bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of action biomarkers predicting response to AKT inhibition in the I-SPY 2 breast cancer trial
Authors: Wolf Denise M. , Yau Christina , Wulfkuhle Julia , Brown-Swigart Lamorna , Gallagher Rosa I. , Jesus M. Magbanua Mark , O’Grady Nick , Hirst Gillian ,   I-SPY 2 TRIAL Investigators, Asare Smita , Tripathy Debu , Berry Don , Esserman Laura , Chien A. Jo , Petricoin Emanuel F. , van ‘t Veer Laura 
Published: October 2020

AbstractThe AKT inhibitor MK2206 (M) was evaluated in I-SPY 2 and graduated in the HER2+, HR−, and HR− HER2+ signatures. We hypothesized that AKT signaling axis proteins/genes may specifically predict response to M and tested 26 phospho-proteins and 10 genes involved in AKT-mTOR-HER signaling; in addition, we tested 9 genes from a previous study in the metastatic setting. One hundred and fifty patients had gene expression data from pretreatment biopsies available for analysis (M: 94, control: 56) and 138 had protein data (M: 87, control: 51). Logistic modeling was used to assess biomarker performance in pre-specified analysis. In general, phospho-protein biomarkers of activity in the AKT-mTOR-HER pathway appeared more predictive of response to M than gene expression or total protein biomarkers in the same pathway; however, the nature of the predictive biomarkers differed in the HER2+ and TN groups. In the HER2+ subset, patients achieving a pCR in M had higher levels of multiple AKT kinase substrate phospho-proteins (e.g., pmTOR, pTSC2). In contrast, in the TN subset responding patients had lower levels of AKT pathway phospho-proteins, such as pAKT, pmTOR, and pTSC2. Pathway mutations did not appear to account for these associations. Additional exploratory whole-transcriptome analysis revealed immune signaling as strongly associated with response to M in the HER2+ subset. While our sample size is small, these results suggest that the measurement of particular AKT kinase substrate phospho-proteins could be predictive of MK2206 efficacy in both HER2+ and TN tumors and that immune signaling may play a role in response in HER2+ patients.
Using machine learning-based analysis for behavioral differentiation between anxiety and depression
Authors: Richter Thalia , Fishbain Barak , Markus Andrey , Richter-Levin Gal , Okon-Singer Hadas 
Published: October 2020

AbstractAnxiety and depression are distinct—albeit overlapping—psychiatric diseases, currently diagnosed by self-reported-symptoms. This research presents a new diagnostic methodology, which tests rigorously for differences in cognitive biases among subclinical anxious and depressed individuals. 125 participants were divided into four groups based on the levels of their anxiety and depression symptoms. A comprehensive behavioral test battery detected and quantified various cognitive–emotional biases. Advanced machine-learning tools, developed for this study, analyzed these results. These tools detect unique patterns that characterize anxiety versus depression to predict group membership. The prediction model for differentiating between symptomatic participants (i.e., high symptoms of depression, anxiety, or both) compared to the non-symptomatic control group revealed a 71.44% prediction accuracy for the former (sensitivity) and 70.78% for the latter (specificity). 68.07% and 74.18% prediction accuracy was obtained for a two-group model with high depression/anxiety, respectively. The analysis also disclosed which specific behavioral measures contributed to the prediction, pointing to key cognitive mechanisms in anxiety versus depression. These results lay the ground for improved diagnostic instruments and more effective and focused individually-based treatment.
Relative overhydration is independently associated with left ventricular hypertrophy in dialysis naïve patients with stage 5 chronic kidney disease
Authors: Han Byoung-Geun , Lee Jun Young , Choi Seung Ok , Yang Jae-Won , Kim Jae-Seok 
Published: October 2020

