bluuebunny/crossref_metadata_2025 huggingface dataset:
Tracking regional brain growth up to age 13 in children born term and very preterm
Authors: Thompson Deanne K. , Matthews Lillian G. , Alexander Bonnie , Lee Katherine J. , Kelly Claire E. , Adamson Chris L. , Hunt Rod W. , Cheong Jeanie L. Y. , Spencer-Smith Megan , Neil Jeffrey J. , Seal Marc L. , Inder Terrie E. , Doyle Lex W. , Anderson Peter J.
Published: February 2020

Serial regional brain growth from the newborn period to adolescence has not been described. Here, we measured regional brain growth in 216 very preterm (VP) and 45 full-term (FT) children. Brain MRI was performed at term-equivalent age, 7 and 13 years in 82 regions. Brain volumes increased between term-equivalent and 7 years, with faster growth in the FT than VP group. Perinatal brain abnormality was associated with less increase in brain volume between term-equivalent and 7 years in the VP group. Between 7 and 13 years, volumes were relatively stable, with some subcortical and cortical regions increasing while others reduced. Notably, VP infants continued to lag, with overall brain size generally less than that of FT peers at 13 years. Parieto–frontal growth, mainly between 7 and 13 years in FT children, was associated with higher intelligence at 13 years. This study improves understanding of typical and atypical regional brain growth.
Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles
Authors: Tsujinaka Hiroki , Fu Jie , Shen Jikui , Yu Yun , Hafiz Zibran , Kays Joshua , McKenzie David , Cardona Delia , Culp David , Peterson Ward , Gilger Brian C. , Crean Christopher S. , Zhang Jin-Zhong , Kanan Yogita , Yu Weiling , Cleland Jeffrey L. , Yang Ming , Hanes Justin , Campochiaro Peter A.
Published: February 2020

Neovascular age-related macular degeneration and diabetic retinopathy are prevalent causes of vision loss requiring frequent intravitreous injections of VEGF-neutralizing proteins, and under-treatment is common and problematic. Here we report incorporation of sunitinib, a tyrosine kinase inhibitor that blocks VEGF receptors, into a non-inflammatory biodegradable polymer to generate sunitinib microparticles specially formulated to self-aggregate into a depot. A single intravitreous injection of sunitinib microparticles potently suppresses choroidal neovascularization in mice for six months and in another model, blocks VEGF-induced leukostasis and retinal nonperfusion, which are associated with diabetic retinopathy progression. After intravitreous injection in rabbits, sunitinib microparticles self-aggregate into a depot that remains localized and maintains therapeutic levels of sunitinib in retinal pigmented epithelium/choroid and retina for more than six months. There is no intraocular inflammation or retinal toxicity. Intravitreous injection of sunitinib microparticles provides a promising approach to achieve sustained suppression of VEGF signaling and improve outcomes in patients with retinal vascular diseases.
Bridging non-overlapping reads illuminates high-order epistasis between distal protein sites in a GPCR
Authors: Yoo Justin I. , Daugherty Patrick S. , O’Malley Michelle A.
Published: February 2020

Epistasis emerges when the effects of an amino acid depend on the identities of interacting residues. This phenomenon shapes fitness landscapes, which have the power to reveal evolutionary paths and inform evolution of desired functions. However, there is a need for easily implemented, high-throughput methods to capture epistasis particularly at distal sites. Here, we combine deep mutational scanning (DMS) with a straightforward data processing step to bridge reads in distal sites within genes (BRIDGE). We use BRIDGE, which matches non-overlapping reads to their cognate templates, to uncover prevalent epistasis within the binding pocket of a human G protein-coupled receptor (GPCR) yielding variants with 4-fold greater affinity to a target ligand. The greatest functional improvements in our screen result from distal substitutions and substitutions that are deleterious alone. Our results corroborate findings of mutational tolerance in GPCRs, even in conserved motifs, but reveal inherent constraints restricting tolerated substitutions due to epistasis.
A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation
Authors: Voigt Stefanie , Sterz Kai R. , Giehler Fabian , Mohr Anne-Wiebe , Wilson Joanna B. , Moosmann Andreas , Kieser Arnd
Published: February 2020

IκB kinase 2 (IKK2) is well known for its pivotal role as a mediator of the canonical NF-κB pathway, which has important functions in inflammation and immunity, but also in cancer. Here we identify a novel and critical function of IKK2 and its co-factor NEMO in the activation of oncogenic c-Jun N-terminal kinase (JNK) signaling, induced by the latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV). Independent of its kinase activity, the TGFβ-activated kinase 1 (TAK1) mediates LMP1 signaling complex formation, NEMO ubiquitination and subsequent IKK2 activation. The tumor progression locus 2 (TPL2) kinase is induced by LMP1 via IKK2 and transmits JNK activation signals downstream of IKK2. The IKK2-TPL2-JNK axis is specific for LMP1 and differs from TNFα, Interleukin−1 and CD40 signaling. This pathway mediates essential LMP1 survival signals in EBV-transformed human B cells and post-transplant lymphoma, and thus qualifies as a target for treatment of EBV-induced cancer.
Format-dependent and format-independent representation of sequential and simultaneous numerosity in the crow endbrain
Authors: Ditz Helen M. , Nieder Andreas
Published: February 2020

