bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic Representation of the Subjective Value of Information
Authors: Kobayashi Kenji , Lee Sangil , Filipowicz Alexandre L. S. , McGaughey Kara D. , Kable Joseph W. , Nassar Matthew R. 
Published: February 2021

AbstractTo improve future decisions, people should seek information based on the value of information (VOI), which depends on the current evidence and the reward structure of the upcoming decision. When additional evidence is supplied, people should updateVOIto adjust subsequent information seeking, but the neurocognitive mechanisms of this updating process remain unknown. We used a modified beads task to examine how theVOIis represented and updated in the human brain. We theoretically derived, and empirically verified, a normative prediction that theVOIdepends on decision evidence and is biased by reward asymmetry. Using fMRI, we found that the subjectiveVOIis represented in right dorsolateral prefrontal cortex (DLPFC). Critically, thisVOIrepresentation was updated when additional evidence was supplied, showing that DLPFC dynamically tracks the up-to-dateVOIover time. These results provide new insights into how humans adaptively seek information in the service of decision making.
Synergistic application of continuous granulation and selective laser sintering 3D printing for the development of pharmaceutical dosage forms with enhanced dissolution rates and physical properties
Authors: Thakkar Rishi , Zhang Yu , Zhang Jiaxiang , Maniruzzaman Mohammed 
Published: February 2021

AbstractThis study demonstrated the first case of combining novel continuous granulation with powder-based pharmaceutical 3-dimensional (3D) printing processes to enhance the dissolution rate and physical properties of a poorly water-soluble drug. Powder bed fusion (PBF) and binder jetting 3D printing processes have gained much attention in pharmaceutical dosage form manufacturing in recent times. Although powder bed-based 3D printing platforms have been known to face printing and uniformity problems due to the inherent poor flow properties of the pharmaceutical physical mixtures (feedstock). Moreover, techniques such as binder jetting currently do not provide any solubility benefits to active pharmaceutical ingredients (APIs) with poor aqueous solubility (>40% of marketed drugs). For this study, a hot-melt extrusion-based versatile granulation process equipped with UV-Vis process analytical technology (PAT) tools for the in-line monitoring of critical quality attributes (i.e., solid-state) of indomethacin was developed. The collected granules with enhanced flow properties were mixed with vinylpyrrolidone-vinyl acetate copolymer and a conductive excipient for efficient sintering. These mixtures were further characterized for their bulk properties observing an excellent flow and later subjected to a PBF-3D printing process. The physical mixtures, processed granules, and printed tablets were characterized using conventional as well as advanced solid-state characterization. These characterizations revealed the amorphous nature of the drug in the processed granules and printed tablets. Further, thein vitrorelease testing of the tablets with produced granules as a reference standard depicted a notable solubility advantage (100% drug released in 5 minutes at >pH 6.8) over the pure drug and the physical mixture. Our developed system known as DosePlus combines innovative continuous granulation and PBF-3D printing process which can potentially improve the physical properties of the bulk drug and formulations in comparison to when used in isolation. This process can further find application in continuous manufacturing of granules and additive manufacturing of pharmaceuticals to produce dosage forms with excellent uniformity and solubility advantage.Abstract Figure
Forest loss in Indonesian New Guinea: trends, drivers, and outlook
Authors: Gaveau David L.A. , Santos Lucas , Locatelli Bruno , Salim Mohammad A. , Husnayaen Husnayaen , Meijaard Erik , Heatubun Charlie , Sheil Douglas 
Published: February 2021