AbstractPatients with chronic kidney disease (CKD) have a high prevalence of left ventricular hypertrophy (LVH), which increases as kidney function decreases. LVH pathophysiology is complex, making it difficult to generalise its evolution in CKD. Therefore, early detection and prevention of risk factors are critical. Assessment and management of volume status can minimise cardiovascular complications including LVH. We retrospectively investigated the associations between fluid overload and LVH in patients with stage 5 CKD not undergoing dialysis in prospective cohort of 205 patients (age: 59.34 ± 13.51 years; women: 43.4%). All patients, free of intrinsic heart disease, were assessed for relative overhydration/extracellular water (OH/ECW) by bioimpedance spectroscopy. Our results show that markers reflecting fluid balance were significantly higher in the LVH group and as OH/ECW increased, the left ventricular mass index (LVMI) trended higher. Furthermore, our results show that systolic blood pressure, serum phosphorus levels, and OH/ECW were independently associated with LVMI and that OH/ECW was independently associated with LVH. Structural and functional evaluation of the heart using echocardiography and volume status assessment using bioimpedance should be performed simultaneously in patients with early-stage CKD, even in those without evident cardiovascular disease.
Characterization of five novel vasopressin V2 receptor mutants causing nephrogenic diabetes insipidus reveals a role of tolvaptan for M272R-V2R mutation
Authors: Prosperi Federica , Suzumoto Yoko , Marzuillo Pierluigi , Costanzo Vincenzo , Jelen Sabina , Iervolino Anna , Guarino Stefano , La Manna Angela , Miraglia Del Giudice Emanuele , Perna Alessandra F. , Zacchia Miriam , Cordat Emmanuelle , Capasso Giovambattista , Trepiccione Francesco 
Published: October 2020

AbstractNephrogenic diabetes insipidus (NDI) is a rare tubulopathy characterized by urinary concentration defect due to renal resistance to vasopressin. Loss-of-function mutations of vasopressin V2 receptor (V2R) gene (AVPR2) is the most common cause of the disease. We have identified five novel mutations L86P, R113Q, C192S, M272R, and W323_I324insR from NDI-affected patients. Functional characterization of these mutants revealed that R113Q and C192S were normally localized at the basolateral membrane of polarized Madin-Darby Canine Kidney (MDCK) cells and presented proper glycosylation maturation. On the other side, L86P, M272R, and W323_I324insR mutants were retained in endoplasmic reticulum and exhibited immature glycosylation and considerably reduced stability. All five mutants were resistant to administration of vasopressin analogues as evaluated by defective response in cAMP release. In order to rescue the function of the mutated V2R, we tested VX-809, sildenafil citrate, ibuprofen and tolvaptan in MDCK cells. Among these, tolvaptan was effective in rescuing the function of M272R mutation, by both allowing proper glycosylation maturation, membrane sorting and response to dDAVP. These results show an important proof of concept for the use of tolvaptan in patients affected by M272R mutation of V2R causing NDI.
Serial changes in the aqueous IL-10 level after intravitreal methotrexate injection as an indicator of primary vitreoretinal lymphoma recurrence
Authors: Park Young Gun , Park Woo-Kyung , Kim Rae-Young , Kim Mirinae , Park Young-Hoon 
Published: October 2020

AbstractPrimary vitreoretinal lymphoma (PVRL) often masquerades as other uveitic diseases. We investigated the aqueous cytokine level changes and the effects of intraocular methotrexate (MTX) in patients with PVRL. In this retrospective consecutive case-series study, we reviewed the records of 14 consecutive patients with PVRL treated between 2018 and 2020. The concentrations of interleukin (IL)-2, IL-6, IL-10, IL-12, IL-17, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were determined at baseline and several time points after intravitreal MTX injections during follow-up. Markedly elevated IL-10 levels and a higher IL-10/IL-6 ratio were found in patients with PVRL. The aqueous levels of IL-10, IL-12, and TNF-α, and the IL-10/IL-6 ratio significantly decreased at 1 month after intravitreal MTX therapy onset compared with the baseline values (P = 0.001, 0.002, 0.001, and 0.001, respectively). The mean duration to normalized IL-10 levels was 1.17 ± 0.4 months. Where serially recorded IL-10 levels were available, regular intravitreal MTX treatment was associated with rapid reduction in IL-10 levels, while elevated IL-10 level was associated with disease recurrence. Elevated IL-10 levels and high IL-10/IL-6 ratio may aid in the diagnosis of PVRL. Aqueous IL-10 level monitoring can help assess the therapeutic response and indicate disease recurrence.
DDxNet: a deep learning model for automatic interpretation of electronic health records, electrocardiograms and electroencephalograms
Authors: Thiagarajan Jayaraman J. , Rajan Deepta , Katoch Sameeksha , Spanias Andreas 
Published: October 2020