Humans’ symbolic counting skills are built on a primordial ability to approximately estimate the number of items, or numerosity. To date it is debated whether numerosities presented in categorically different formats, that is as temporal sequences versus spatial arrays, are represented abstractly in the brain. To address this issue, we identified the behavioral characteristics and neuronal codes for sequential and simultaneous number formats in crows. We find a format-dependent representation by distinct groups of selective neurons during the sensory encoding stage. However, an abstract and format-independent numerosity code emerges once the encoding phase is completed and numerosities needed to be memorized. These results suggest a successive two-stage code for categorically different number formats and help to reconcile conflicting findings observed in psychophysics and brain imaging.
DNA repair by Rad52 liquid droplets
Authors: Oshidari Roxanne , Huang Richard , Medghalchi Maryam , Tse Elizabeth Y. W. , Ashgriz Nasser , Lee Hyun O. , Wyatt Haley , Mekhail Karim
Published: February 2020

Cellular processes are influenced by liquid phase separation, but its role in DNA repair is unclear. Here, we show that in Saccharomyces cerevisiae, liquid droplets made up of DNA repair proteins cooperate with different types of DNA damage-inducible intranuclear microtubule filaments (DIMs) to promote the clustering of DNA damage sites and maintain genome stability. Rad52 DNA repair proteins at different DNA damage sites assemble in liquid droplets that fuse into a repair centre droplet via the action of petite DIMs (pti-DIMs). This larger droplet concentrates tubulin and projects short aster-like DIMs (aster-DIMs), which tether the repair centre to longer DIMs mediating the mobilization of damaged DNA to the nuclear periphery for repair. Our findings indicate that cooperation between Rad52 liquid droplets and various types of nuclear filaments promotes the assembly and function of the DNA repair centre.
Folate receptor alpha expression associates with improved disease-free survival in triple negative breast cancer patients
Authors: Norton Nadine , Youssef Bahaaeldin , Hillman David W. , Nassar Aziza , Geiger Xochiquetzal J. , Necela Brian M. , Liu Heshan , Ruddy Kathryn J. , Polley Mei-Yin C. , Ingle James N. , Couch Fergus J. , Perez Edith A. , Liu Minetta C. , Carter Jodi M. , Leon-Ferre Roberto A. , Boughey Judy C. , Somers Elizabeth B. , Kalari Krishna R. , Visscher Daniel W. , Goetz Matthew P. , Knutson Keith L.
Published: February 2020

Triple negative breast cancer (TNBC) comprises 15–20% of all invasive breast cancer and is associated with a poor prognosis. As therapy options are limited for this subtype, there is a significant need to identify new targeted approaches for TNBC patient management. The expression of the folate receptor alpha (FRα) is significantly increased in patients with TNBC and is therefore a potential biomarker and therapeutic target. We optimized and validated a FRα immunohistochemistry method, specific to TNBC, to measure FRα expression in a centrally confirmed cohort of 384 patients with TNBC in order to determine if expression of the protein is associated with invasive disease-free survival (IDFS) and overall survival (OS). The FRα IHC demonstrated exceptional performance characteristics with low intra- and interassay variability as well as minimal lot-to-lot variation. FRα expression, which varied widely from sample to sample, was detected in 274 (71%) of the TNBC lesions. In a multivariable model adjusted for baseline characteristics, FRα expression was associated with improved IDFS (HR = 0.63, p = 0.01) but not with OS. The results demonstrate the potential of targeting the FRα in the majority of TNBC patients and suggest that variable expression may point to a need to stratify on FRα expression in clinical studies.
An articulated Late Triassic (Norian) thalattosauroid from Alaska and ecomorphology and extinction of Thalattosauria
Authors: Druckenmiller Patrick S. , Kelley Neil P. , Metz Eric T. , Baichtal James
Published: February 2020

Thalattosaurians are a cosmopolitan clade of secondarily aquatic tetrapods that inhabited low-latitude, nearshore environments during the Triassic. Despite their low taxic diversity, thalattosaurians exhibit remarkable morphological disparity, particularly with respect to rostral and dental morphology. However, a paucity of well-preserved material, especially leading up to their extinction, has hampered efforts to develop a robust picture of their evolutionary trajectories during a time of profound marine ecological change. Here, we describe a new taxon based on an articulated and nearly complete skeleton from Norian sediments of southeastern Alaska, USA. The holotype is the most complete North American thalattosaurian yet described and one of the youngest occurrences of the clade worldwide. We present a new hypothesis of interrelationships for Thalattosauria and investigate potential feeding modes in the Alaskan taxon. An integrated view suggests that the absence of pelagic lifestyles and restricted ecological roles may have contributed to thalattosaurs’ eventual extinction.
A New Function for Perivascular Adipose Tissue (PVAT): Assistance of Arterial Stress Relaxation
Authors: Watts Stephanie W. , Flood Emma D. , Garver Hannah , Fink Gregory D. , Roccabianca Sara
Published: February 2020

In health, PVAT secretes anti-contractile factors that relax the underlying artery. PVAT’s contributions to vascular function include more than production of vasoactive substances. We hypothesized that PVAT benefits the artery by assisting the function of stress (–induced) relaxation. Thoracic aorta rings from Sprague Dawley rats were mounted in isolated tissue baths with (+) and without (−) PVAT. A cumulative length tension (0–6 grams) was generated. The tension to which the tissue stress relaxed over 30 minutes was recorded; the tension lost was stress relaxation. The presence of PVAT increased the amount of stress relaxation (final tension in mgs; aortic ring −PVAT = 4578 ± 190; aortic ring + PVAT = 2730 ± 274, p < 0.05). PVAT left attached but not encompassing the aorta provided no benefit in cumulative stress relaxation (aortic ring +/− PVAT = 4122 ± 176; p > 0.05 vs −PVAT). A PVAT ring separated from the aorta demonstrated more profound stress relaxation than did the aortic ring itself. Finally, PVAT-assisted stress relaxation was observed in an artery with white fat (superior mesenteric artery) and in aorta from both male and female of another rat strain, the Dahl S rat. Knowledge of this new PVAT function supports PVAT as an essential player in vascular health.
Compatibility of aztreonam in four commercial peritoneal dialysis fluids
Authors: Tobudic Selma , Prager Isabella , Kussmann Manuel , Obermüller Markus , Ursli Martin , Zeitlinger Markus , Wiesholzer Martin , Burgmann Heinz , Poeppl Wolfgang , Reznicek Gottfried
Published: February 2020

