bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pomalidomide, bortezomib, and dexamethasone for multiple myeloma previously treated with lenalidomide (OPTIMISMM): outcomes by prior treatment at first relapse
Authors: Dimopoulos Meletios , Weisel Katja , Moreau Philippe , Anderson Larry D. , White Darrell , San-Miguel Jesus , Sonneveld Pieter , Engelhardt Monika , Jenner Matthew , Corso Alessandro , Dürig Jan , Pavic Michel , Salomo Morten , Casal Eva , Srinivasan Shankar , Yu Xin , Nguyen Tuong Vi , Biyukov Tsvetan , Peluso Teresa , Richardson Paul 
Published: September 2020

AbstractIn the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P < 0.001) and lenalidomide-nonrefractory (95.7% vs 60.0%; P < 0.001) patients, with similar results regardless of prior bortezomib or SCT. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments.
Cocaine-mediated circadian reprogramming in the striatum through dopamine D2R and PPARγ activation
Authors: Brami-Cherrier Karen , Lewis Robert G. , Cervantes Marlene , Liu Yu , Tognini Paola , Baldi Pierre , Sassone-Corsi Paolo , Borrelli Emiliana 
Published: September 2020

AbstractSubstance abuse disorders are linked to alteration of circadian rhythms, although the molecular and neuronal pathways implicated have not been fully elucidated. Addictive drugs, such as cocaine, induce a rapid increase of dopamine levels in the brain. Here, we show that acute administration of cocaine triggers reprogramming in circadian gene expression in the striatum, an area involved in psychomotor and rewarding effects of drugs. This process involves the activation of peroxisome protein activator receptor gamma (PPARγ), a nuclear receptor involved in inflammatory responses. PPARγ reprogramming is altered in mice with cell-specific ablation of the dopamine D2 receptor (D2R) in the striatal medium spiny neurons (MSNs) (iMSN-D2RKO). Administration of a specific PPARγ agonist in iMSN-D2RKO mice elicits substantial rescue of cocaine-dependent control of circadian genes. These findings have potential implications for development of strategies to treat substance abuse disorders.
Engineered systems of inducible anti-repressors for the next generation of biological programming
Authors: Groseclose Thomas M. , Rondon Ronald E. , Herde Zachary D. , Aldrete Carlos A. , Wilson Corey J. 
Published: September 2020

AbstractTraditionally engineered genetic circuits have almost exclusively used naturally occurring transcriptional repressors. Recently, non-natural transcription factors (repressors) have been engineered and employed in synthetic biology with great success. However, transcriptional anti-repressors have largely been absent with regard to the regulation of genes in engineered genetic circuits. Here, we present a workflow for engineering systems of non-natural anti-repressors. In this study, we create 41 inducible anti-repressors. This collection of transcription factors respond to two distinct ligands, fructose (anti-FruR) or D-ribose (anti-RbsR); and were complemented by 14 additional engineered anti-repressors that respond to the ligand isopropyl β-d-1-thiogalactopyranoside (anti-LacI). In turn, we use this collection of anti-repressors and complementary genetic architectures to confer logical control over gene expression. Here, we achieved all NOT oriented logical controls (i.e., NOT, NOR, NAND, and XNOR). The engineered transcription factors and corresponding series, parallel, and series-parallel genetic architectures represent a nascent anti-repressor based transcriptional programming structure.
Unique cellular protrusions mediate breast cancer cell migration by tethering to osteogenic cells
Authors: Muscarella Aaron M. , Dai Wei , Mitchell Patrick G. , Zhang Weijie , Wang Hai , Jia Luyu , Stossi Fabio , Mancini Michael A. , Chiu Wah , Zhang Xiang H.-F. 
Published: September 2020

