bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractEpistasis 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

AbstractIκB 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

AbstractHumans’ 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

AbstractCellular 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

AbstractTriple 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

AbstractThalattosaurians 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

AbstractIn 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

AbstractThe 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

AbstractThyroid 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

AbstractThe 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

AbstractPrediction 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

AbstractConventional 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

AbstractParaquat (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

AbstractStructural 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

AbstractThe 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.