The preferable route for treatment of peritoneal dialysis related peritonitis remains the intraperitoneal administration of antibiotics admixed to peritoneal dialysis fluids. It is important to know whether the administered drug is compatible with the PD fluids and its container. In the present study the compatibility of aztreonam with four commercial PDFs at storing temperatures and duration representative for storing conditions in the clinical settings was investigated. Aztreonam concentrations were determined using high-performance liquid chromatography. The antimicrobial activity of aztreonam was evaluated using an E. coli diffusion disk inhibition assay and P. aeruginosa time-kill curves. In Extraneal evaluated at 6 °C, 25 °C and 37 °C aztreonam was stable over the whole study period of 14 days and 24 hours, respectively. In Physioneal and Nutrineal aztreonam was stable at 6 °C for up to 14 days. Antimicrobial activity was retained in all PD fluids over the whole study period. Aztreonam remained stable and was compatible with the PD fluids, particularly with Extraneal or Nutrineal, and no compensatory dose adjustment is needed when stored for up to 14 days at refrigeration temperature before use.
AATF and SMARCA2 are associated with thyroid volume in Hashimoto’s thyroiditis patients
Authors: Brčić Luka , Barić Ana , Benzon Benjamin , Brekalo Marko , Gračan Sanda , Kaličanin Dean , Škrabić Veselin , Zemunik Tatijana , Barbalić Maja , Novak Ivana , Pešutić Pisac Valdi , Punda Ante , Boraska Perica Vesna
Published: February 2020

Thyroid volume of Hashimoto’s thyroiditis (HT) patients varies in size over the course of disease and it may reflect changes in biological function of thyroid gland. Patients with subclinical hypothyroidism predominantly have increased thyroid volume whereas patients with more pronounced hypothyroidism have smaller thyroid volumes. Suggested mechanism for thyroid atrophy is thyrocyte death due to apoptosis. We performed the first genome-wide association study (GWAS) of thyroid volume in two groups of HT patients, depending on levothyroxine (LT4) therapy, and then meta-analysed across. Study included 345 HT patients in total and 6 007 322 common autosomal genetic variants. Underlying hypothesis was that genetic components that are involved in regulation of thyroid volume display their effect in specific pathophysiologic conditions of thyroid gland of HT patients. We additionally performed immunohistochemical analysis using thyroid tissues and analysed differences in expression levels of identified proteins and apoptotic marker between HT patients and controls. We found genome-wide significant association of two loci, both involved in apoptosis, with thyroid volume of HT patients: rs7212416 inside apoptosis-antagonizing transcription factor AATF (P = 8.95 × 10−9) and rs10738556 near chromatin-remodeling SMARCA2 (P = 2.83 × 10−8). In immunohistochemical analysis we observed that HT patients with homozygous AATF risk genotypes have decreased AATF expression (0.46-fold, P < 0.0001) and increased apoptosis (3.99-fold, P = 0.0001) in comparison to controls. HT patients with heterozygous SMARCA2 genotypes have decreased SMARCA2 expression, albeit without reaching statistical significance (1.07-fold, P = 0.5876), and significantly increased apoptosis (4.11-fold, P < 0.0001). By two lines of evidence we show that two highly plausible genetic loci, AATF and SMARCA2, may be involved in determining the thyroid volume of HT patients. The results of our study significantly add to the current knowledge of disturbed biological mechanisms in thyroid gland of HT patients.
Global phylogeography and genetic diversity of the long-finned pilot whale Globicephala melas, with new data from the southeastern Pacific
Authors: Kraft Sebastián , Pérez-Álvarez MJosé , Olavarría Carlos , Poulin Elie
Published: February 2020

The matrilineal long-finned pilot whale presents an antitropical distribution and is divided into two subspecies, one in the temperate seas of the Southern Hemisphere and the other restricted to the North Atlantic and Mediterranean. Until now, population genetic and phylogeographic studies have included localities of most of its Northern Hemisphere distribution, while only the southwestern Pacific has been sampled in the Southern Hemisphere. We add new genetic data from the southeastern Pacific to the published sequences. Low mitochondrial and nuclear diversity was encountered in this new area, as previously reported for other localities. Four haplotypes were found with only one new for the species. Fifteen haplotypes were detected in the global dataset, underlining the species’ low diversity. As previously reported, the subspecies shared two haplotypes and presented a strong phylogeographic structure. The extant distribution of this species has been related to dispersal events during the Last Glacial Maximum. Using the genetic data and Approximate Bayesian Calculations, this study supports this historical biogeographic scenario. From a taxonomic perspective, even if genetic analyses do not support the subspecies category, this study endorses the incipient divergence process between hemispheres, thus maintaining their status and addressing them as Demographically Independent Populations is recommended.
Cutaneous and stick rabbit illusions in individuals with autism spectrum disorder
Authors: Wada Makoto , Ide Masakazu , Ikeda Hanako , Sano Misako , Tanaka Ari , Suzuki Mayuko , Agarie Hiromi , Kim Sooyung , Tajima Seiki , Nishimaki Kengo , Fukatsu Reiko , Nakajima Yasoichi , Miyazaki Makoto
Published: February 2020