AbstractMigration and invasion are key properties of metastatic cancer cells. These properties can be acquired through intrinsic reprogramming processes such as epithelial-mesenchymal transition. In this study, we discovered an alternative “migration-by-tethering” mechanism through which cancer cells gain the momentum to migrate by adhering to mesenchymal stem cells or osteoblasts. This tethering is mediated by both heterotypic adherens junctions and gap junctions, and leads to a unique cellular protrusion supported by cofilin-coated actin filaments. Inhibition of gap junctions or depletion of cofilin reduces migration-by-tethering. We observed evidence of these protrusions in bone segments harboring experimental and spontaneous bone metastasis in animal models. These data exemplify how cancer cells may acquire migratory ability without intrinsic reprogramming. Furthermore, given the important roles of osteogenic cells in early-stage bone colonization, our observations raise the possibility that migration-by-tethering may drive the relocation of disseminated tumor cells between different niches in the bone microenvironment.
Efficient construction of linear models in materials modeling and applications to force constant expansions
Authors: Fransson Erik , Eriksson Fredrik , Erhart Paul 
Published: September 2020

AbstractLinear models, such as force constant (FC) and cluster expansions, play a key role in physics and materials science. While they can in principle be parametrized using regression and feature selection approaches, the convergence behavior of these techniques, in particular with respect to thermodynamic properties is not well understood. Here, we therefore analyze the efficacy and efficiency of several state-of-the-art regression and feature selection methods, in particular in the context of FC extraction and the prediction of different thermodynamic properties. Generic feature selection algorithms such as recursive feature elimination with ordinary least-squares (OLS), automatic relevance determination regression, and the adaptive least absolute shrinkage and selection operator can yield physically sound models for systems with a modest number of degrees of freedom. For large unit cells with low symmetry and/or high-order expansions they come, however, with a non-negligible computational cost that can be more than two orders of magnitude higher than that of OLS. In such cases, OLS with cutoff selection provides a viable route as demonstrated here for both second-order FCs in large low-symmetry unit cells and high-order FCs in low-symmetry systems. While regression techniques are thus very powerful, they require well-tuned protocols. Here, the present work establishes guidelines for the design of protocols that are readily usable, e.g., in high-throughput and materials discovery schemes. Since the underlying algorithms are not specific to FC construction, the general conclusions drawn here also have a bearing on the construction of other linear models in physics and materials science.
Unusual magnetoelectric effect in paramagnetic rare-earth langasite
Authors: Weymann Lukas , Bergen Lorenz , Kain Thomas , Pimenov Anna , Shuvaev Alexey , Constable Evan , Szaller David , Mill Boris V. , Kuzmenko Artem M. , Ivanov Vsevolod Yu. , Kostyuchenko Nadezhda V. , Popov Alexander I. , Zvezdin Anatoly K. , Pimenov Andrei , Mukhin Alexander A. , Mostovoy Maxim 
Published: September 2020

AbstractViolation of time reversal and spatial inversion symmetries has profound consequences for elementary particles and cosmology. Spontaneous breaking of these symmetries at phase transitions gives rise to unconventional physical phenomena in condensed matter systems, such as ferroelectricity induced by magnetic spirals, electromagnons, non-reciprocal propagation of light and spin waves, and the linear magnetoelectric (ME) effect—the electric polarization proportional to the applied magnetic field and the magnetization induced by the electric field. Here, we report the experimental study of the holmium-doped langasite, HoxLa3−xGa5SiO14, showing a puzzling combination of linear and highly non-linear ME responses in the disordered paramagnetic state: its electric polarization grows linearly with the magnetic field but oscillates many times upon rotation of the magnetic field vector. We propose a simple phenomenological Hamiltonian describing this unusual behavior and derive it microscopically using the coupling of magnetic multipoles of the rare-earth ions to the electric field.
Quantum oscillations from networked topological interfaces in a Weyl semimetal
Authors: Liu I-Lin , Heikes Colin , Yildirim Taner , Eckberg Chris , Metz Tristin , Kim Hyunsoo , Ran Sheng , Ratcliff William D. , Paglione Johnpierre , Butch Nicholas P. 
Published: September 2020