AbstractEffective patient care mandates rapid, yet accurate, diagnosis. With the abundance of non-invasive diagnostic measurements and electronic health records (EHR), manual interpretation for differential diagnosis has become time-consuming and challenging. This has led to wide-spread adoption of AI-powered tools, in pursuit of improving accuracy and efficiency of this process. While the unique challenges presented by each modality and clinical task demand customized tools, the cumbersome process of making problem-specific choices has triggered the critical need for a generic solution to enable rapid development of models in practice. In this spirit, we develop DDxNet, a deep architecture for time-varying clinical data, which we demonstrate to be well-suited for diagnostic tasks involving different modalities (ECG/EEG/EHR), required level of characterization (abnormality detection/phenotyping) and data fidelity (single-lead ECG/22-channel EEG). Using multiple benchmark problems, we show that DDxNet produces high-fidelity predictive models, and sometimes even provides significant performance gains over problem-specific solutions.
Seasonal dynamics of lotic bacterial communities assessed by 16S rRNA gene amplicon deep sequencing
Authors: Paruch Lisa , Paruch Adam M. , Eiken Hans Geir , Skogen Monica , Sørheim Roald 
Published: October 2020

AbstractAquatic microbial diversity, composition, and dynamics play vital roles in sustaining water ecosystem functionality. Yet, there is still limited knowledge on bacterial seasonal dynamics in lotic environments. This study explores a temporal pattern of bacterial community structures in lotic freshwater over a 2-year period. The aquatic bacterial communities were assessed using Illumina MiSeq sequencing of 16S rRNA genes. Overall, the communities were dominated by α-, β-, and γ-Proteobacteria, Bacteroidetes, Flavobacteriia, and Sphingobacteriia. The bacterial compositions varied substantially in response to seasonal changes (cold vs. warm), but they were rather stable within the same season. Furthermore, higher diversity was observed in cold seasons compared to warm periods. The combined seasonal-environmental impact of different physico-chemical parameters was assessed statistically, and temperature, suspended solids, and nitrogen were determined to be the primary abiotic factors shaping the temporal bacterial assemblages. This study enriches particular knowledge on the seasonal succession of the lotic freshwater bacteria.
Loss of bacterial diversity in the sinuses is associated with lower smell discrimination scores
Authors: Biswas Kristi , Wagner Mackenzie Brett , Ballauf Charlotte , Draf Julia , Douglas Richard G. , Hummel Thomas 
Published: October 2020

AbstractOlfactory impairment affects ~ 20% of the population and has been linked to various serious disorders. Microbes in the nasal cavity play a key role in priming the physiology of the olfactory epithelium and maintaining a normal sense of smell by the host. The aim of this study was to explore the link between olfactory dysfunction and nasal bacterial communities. A total of 162 subjects were recruited for this study from a specialized olfactory dysfunction clinic and placed into one of three groups: anosmia, hyposmia or normosmia. Swabs from the nasal middle meatus were collected from each subject then processed for bacterial 16S rRNA gene sequencing. No overall differences in bacterial diversity or composition were observed between the three cohorts in this study. However, the relative abundances of Corynebacterium spp. and Streptococcus spp. were significantly (p < 0.05) different in subjects with olfactory loss. Furthermore, subjects with deficiencies in discriminating between smells (based on discrimination scores) had a lower bacterial diversity (Simpson’s evenness p < 0.05). While these results are preliminary in nature, potential bacterial biomarkers for olfactory loss were identified. These findings need to be further validated and biologically tested in animal models.
Effects of knee flexor submaximal isometric contraction until exhaustion on semitendinosus and biceps femoris long head shear modulus in healthy individuals
Authors: Mendes Bruno , Firmino Telmo , Oliveira Raúl , Neto Tiago , Cruz-Montecinos Carlos , Cerda Mauricio , Correia José P. , Vaz João R. , Freitas Sandro R. 
Published: October 2020

AbstractThis study examined whether a knee flexor isometric contraction at 20% of maximal voluntary isometric contraction until exhaustion would alter the biceps femoris long head (BFlh) and semitendinosus (ST) active stiffness, assessed using ultrasound-based shear wave elastography. Twelve healthy individuals participated in 2 sessions separated by 7 days. Time to exhaustion was similar in both sessions (day 1: 443.8 ± 192.5 s; day 2: 474.6 ± 131.7 s; p = 0.323). At the start of the fatigue task, the ST showed greater active stiffness than the BFlh (p < 0.001), with no differences between days (p = 0.08). The ST active stiffness then decreased from 40% of the task time to exhaustion (− 2.2 to − 13.3%, p = 0.027) until the end of the task (− 16.1 to − 22.9%, p = 0.012), while no significant changes were noted in the BFlh (p = 0.771). Immediately after the fatigue task, a decrease in active stiffness was observed in the ST (− 11.8 to − 17.8%, p < 0.001), but not in the BFlh (p = 0.551). Results were consistent between the 2 testing sessions (p = 0.07–0.959). The present results indicate that fatigue alters the hamstring active stiffness pattern.
Trigonelline recovers memory function in Alzheimer’s disease model mice: evidence of brain penetration and target molecule
Authors: Farid Mai M. , Yang Ximeng , Kuboyama Tomoharu , Tohda Chihiro 
Published: October 2020