Prediction is the process by which future events are anticipated based on past events; in contrast, postdiction is the retrospective interpretation of past events based on latter, more recent events. The prediction and postdiction are suggested to be similar based on theoretical models. Previous studies suggest that prediction is impaired in individuals with autism spectrum disorder (ASD). However, it is unclear whether postdiction is also impaired in individuals with ASD. In this study, we evaluated postdiction in individuals with ASD using the cutaneous and stick rabbit illusion paradigms in which the perceived location of a touch shifts postdictively in response to a subsequent touch stimulus. We observed significant cutaneous and stick rabbit illusion in both typically developing (TD) and ASD groups; therefore, postdiction was functional in individuals with ASD. Our present results suggest that postdiction involves a different neuronal process than prediction. We also observed that the ASD group exhibited significantly larger individual difference compared with the TD group in the stick rabbit illusion, which is considered to reflect extension of body schema to external objects. We discuss implications of the individual difference among the ASD participants in the context of sports requiring interactions between the body and external objects.
Recent magmatism drives hydrocarbon generation in north-east Java, Indonesia
Authors: Zaputlyaeva Alexandra , Mazzini Adriano , Blumenberg Martin , Scheeder Georg , Kürschner Wolfram Michael , Kus Jolanta , Jones Morgan Thomas , Frieling Joost
Published: February 2020

Conventional studies of petroleum basins associate oil generation with the gradual burial of organic-rich sediments. These classical models rely on the interplay between pressure, temperature, and the time required for organic matter transformation to oil and gas. These processes usually occur over geological timescales, but may be accelerated by rapid reactions when carbon-rich sediments are exposed to migrating magmatic fluids. The spectacular Lusi eruption (north-east Java, Indonesia) is the surface expression of the present-day deep interaction between volcanic and sedimentary domains. Here we report the ongoing generation of large amounts of hydrocarbons induced by a recent magmatic intrusion from the neighbouring Arjuno-Welirang volcanic complex. We have investigated a unique suite of oil and clast samples, and developed a detailed conceptual model for the complex hydrocarbon migration history in this part of the basin by integrating multidisciplinary techniques. Our results show that palynology, organic petrology, and chlorite microthermometry are the most sensitive geothermometers for basins affected by recent magmatic activity. These findings further our understanding of the driving mechanisms fueling the world’s largest active mud eruption and provide a unique dataset to investigate modern hydrocarbon generation processes.
Toxicology of paraquat and pharmacology of the protective effect of 5-hydroxy-1-methylhydantoin on lung injury caused by paraquat based on metabolomics
Authors: Gao Lina , Yuan Huiya , Xu Enyu , Liu Junting
Published: February 2020

Paraquat (PQ) is a non-selective herbicide and is exceedingly toxic to humans. The mechanism of PQ toxicity is very complex and has not been clearly defined. There is no specific antidote for PQ poisoning. 5-hydroxy-1-methylhydantoin (HMH) is an intrinsic antioxidant and can protect against renal damage caused by PQ. The mechanism of PQ toxicology and the possible effects of HMH on PQ-induced lung injury were determined in this study. It was found that PQ decreased superoxide dismutase (SOD) activity and elevated the level of malondialdehyde (MDA), while HMH elevated SOD activity and decreased the level of MDA. Based on metabolomics, the citrate cycle, glutathione metabolism, taurine and hypotaurine metabolism, regulation of lipolysis in adipocytes, inflammatory mediator regulation of TRP channels, purine and pyrimidine metabolism, aldosterone synthesis and secretion, and phenylalanine metabolism were changed in the PQ group. Compared with the PQ group, the levels of N-acetyl-l-aspartic acid, L-glutamic acid, L-aspartic acid, mesaconic acid, adenosine 5′ monophosphate, methylmalonic acid, cytidine, phosphonoacetic acid, hypotaurine, glutathione (reduced) and cysteinylglycine increased, while the levels of corticosterone, xanthine, citric acid, prostaglandin G2, 4-pyridoxic acid and succinyl proline decreased in the HMH group. These metabolites revealed that HMH can alleviate inflammation caused by PQ and elevate the activity of intrinsic antioxidants. In conclusion, our results revealed PQ toxicology and the pharmacology underlying the protective effect of HMH on lung injury due to PQ. Toxicity caused by PQ results in lipid peroxidation and an increase in reactive oxygen species (ROS), nitric oxide (NO), damage to the biliary system, gastrointestinal system and nervous system, in addition to lungs, kidneys, and the liver. HMH is a good antioxidant and protects against lung injury caused by PQ. In summary, HMH efficiently reduced PQ-induced lung injury in mice.
Rac1 is a downstream effector of PKCα in structural synaptic plasticity
Authors: Tu Xun , Yasuda Ryohei , Colgan Lesley A.
Published: February 2020