AbstractLayered transition metal chalcogenides are promising hosts of electronic Weyl nodes and topological superconductivity. MoTe2 is a striking example that harbors both noncentrosymmetric Td and centrosymmetric T’ phases, both of which have been identified as topologically nontrivial. Applied pressure tunes the structural transition separating these phases to zero temperature, stabilizing a mixed Td–T’ matrix that entails a network of interfaces between the two nontrivial topological phases. Here, we show that this critical pressure range is characterized by distinct coherent quantum oscillations, indicating that the difference in topology between topologically nonvtrivial Td and T’ phases gives rise to an emergent electronic structure: a network of topological interfaces. A rare combination of topologically nontrivial electronic structures and locked-in transformation barriers leads to this counterintuitive situation, wherein quantum oscillations can be observed in a structurally inhomogeneous material. These results further open the possibility of stabilizing multiple topological phases coexisting with superconductivity.
Language disturbances in schizophrenia: the relation with antipsychotic medication
Authors: de Boer J. N. , Voppel A. E. , Brederoo S. G. , Wijnen F. N. K. , Sommer I. E. C. 
Published: September 2020

AbstractLanguage disturbances are key aberrations in schizophrenia. Little is known about the influence of antipsychotic medication on these symptoms. Using computational language methods, this study evaluated the impact of high versus low dopamine D2receptor (D2R) occupancy antipsychotics on language disturbances in 41 patients with schizophrenia, relative to 40 healthy controls. Patients with high versus low D2R occupancy antipsychotics differed by total number of words and type-token ratio, suggesting medication effects. Both patient groups differed from the healthy controls on percentage of time speaking and clauses per utterance, suggesting illness effects. Overall, more severe negative language disturbances (i.e. slower articulation rate, increased pausing, and shorter utterances) were seen in the patients that used high D2R occupancy antipsychotics, while less prominent disturbances were seen in low D2R occupancy patients. Language analyses successfully predicted drug type (sensitivity = 80.0%, specificity = 76.5%). Several language disturbances were more related to drug type and dose, than to other psychotic symptoms, suggesting that language disturbances may be aggravated by high D2R antipsychotics. This negative impact of high D2R occupancy drugs may have clinical implications, as impaired language production predicts functional outcome and degrades the quality of life.
Neuroadaptive modelling for generating images matching perceptual categories
Authors: Kangassalo Lauri , Spapé Michiel , Ruotsalo Tuukka 
Published: September 2020

AbstractBrain–computer interfaces enable active communication and execution of a pre-defined set of commands, such as typing a letter or moving a cursor. However, they have thus far not been able to infer more complex intentions or adapt more complex output based on brain signals. Here, we present neuroadaptive generative modelling, which uses a participant’s brain signals as feedback to adapt a boundless generative model and generate new information matching the participant’s intentions. We report an experiment validating the paradigm in generating images of human faces. In the experiment, participants were asked to specifically focus on perceptual categories, such as old or young people, while being presented with computer-generated, photorealistic faces with varying visual features. Their EEG signals associated with the images were then used as a feedback signal to update a model of the user’s intentions, from which new images were generated using a generative adversarial network. A double-blind follow-up with the participant evaluating the output shows that neuroadaptive modelling can be utilised to produce images matching the perceptual category features. The approach demonstrates brain-based creative augmentation between computers and humans for producing new information matching the human operator’s perceptual categories.
Advanced age and increased CRP concentration are independent risk factors associated with Clostridioides difficile infection mortality
Authors: Bednarska Agnieszka , Bursa Dominik , Podlasin Regina , Paciorek Marcin , Skrzat-Klapaczyńska Agata , Porowski Dawid , Raczyńska Joanna , Puła Joanna , Krogulec Dominika , Makowiecki Michał , Horban Andrzej 
Published: September 2020