AbstractTrigonelline (TGN; 1-methylpyridin-1-ium-3-carboxylate) is a widely distributed alkaloid derived from plants. Since we previously found a neurite outgrowth effect of TGN, we hypothesised that TGN might help to improve memory deficits. Here, the efficacy of TGN in restoring amyloid β (Aβ)-induced axonal degeneration and in improving memory function was investigated in Alzheimer’s disease 5XFAD model mice that overexpress mutated APP and PS1 genes. Exposure of Aβ25-35 for 3 days induced atrophy of axons and dendrites. Post treatment of TGN recovered the lengths of axons and dendrites. Following oral administration of TGN in mice, TGN itself was detected in the plasma and cerebral cortex. Oral administration of TGN to 5XFAD mice for 14 days showed significant improvement in object recognition memory (P < 0.001) and object location memory (P < 0.01). TGN administration also normalised neurofilament light levels in the cerebral cortex (P < 0.05), which is an axonal damage-associated biomarker. Analysis of target proteins of TGN in neurons by a drug affinity responsive target stability (DARTS) method identified that creatine kinase B-type (CKB) is a direct binding protein of TGN. Treatment with a CKB inhibitor cancelled the TGN-induced axonal and dendritic growth. In conclusion, we found for the first time that TGN penetrates the brain and may activate CKB, leading to axonal formation. This study shows the potential of TGN as a new drug candidate, and a new target molecule, CKB, in memory recovery signalling.
Deep phylogeny of cancer drivers and compensatory mutations
Authors: Rochman Nash D. , Wolf Yuri I. , Koonin Eugene V. 
Published: October 2020

AbstractDriver mutations (DM) are the genetic impetus for most cancers. The DM are assumed to be deleterious in species evolution, being eliminated by purifying selection unless compensated by other mutations. We present deep phylogenies for 84 cancer driver genes and investigate the prevalence of 434 DM across gene-species trees. The DM are rare in species evolution, and 181 are completely absent, validating their negative fitness effect. The DM are more common in unicellular than in multicellular eukaryotes, suggesting a link between these mutations and cell proliferation control. 18 DM appear as the ancestral state in one or more major clades, including 3 among mammals. We identify within-gene, compensatory mutations for 98 DM and infer likely interactions between the DM and compensatory sites in protein structures. These findings elucidate the evolutionary status of DM and are expected to advance the understanding of the functions and evolution of oncogenes and tumor suppressors.
Axon hillock currents enable single-neuron-resolved 3D reconstruction using diamond nitrogen-vacancy magnetometry
Authors: Parashar Madhur , Saha Kasturi , Bandyopadhyay Sharba 
Published: October 2020

AbstractSensing neuronal action potential associated magnetic fields (APMFs) is an emerging viable alternative of functional brain mapping. Measurement of APMFs of large axons of worms have been possible due to their size. In the mammalian brain, axon sizes, their numbers and routes, restricts using such functional imaging methods. With a segmented model of mammalian pyramidal neurons, we show that the APMF of intra-axonal currents in the axon hillock are two orders of magnitude larger than other neuronal locations. Expected 2D magnetic field maps of naturalistic spiking activity of a volume of neurons via widefield diamond-nitrogen-vacancy-center-magnetometry were simulated. A dictionary-based matching pursuit type algorithm applied to the data using the axon-hillock’s APMF signature allowed spatiotemporal reconstruction of action potentials in the volume of brain tissue at single cell resolution. Enhancement of APMF signals coupled with magnetometry advances thus can potentially replace current functional brain mapping techniques.
NuSTAR observation of GRO J1744–28 at low mass accretion rate
Authors: König Ole , Fürst Felix , Kretschmar Peter , Ballhausen Ralf , Sokolova-Lapa Ekaterina , Dauser Thomas , Sánchez-Fernández Celia , Hemphill Paul B. , Wolff Michael T. , Pottschmidt Katja , Wilms Jörn 
Published: October 2020