Structural and functional plasticity of dendritic spines is the basis of animal learning. The rapid remodeling of actin cytoskeleton is associated with spine enlargement and shrinkage, which are essential for structural plasticity. The calcium-dependent protein kinase C isoform, PKCα, has been suggested to be critical for this actin-dependent plasticity. However, mechanisms linking PKCα and structural plasticity of spines are unknown. Here, we examine the spatiotemporal activation of actin regulators, including small GTPases Rac1, Cdc42 and Ras, in the presence or absence of PKCα during single-spine structural plasticity. Removal of PKCα expression in the postsynapse attenuated Rac1 activation during structural plasticity without affecting Ras or Cdc42 activity. Moreover, disruption of a PDZ binding domain within PKCα led to impaired Rac1 activation and deficits in structural spine remodeling. These results demonstrate that PKCα positively regulates the activation of Rac1 during structural plasticity.
Initial Biomechanical Properties of Transtibial Meniscal Root Repair are Improved By Using a Knotless Anchor as a Post-Insertion Tensioning Device
Authors: Prado-Novoa Maria , Perez-Blanca Ana , Espejo-Reina Alejandro , Espejo-Reina Maria Jose , Espejo-Baena Alejandro
Published: February 2020

The importance of meniscal root integrity to preserve contact load distribution and stability at the knee joint is recognised. Transosseous suture technique is commonly used to repair meniscal root tears. However, clinical results are not completely satisfactory. Specifically, concern exists about the development of substantial displacements at the repaired root. This study aims to assess if the use of a post-insertion tensioning knotless-anchor at the distal exit of the tibial tunnel improves time-zero biomechanical properties of the transtibial repair compared to knotting sutures over a cortical button. Twenty porcine tibia with detached posterior medial meniscal roots were randomized into two groups depending on the method to fix the sutures after root repair: knotless-anchor (KA) or suture-button (SB). Specimens underwent cyclic and load-to-failure testing. Group KA showed significantly smaller residual root displacements after low-level repetitive loads. At the load-to-failure test, Group KA exhibited significantly lower displacements at representative subcritical loads and higher resistance to development of clinically relevant displacements. The authors conclude that use of a knotless suture anchor attached at the distal outlet of the bone tunnel may be an effective solution to reduce root displacements in transtibial meniscal root repairs, a matter reported to alter biomechanics of joint contact.
Left atrial dysfunction in sickle cell anemia is associated with diffuse myocardial fibrosis, increased right ventricular pressure and reduced exercise capacity
Authors: Alsaied Tarek , Niss Omar , Tretter Justin T. , Powell Adam W. , Chin Clifford , Fleck Robert J. , Cnota James F. , Malik Punam , Quinn Charles T. , Nagueh Sherif F. , Taylor Michael D. , Mazur Wojciech M.
Published: February 2020

Increased extracellular volume (ECV) by CMR is a marker of interstitial myocardial fibrosis and is associated with diastolic dysfunction in sickle cell anemia (SCA). Left atrial (LA) dysfunction and stiffness contribute to the development of diastolic heart failure in other settings. We aimed to evaluate LA function and stiffness associations with ECV, tricuspid regurgitation jet velocity (TRV) and exercise abnormalities in SCA. In a prospective study, individuals with SCA underwent CMR, echocardiography and exercise test. ECV was measured using MOLLI sequence. Atrial strain was studied in the 4- and 2-chamber views. LA stiffness was calculated as the ratio of echocardiographic E/e’-to-LA reservoir strain. Twenty-four participants with SCA were included (median age 20 years). ECV was increased in participant with SCA compared to our lab normal values (mean 0.44 ± 0.08 vs 0.26 ± 0.02, P < 0.0001). Six (25%) had LA LGE. ECV positively correlated with LA stiffness (r = 0.45, p = 0.04). There was a negative correlation between LA stiffness and %predicted VO2 (r = −0.50, p = 0.04). LA stiffness was moderately associated with increased TRV (r = 0.55, p < 0.005). LA stiffness is associated with ECV, exercise impairment and increased TRV. This study sheds insights on the interaction between LA function, RV hypertension, and myocardial fibrosis in SCA.
Direct regulation of fibroblast growth factor 23 by energy intake through mTOR
Authors: Vidal Angela , Rios Rafael , Pineda Carmen , Lopez Ignacio , Muñoz-Castañeda Juan R. , Rodriguez Mariano , Aguilera-Tejero Escolastico , Raya Ana I.
Published: February 2020

To test the hypothesis that fibroblast growth factor 23 (FGF23) is directly regulated by energy intake, in vivo and in vitro experiments were conducted. Three groups of rats were fed diets with high (HC), normal (NC) and low (LC) caloric content that resulted in different energy intake. In vitro, UMR106 cells were incubated in high (HG, 4.5 g/l) or low glucose (LG, 1 g/l) medium. Additional treatments included phosphorus (P), mannitol, rapamycin and everolimus. Intestinal absorption of P and plasma P concentrations were similar in the three groups of rats. As compared with NC, plasma FGF23 concentrations were increased in HC and decreased in the LC group. A significant correlation between energy intake and plasma FGF23 concentrations was observed. In vitro, mRNA FGF23 was significantly higher in UMR106 cells cultured in HG than in LG. When exposed to high P, mRNA FGF23 increased but only when cells were cultured in HG. Cells incubated with HG and mechanistic target of rapamycin (mTOR) inhibitors expressed low mRNA FGF23, similar to the values obtained in LG. In conclusion, this study shows a direct regulation of FGF23 production by energy availability and demonstrates that the mTOR signaling pathway plays a central role in this regulatory system.
Effectiveness and Safety of Off-label Dosing of Non–vitamin K Antagonist Anticoagulant for Atrial Fibrillation in Asian Patients
Authors: Lee Kwang-No , Choi Jong-Il , Boo Ki Yung , Kim Do Young , Kim Yun Gi , Oh Suk-Kyu , Baek Yong-Soo , Lee Dae In , Roh Seung-Young , Shim Jaemin , Kim Jin Seok , Kim Young-Hoon
Published: February 2020

