okada Mitsuhiro , Nakamura Hiroaki
Published: February 2021

Peripheral nerve regeneration using nerve conduits has been less effective than autogenous nerve grafts. To overcome this hurdle, we developed a tissue-engineered nerve conduit coated with mouse induced pluripotent stem cell (iPSC)-derived neurospheres, for the first time, which accelerated nerve regeneration in mice. We previously demonstrated the long-term efficacy and safety outcomes of this hybrid nerve conduit for mouse peripheral nerve regeneration. In this study, we investigated the therapeutic potential of nerve conduits coated with human iPSC (hiPSC)-derived neurospheres in rat sciatic nerve defects, as a translational preclinical study. The hiPSC-derived quaternary neurospheres containing neural stem/progenitor cells were three-dimensionally cultured within the nerve conduit (poly l-lactide and polycaprolactone copolymer) for 14 days. Complete 5-mm defects were created as a small size peripheral nerve defect in sciatic nerves of athymic nude rats and reconstructed with nerve conduit alone (control group), nerve conduits coated with hiPSC-derived neurospheres (iPS group), and autogenous nerve grafts (autograft group) (n = 8 per group). The survival of the iPSC-derived neurospheres was continuously tracked using in vivo imaging. At 12 weeks postoperatively, motor and sensory function and histological nerve regeneration were evaluated. Before implantation, the hiPSC-derived quaternary neurospheres that three-dimensional coated the nerve conduit were differentiated into Schwann-like cells. The transplanted hiPSC-derived neurospheres survived for at least 56 days after implantation. The iPS group showed non-significance higher sensory regeneration than the autograft group. Although there was no actual motor functional nerve regeneration in the three groups: control, iPS, and autograft groups, the motor function in the iPS group recovered significantly better than that in the control group, but it did not recover to the same level as that in the autograft group. Histologically, the iPS group demonstrated significantly higher axon numbers and areas, and lower G-ratio values than the control group, whereas the autograft group demonstrated the highest axon numbers and areas and the lowest G-ratio values. Nerve conduit three-dimensionally coated with hiPSC-derived neurospheres promoted axonal regeneration and functional recovery in repairing rat sciatic nerve small size defects. Transplantation of hiPSC-derived neurospheres with nerve conduits is a promising clinical iPSC-based cell therapy for the treatment of peripheral nerve defects.