AbstractClostridioides difficile (C.difficile) is a Gram-positive, spore-forming, toxin-producing anaerobic bacillus, which is one of the most common causes of health-care-associated infection developed mainly by elderly patients. The objective of this study was to assess mortality among the patients of the Hospital for Infectious Diseases in Warsaw related to C.difficile infection. Analysis was conducted of 1638 records reporting the medical histories of patients hospitalized for the first time due to Clostridioides difficile infection (CDI) in the Hospital for Infectious Diseases in Warsaw from 2010 to 2017. The inclusion criteria were any (principal or secondary) discharge diagnosis code for CDI according to ICD-10 and being an adult (≥ 18 years). 108 out of 1638 (7%) of the patients died. The median age in this group was 83 years. The largest number of deaths (90%) occurred in the group of patients aged 65 years or older and 81–90 years old (53% of all the deaths). In the multivariate logistic regression model relevant only to the age groups, not to sepsis—age over 80 and over 90 were independent predictors of death, increasing the risk of death by 3.4 and 1.8 times, respectively. The result of the receiver operating curve (ROC) analysis determined the age of 77 years as the threshold value, indicating the increased risk of death (AUC 0.727, standard error 0.025, 95% CI 0.678–0.776, p < 0.0001). In addition, other quantitative variables, namely CRP, creatinine and leucocytes were studied and turned out to be independent death predictors as well. The diagnosis of sepsis increased the risk of death fourfold (OR = 4.042; 95% Cl 2.4–6.7; p < 0.001). Increased inflammatory parameters, namely CRP and white blood cell count, advanced age, particularly over the age of 80, as well as a diagnosis of sepsis are independent risk factors for death and could be used as predictive markers of poor outcome in CDI.
Mechanism underlying hippocampal long-term potentiation and depression based on competition between endocytosis and exocytosis of AMPA receptors
Authors: Sumi Tomonari , Harada Kouji 
Published: September 2020

AbstractN-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and long-term depression (LTD) of signal transmission form neural circuits and thus are thought to underlie learning and memory. These mechanisms are mediated by AMPA receptor (AMPAR) trafficking in postsynaptic neurons. However, the regulatory mechanism of bidirectional plasticity at excitatory synapses remains unclear. We present a network model of AMPAR trafficking for adult hippocampal pyramidal neurons, which reproduces both LTP and LTD. We show that the induction of both LTP and LTD is regulated by the competition between exocytosis and endocytosis of AMPARs, which are mediated by the calcium-sensors synaptotagmin 1/7 (Syt1/7) and protein interacting with C-kinase 1 (PICK1), respectively. Our result indicates that recycling endosomes containing AMPAR are always ready for Syt1/7-dependent exocytosis of AMPAR at peri-synaptic/synaptic membranes. This is because molecular motor myosin Vb constitutively transports the recycling endosome toward the membrane in a Ca2+-independent manner.
Exploiting the potential of commercial digital holographic microscopy by combining it with 3D matrix cell culture assays
Authors: Hellesvik Monica , Øye Hanne , Aksnes Henriette 
Published: September 2020

Abstract3D cell culture assays are becoming increasingly popular due to their higher resemblance to tissue environment. These provide an increased complexity compared to the growth on 2D surface and therefore allow studies of advanced cellular properties such as invasion. We report here on the use of 3D Matrigel cell preparations combined with a particular gentle and informative type of live-cell microscopy: quantitative digital holographic microscopy (DHM), here performed by a commercial software-integrated system, currently mostly used for 2D cell culture preparations. By demonstrating this compatibility, we highlight the possible time-efficient quantitative analysis obtained by using a commercial software-integrated DHM system, also for cells in a more advanced 3D culture environment. Further, we demonstrate two very different examples making use of this advantage by performing quantitative DHM analysis of: (1) wound closure cell monolayer Matrigel invasion assay and (2) Matrigel-trapped single and clumps of suspension cells. For both these, we benefited from the autofocus functionality of digital phase holographic imaging to obtain 3D information for cells migrating in a 3D environment. For the latter, we demonstrate that it is possible to quantitatively measure tumourigenic properties like growth of cell clump (or spheroid) over time, as well as single-cell invasion out of cell clump and into the surrounding extracellular matrix. Overall, our findings highlight several possibilities for 3D digital holographic microscopy applications combined with 3D cell preparations, therein studies of drug response or genetic alterations on invasion capacity as well as on tumour growth and metastasis.
Microglia dynamics in retinitis pigmentosa model: formation of fundus whitening and autofluorescence as an indicator of activity of retinal degeneration
Authors: Makabe Kenichi , Sugita Sunao , Mandai Michiko , Futatsugi Yoko , Takahashi Masayo 
Published: September 2020