Non–vitamin K antagonist anticoagulants (NOACs) have been used to prevent thromboembolism in patients with atrial fibrillation (AF) and shown favorable clinical outcomes compared with warfarin. However, off-label use of NOACs is frequent in practice, and its clinical results are inconsistent. Furthermore, the quality of anticoagulation available with warfarin is often suboptimal and even inaccurate in real-world data. We have therefore compared the effectiveness and safety of off-label use of NOACs with those of warfarin whose anticoagulant intensity was accurately estimated. We retrospectively analyzed data from 2,659 and 3,733 AF patients at a tertiary referral center who were prescribed warfarin and NOACs, respectively, between 2013 and 2018. NOACs were used at off-label doses in 27% of the NOAC patients. After adjusting for significant covariates, underdosed NOAC (off-label use of the reduced dose) was associated with a 2.5-times increased risk of thromboembolism compared with warfarin, and overdosed NOAC (off-label use of the standard dose) showed no significant difference in either thromboembolism or major bleeding compared with warfarin. Well-controlled warfarin (TTR ≥ 60%) reduced both thromboembolism and bleeding events. In conclusion, the effectiveness of NOACs was decreased by off-label use of the reduced dose.
Rain induces temporary shifts in epiphytic bacterial communities of cucumber and tomato fruit
Authors: Allard Sarah M. , Ottesen Andrea R. , Micallef Shirley A.
Published: February 2020

Understanding weather-related drivers of crop plant-microbiome relationships is important for food security and food safety in the face of a changing climate. Cucumber and tomato are commercially important commodities that are susceptible to plant disease and have been implicated in foodborne disease outbreaks. To investigate the influence of precipitation on plant-associated microbiomes, epiphytically associated bacterial communities of cucumber and tomato samples were profiled by 16 S rRNA gene sequencing (V1-V3) in the days surrounding two rain events over a 17-day period. Following rain, α (within-sample) diversity measured on cucumber and tomato fruit surfaces, but not tomato leaf surfaces, increased significantly and remained elevated for several days. Bacterial β (between-sample) diversity on cucumber and tomato fruit responded to precipitation. In the cucumber fruit surface (carpoplane), notable shifts in the families Xanthomonadaceae, Oxalobacteriaceae, Sphingobacteriaceae and Comamonadaceae were detected following precipitation. In the tomato carpoplane, shifts were detected in the families Enterobacteriaceae and Xanthomonadaceae following the first rain event, and in the Pseudomonadaceae and Oxalobacteriaceae following the second rain event. Few taxonomic shifts were detected in the tomato leaf surface (phylloplane). Exploring rain-induced shifts in plant microbiomes is highly relevant to crop protection, food safety and agroecology, and can aid in devising ways to enhance crop resilience to stresses and climate fluctuations.
Characterization of Myeloid Cellular Populations in Mesenteric and Subcutaneous Adipose Tissue of Holstein-Friesian Cows
Authors: Oliveira Bárbara M. , Pinto Ana , Correia Alexandra , Ferreira Paula G. , Vilanova Manuel , Teixeira Luzia
Published: February 2020

Immune cells resident in adipose tissue have important functions in local and systemic metabolic homeostasis. Nevertheless, these immune cell populations remain poorly characterized in bovines. Recently, we described diverse lymphocyte subpopulations in adipose tissue of Holstein-Friesian cows. Here, we aimed at characterising myeloid cell populations present in bovine adipose tissue using multicolour flow cytometry, cell sorting and histochemistry/immunohistochemistry. Macrophages, CD14+CD11b+MHC-II+CD45+ cells, were identified in mesenteric and subcutaneous adipose tissue, though at higher proportions in the latter. Mast cells, identified as SSC-AhighCD11b−/+CD14−MHC-II−CH138A−CD45+ cells, were also observed in adipose tissue and found at higher proportions than macrophages in mesenteric adipose tissue. Neutrophils, presenting a CH138A+CD11b+ phenotype, were also detected in mesenteric and subcutaneous adipose tissue, however, at much lower frequencies than in the blood. Our gating strategy allowed identification of eosinophils in blood but not in adipose tissue although being detected by morphological analysis at low frequencies in some animals. A population not expressing CD45 and with the CH138A+ CD11b−MHC-II− phenotype, was found abundant and present at higher proportions in mesenteric than subcutaneous adipose tissue. The work reported here may be useful for further studies addressing the function of the described cells.
Phase variation in pneumococcal populations during carriage in the human nasopharynx
Authors: De Ste Croix M. , Mitsi E. , Morozov A. , Glenn S. , Andrew P. W. , Ferreira D. M. , Oggioni M. R.
Published: February 2020

Streptococcus pneumoniae is one of the world’s leading bacterial pathogens, responsible for pneumonia, septicaemia and meningitis. Asymptomatic colonisation of the nasopharynx is considered to be a prerequisite for these severe infections, however little is understood about the biological changes that permit the pneumococcus to switch from asymptomatic coloniser to invasive pathogen. A phase variable type I restriction-modification (R-M) system (SpnIII) has been linked to a change in capsule expression and to the ability to successfully colonise the murine nasopharynx. Using our laboratory data, we have developed a Markov change model that allows prediction of the expected level of phase variation within a population, and as a result measures when populations deviate from those expected at random. Using this model, we have analysed samples from the Experimental Human Pneumococcal Carriage (EHPC) project. Here we show, through mathematical modelling, that the patterns of dominant SpnIII alleles expressed in the human nasopharynx are significantly different than those predicted by stochastic switching alone. Our inter-disciplinary work demonstrates that the expression of alternative methylation patterns should be an important consideration in studies of pneumococcal colonisation.
The upper cervical spinal cord in ALS assessed by cross-sectional and longitudinal 3T MRI
Authors: Wimmer Thomas , Schreiber Frank , Hensiek Nathalie , Garz Cornelia , Kaufmann Jörn , Machts Judith , Vogt Susanne , Prudlo Johannes , Dengler Reinhard , Petri Susanne , Heinze Hans-Jochen , Nestor Peter J , Vielhaber Stefan , Schreiber Stefanie
Published: February 2020