Context. Neutron stars in low-mass X-ray binaries are important systems for studying the physics of accretion onto compact objects. The system GRO J1744–28 is particularly interesting as it usually shows clear pulsations as well as X-ray bursts. Additionally, there are claims for a magnetic field of 5 × 1011 G through the detection of a cyclotron resonant scattering feature (CRSF).
Aims. We present the spectral analysis of GRO J1744–28 using ∼29 ks of NuSTAR data taken in 2017 February at a low luminosity of 3.2 × 1036 erg s−1 (3−50 keV). Our goal is to study the variability of the source spectrum with pulse phase and to search for the claimed CRSF.
Methods. The continuum spectrum was modeled with an absorbed power law with exponential cutoff, and an additional iron line component. We found no obvious indications for a CRSF, and therefore performed a detailed cyclotron line search using statistical methods. We performed this search on pulse phase-averaged spectra and on phase-resolved spectra.
Results. GRO J1744–28 was observed in a low-luminosity state. The previously detected Type II X-ray bursts are absent. Clear pulsations at a period of 2.141124(9) Hz are detected. The pulse profile shows an indication of a secondary peak that was not seen at higher flux. The upper limit for the strength of a CRSF in the 3−20 keV band is 0.07 keV (90% CL), lower than the strength of the line found at higher luminosity.
Conclusions. The detection of pulsations shows that the source did not enter the “propeller” regime, even though the source flux of 4.15 × 10−10 erg cm−2 s−1 was almost one order of magnitude below the threshold for the propeller regime claimed in previous studies on this source. The transition into the propeller regime in GRO J1744–28 must therefore be below a luminosity of 3.2 × 1036 erg s−1 (3−50 keV), which implies a surface magnetic field ≲2.9 × 1011 G and mass accretion rate ≲1.7 × 1016 g s−1. A change of the CRSF depth as function of luminosity is not unexpected and has been observed in other sources. This result possibly implies a change in emission geometry as function of mass accretion rate to reduce the depth of the line below our detection limit.
A miniaturized acoustic vector sensor with PIN-PMN-PT single crystal cantilever beam accelerometers
Authors: Cho Yohan , Je Yub , Jeong Weui-Bong 
Published: October 2020

Directional sound detection using vector sensors rather than large hydrophone arrays is highly advantageous for target detection in SONAR. However, developing highly sensitive and compact vector sensors for use in a system whose size is limited has been a challenging issue. In this paper, we describe a miniaturized acoustic vector sensor with piezoelectric single crystal accelerometers for the application in towed line arrays. A mass-loaded cantilever beam accelerometer with a [011] poled PIN-PMN-PT single crystal shows a better signal-to-noise ratio compared to accelerometers with other piezoelectric materials because of its superior piezoelectric properties in the 32 direction. We suggested a sufficiently compact vector sensor by using a cylindrical hydrophone with 10 mm in diameter as a housing of the single crystal accelerometers. Two single crystal accelerometers were orthogonally mounted inside the cylindrical hydrophone to detect direction of sound in the transverse plane of the line array. The receiving voltage sensitivity of the accelerometers and hydrophone was −199 and −196 dB, respectively, at 3 kHz. The directional cardioid beams generated by summing the omnidirectional beam from the hydrophone and the dipole beam from the accelerometers were validated over the entire operating frequency.
The role of fibril structure and surface hydrophobicity in secondary nucleation of amyloid fibrils
Authors: Thacker Dev , Sanagavarapu Kalyani , Frohm Birgitta , Meisl Georg , Knowles Tuomas P. J. , Linse Sara 
Published: October 2020

Significance
Alzheimer’s disease affects a rapidly growing number of individuals worldwide. Key unresolved questions relate to the onset and propagation of the disease, linked to the self-assembly of amyloid β peptide into fibrillar and smaller aggregates. This study investigates the propagation of aggregates of amyloid β peptide and asks whether hydrophobic molecular features observed on the fibril surface correlate with its ability to catalyze the formation of new aggregates. This question is motivated by the associated formation of intermediate forms that are toxic to neuronal cells. The results imply that surface catalysis is independent of surface details but requires that the monomers that form the new aggregate can adopt the structure of the parent aggregate without steric clashes.