AbstractIn patients with retinitis pigmentosa (RP), color fundus photography and fundus autofluorescence (FAF) have been used to estimate the disease progression. To understand the origin and the diagnostic interpretation of the fundus color and FAF, we performed in vivo imaging of fundus color and FAF together with histological analyses of the retinal degeneration process using the RP model mice, rd10. FAF partly represented the accumulation of microglia in the photoreceptor outer segments. Fundus whitening suggested the presence of apoptotic cells, which spatiotemporally preceded increase in FAF. We observed two patterns of FAF localization, arcuate and diffuse, each indicating different pattern of apoptosis, wavy and diffuse, respectively. Diffuse pattern of apoptosis was suppressed in dark-raised rd10 mice, in which outer nuclear layer (ONL) loss was significantly suppressed. The occupancy of FAF correlated with the thinning rate of the ONL. Fractalkine, a microglia chemotactic factor, was detected in apoptotic photoreceptors, suggesting chemokine-induced recruitment of microglia into the ONL, which paralleled with accelerated ONL loss and increased FAF occupancy. Thus, we propose that the degree of photoreceptor apoptosis and the rate of ONL thinning in RP patients might be read from the fundus color and the FAF.
High positive predictive value of the combined pituitary dynamic enhanced MRI and high-dose dexamethasone suppression tests in the diagnosis of Cushing’s disease bypassing bilateral inferior petrosal sinus sampling
Authors: Liu Zeyu , Zhang Xiaobo , Wang Zhiwei , You Hui , Li Mingli , Feng Feng , Jin Zhengyu 
Published: September 2020

AbstractThe purpose of the study is to evaluate the positive predictive value of the combined pituitary dynamic enhanced MRI (dMRI) and high-dose dexamethasone suppression tests (HDDST) in the diagnosis of Cushing’s disease (CD) bypassing bilateral inferior petrosal sinus sampling (BIPSS). A total of 118 patients with Cushing’s syndrome (CS), who underwent pituitary dMRI, HDDST and BIPSS were included. Positive predictive value of pituitary dMRI, HDDST, BIPSS and the combined test were calculated and tumor lateralization accuracy was further analyzed. The positive predictive value of the combined pituitary dMRI and HDDST was 98.6%, higher than that of BIPSS. There were 96.8% of patients, who had either negative findings in pituitary dMRI or HDDST, showing centralizing BIPSS results. For tumor lateralization, the accuracy by pituitary dMRI was 88.6%, whereas BIPSS was 57.5%. Therefore, CS patients with both positive findings in pituitary dMRI and HDDST need no further invasive evaluation to establish the definite diagnosis of CD. BIPSS will improve the diagnostic accuracy when negative findings were found in either pituitary dMRI or HDDST.
Prediction of an MMP-1 inhibitor activity cliff using the SAR matrix approach and its experimental validation
Authors: Asawa Yasunobu , Yoshimori Atsushi , Bajorath Jürgen , Nakamura Hiroyuki 
Published: September 2020

AbstractA matrix metalloproteinase 1 (MMP-1) inhibitor activity cliff was predicted using the SAR Matrix method. Compound 4 was predicted as a highly potent activity cliff partner and found to possess 60 times higher inhibitory activity against MMP-1 than the structurally related compound 3. Furthermore, pharmacophore fitting of synthesized compounds indicated that the correctly predicted activity cliff was caused by interactions between the trifluoromethyl group at para position in compound 4 and residue ARG214 of MMP-1.