The upper cervical spinal cord is measured in a large longitudinal amyotrophic lateral sclerosis (ALS) cohort to evaluate its role as a biomarker. Specifically, the cervical spinal cord´s cross-sectional area (CSA) in plane of the segments C1–C3 was measured semi-automatically with T1-weighted 3T MRI sequences in 158 ALS patients and 86 controls. Six-month longitudinal follow-up MRI scans were analyzed in 103 patients. Compared to controls, in ALS there was a significant mean spinal cord atrophy (63.8 mm² vs. 60.8 mm², p = 0.001) which showed a trend towards worsening over time (mean spinal cord CSA decrease from 61.4 mm² to 60.6 mm² after 6 months, p = 0.06). Findings were most pronounced in the caudal segments of the upper cervical spinal cord and in limb-onset ALS. Baseline CSA was related to the revised ALS functional rating scale, disease duration, precentral gyrus thickness and total brain gray matter volume. In conclusion, spinal cord atrophy as assessed in brain MRIs in ALS patients mirrors the extent of overall neurodegeneration and parallels disease severity.
A Spanish case-control study in <5 year-old children reveals the lack of association between MLB and VA astrovirus and diarrhea
Authors: Vu Diem-Lan , Sabrià Aurora , Aregall Nuria , Michl Kristina , Sabrià Jaume , Rodriguez Garrido Virginia , Goterris Lidia , Bosch Albert , Pintó Rosa Maria , Guix Susana
Published: February 2020

Novel human astroviruses (HAstV) were discovered 10 years ago and have been associated with fatal cases of central nervous system infections. Their role in gastroenteritis is controversial, as they have been identified in symptomatic and asymptomatic subjects. The aim of the study was to investigate novel HAstV in a gastroenteritis case-control study including a pediatric population in Spain over a one-year period. We included stool samples from patients with gastroenteritis and negative results for viruses screened by routine diagnostics, and stool samples of control subjects who sought for a routine medical consultation. All samples were screened by real-time RT-PCR assays for novel HAstV. An additional screening for rotavirus, norovirus GI, GII, sapovirus, classic HAstV and adenovirus was also performed for the control group. Overall, 23/363 stool samples from case patients (6.3%) and 8/199 stool samples from control patients (4%) were positive for ≥1 novel HAstV. MLB1 was predominant (64.5% of positives). Seasonality was observed for the case group (p = 0.015), but not the control group (p = 0.95). No difference was observed in the prevalence of novel HAstV between the case and control groups (OR 1.78, 95% CI 0.68–5.45; p = 0.30). Nevertheless, MLB genome copy numbers/ml of fecal suspension was significantly higher in the control group than in the case group (p = 0.008). In our study, we identified a lack of association between novel HAstV and gastroenteritis in the studied population, which could indicate a potential role of reservoir for children, especially given the higher viral load observed in the asymptomatic group for some of them.
Energy harvesting thermocell with use of phase transition
Authors: Shibata Takayuki , Iwaizumi Hiroki , Fukuzumi Yuya , Moritomo Yutaka
Published: February 2020

A thermocell that consists of cathode and anode materials with different temperature coefficients (α = dV/dT) of the redox potential (V) can convert environmental thermal energy to electric energy via the so-called thermal charging effect. The output voltage Vcell of the current thermocell, however, is still low (several tens mV) and depends on temperature, which are serious drawbacks for practical use of the device as an independent power supply. Here, we report that usage of phase transition material as electrode qualitatively improve the device performance. We set the critical temperature (Tc) for the phase transition in cobalt Prussian blue analogue (Co-PBA; NaxCo[Fe(CN)6]y) to just above room temperature, by finely adjusting the Fe concentration (y = 0.82). With increase in the cell temperature (Tcell), Vcell of the NaxCo[Fe(CN)6]0.82 (NCF82)/NaxCo[Fe(CN)6]0.9 (NCF90) cell steeply increases from 0 mV to ~120 mV around 320 K. Our observation indicates that the thermocell with use of phase transition is a promising energy harvesting device.
Isolation, identification, and proposed formation mechanism of a novel hydrophilic compound formed by Maillard reaction between pyridoxamine and pentose
Authors: Nomi Yuri , Otsuka Yuzuru
Published: February 2020

Pyridoxamine (PM) could competitively protect amino groups in proteins from glycating agents. Although PM is expected to react with saccharides, available data therein are limited. In this study, a novel hydrophilic compound from a model reaction solution containing PM and xylose was isolated and identified as (6aR,9aR)-1,8,9-trihydroxy-2,6a-dimethyl-6a,9a-dihydrocyclopenta[5,6]pyrano[3,4-c]pyridin-7(5H)-one with a tricyclic structure. This compound appeared to be specifically formed from pentose via 1-deoxypentosone, and its formation was facilitated over a pH range of 7.0–8.0. After heating at 90 °C for 5 h in a reaction mixture containing 30 mM PM and pentose at pH 7.4, this compound was obtained at a yield of 6.95–8.53 mM.
M3C: Monte Carlo reference-based consensus clustering
Authors: John Christopher R. , Watson David , Russ Dominic , Goldmann Katriona , Ehrenstein Michael , Pitzalis Costantino , Lewis Myles , Barnes Michael
Published: February 2020

Genome-wide data is used to stratify patients into classes for precision medicine using clustering algorithms. A common problem in this area is selection of the number of clusters (K). The Monti consensus clustering algorithm is a widely used method which uses stability selection to estimate K. However, the method has bias towards higher values of K and yields high numbers of false positives. As a solution, we developed Monte Carlo reference-based consensus clustering (M3C), which is based on this algorithm. M3C simulates null distributions of stability scores for a range of K values thus enabling a comparison with real data to remove bias and statistically test for the presence of structure. M3C corrects the inherent bias of consensus clustering as demonstrated on simulated and real expression data from The Cancer Genome Atlas (TCGA). For testing M3C, we developed clusterlab, a new method for simulating multivariate Gaussian clusters.
A randomised controlled trial of rosuvastatin for the prevention of aminoglycoside-induced kidney toxicity in children with cystic fibrosis
Authors: McWilliam Stephen J. , Rosala-Hallas Anna , Jones Ashley P. , Shaw Victoria , Greenhalf William , Jaki Thomas , Smyth Alan R. , Smyth Rosalind L. , Pirmohamed Munir
Published: February 2020

The PROteKT study tested the hypothesis that rosuvastatin can inhibit aminoglycoside-induced nephrotoxicity in children with Cystic Fibrosis (CF). This open label, parallel group, randomised controlled trial recruited children and young people aged 6 to 18 years with CF at 13 paediatric CF treatment centres in the UK. Participants were randomised equally to either receive oral rosuvastatin (10 mg once daily) or no intervention (control) throughout clinically indicated treatment with intravenous tobramycin. The primary outcome was the difference between the groups in mean fold-change in urinary Kidney Injury Molecule-1 (KIM-1). Fifty (rosuvastatin n = 23, control n = 27) participants were recruited between May 2015 and January 2017. Primary outcome data was available for 88% (rosuvastatin n = 20, control n = 24). The estimated mean treatment difference in the geometric mean-fold change of normalised KIM-1 was 1.08 (95% CI 0.87–1.35, p = 0.48). In total there were 12 adverse reactions, all mild, reported by five participants randomised to rosuvastatin, and one serious adverse event in each group. Whilst no protective effect of rosuvastatin was seen, there was a lower than expected level of nephrotoxicity in the cohort. Therefore, we can neither confirm nor refute the hypothesis that rosuvastatin protects against aminoglycoside nephrotoxicity.
Concurrent tracking of strain and noise bursts at ferroelastic phase fronts
Authors: Blaysat Benoît , Balandraud Xavier , Grédiac Michel , Vives Eduard , Barrera Noemi , Zanzotto Giovanni
Published: February 2020

Many technological applications are based on functional materials that exhibit reversible first-order ferroelastic transitions, including elastocaloric refrigeration, energy harvesting, and sensing and actuation. During these phase changes inhomogeneous microstructures are formed which fit together different crystalline phases, and evolve abruptly through strain bursts related to domain nucleation and the propagation of phase fronts, accompanied by acoustic emission. Mechanical performance is strongly affected by such microstructure formation and evolution, yet visualisation of these processes remains challenging. Here we report a detailed study of the bursty dynamics during a reversible stress-induced martensitic transformation in a CuZnAl shape-memory alloy. We combine full-field strain-burst detection, performed by means of an optical grid method, with the acoustic tracking of martensitic strain avalanches using two transducers, which allows for the location of the acoustic-emission events to be determined and the measurement of their energies. The matching of these two techniques reveals interface formation, advancement, jamming and arrest at pinning points within the transforming crystal.
Nucleation and Crystal Growth in Continuous Crystallization
Authors: McGinty John , Yazdanpanah Nima , Price Chris , ter Horst Joop H. , Sefcik Jan
Published: February 2020

This chapter discusses the fundamental aspects of nucleation and particle formation in the continuous crystallization context, with a main focus on nucleation and crystal growth. The classic crystallization phenomena, fundamental, thermodynamic or kinetic driven, will not be covered here. The primary and secondary nucleation, and some methods of nuclei generation in continuous crystallization are discussed in this chapter. The performance of continuous crystallization processes and challenges with process kinetics and control (such as seeding, mixing, and process dynamics) are also addressed in this chapter.
Continuous Crystallization of Bulk and Fine Chemicals
Authors: Kind Matthias
Published: February 2020

Continuous operation is common for most industrial large scale productions of bulk chemicals. Such productions are continuous because of the need to optimize energy efficiency and investment cost. In such continuous production processes the solids formation step (crystallization, precipitation) is also continuous. In addition to their economic optimum, such continuously operated plants have further advantages: They are operated at quasi-steady state and therefore produce products of rather constant quality. Furthermore, they may be operated for very long periods of time (days to weeks) without cleaning and removing of incrustations. In addition, the product quality may be adjusted in a wide range of particle sizes from a few microns to a few millimetres. In contrast to the continuous operation of large scale production of bulk chemicals most processes for fine chemicals are batch- or semi-batch-wise and are carried out in multi-purpose/multi-product plants. Here, the priority lies with the variability and flexibility of the plant. Characteristic is the rather low tonnage of fine chemical products. Nevertheless, the advantages for continuous processes in the bulk chemicals production are valid also for the fine chemicals production, and hence, there is a number of reasons why continuous crystallization may be seen more often in the future.