AbstractThe rich forests of Indonesian New Guinea are threatened. We used satellite data to examine annual forest loss, road development and plantation expansion from 2001 to 2019, then developed a model to predict future deforestation in this understudied region. In 2019, 34.29 million hectares (Mha), or 83% of Indonesian New Guinea, supported old-growth forest. Over nineteen years, two percent (0.75 Mha) were cleared: 45% (0.34 Mha) converted to industrial plantations, roads, mine tailings, or other uses near cities; 55% (0.41 Mha) cleared by transient processes including selective natural timber extraction, inland water bodies-related processes, fires, and shifting agriculture. Industrial plantations expanded by 0.23 Mha, with the majority (0.21 Mha; 28% of forest loss) replacing forests and reaching 0.28 Mha in 2019 (97% oil palm; 3% pulpwood). The Trans-Papua Highway, a ~4,000 km national investment project, increased by 1,554 km. Positive correlations between highway and plantations expansion indicate these are linked processes. Plantations and roads grew rapidly after 2011, peaked in 2015/16, and declined thereafter. Indonesian government allocated 2.62 Mha of land for the development of industrial plantations (90% oil palm 10% pulpwood) of which 74% (1.95 Mha) remained forest in 2019. A spatial model predicts that an additional 4.5 Mha of forest could be cleared by 2036 if Indonesian New Guinea follows similar relationships to Indonesian Borneo. We highlight the opportunities for policy reform and the importance of working with indigenous communities, local leaders, and provincial government to protect the biological and cultural richness still embodied in this remarkable region.
Potent, Novel SARS-CoV-2 PLpro Inhibitors Block Viral Replication in Monkey and Human Cell Cultures
Authors: Shen Zhengnan , Ratia Kiira , Cooper Laura , Kong Deyu , Lee Hyun , Kwon Youngjin , Li Yangfeng , Alqarni Saad , Huang Fei , Dubrovskyi Oleksii , Rong Lijun , Thatcher Gregory , Xiong Rui 
Published: February 2021

ABSTRACTAntiviral agents blocking SARS-CoV-2 viral replication are desperately needed to complement vaccination to end the COVID-19 pandemic. Viral replication and assembly are entirely dependent on two viral cysteine proteases: 3C-like protease (3CLpro) and the papain-like protease (PLpro). PLpro also has deubiquitinase (DUB) activity, removing ubiquitin (Ub) and Ub-like modifications from host proteins, disrupting the host immune response. 3CLpro is inhibited by many known cysteine protease inhibitors, whereas PLpro is a relatively unusual cysteine protease, being resistant to blockade by such inhibitors. A high-throughput screen of biased and unbiased libraries gave a low hit rate, identifying only CPI-169 and the positive control, GRL0617, as inhibitors with good potency (IC50< 10 µM). Analogues of both inhibitors were designed to develop structure-activity relationships; however, without a co-crystal structure of the CPI-169 series, we focused on GRL0617 as a starting point for structure-based drug design, obtaining several co-crystal structures to guide optimization. A series of novel 2-phenylthiophene-based non-covalent SARS-CoV-2 PLpro inhibitors were obtained, culminating in low nanomolar potency. The high potency and slow inhibitor off-rate were rationalized by newly identified ligand interactions with a “BL2 groove” that is distal from the active site cysteine. Trapping of the conformationally flexible BL2 loop by these inhibitors blocks binding of viral and host protein substrates; however, until now it has not been demonstrated that this mechanism can induce potent and efficacious antiviral activity. In this study, we report that novel PLpro inhibitors have excellent antiviral efficacy and potency against infectious SARS-CoV-2 replication in cell cultures. Together, our data provide structural insights into the design of potent PLpro inhibitors and the first validation that non-covalent inhibitors of SARS-CoV-2 PLpro can block infection of human cells with low micromolar potency.
APOBEC mutagenesis inhibits breast cancer growth through induction of a T cell-mediated antitumor immune response
Authors: DiMarco Ashley V. , Qin Xiaodi , Van Alsten Sarah , McKinney Brock , Garcia Nina Marie G. , Force Jeremy , Hanks Brent A. , Troester Melissa A. , Owzar Kouros , Xie Jichun , Alvarez James V. 
Published: February 2021

ABSTRACTThe APOBEC family of cytidine deaminases is one of the most common endogenous sources of mutations in human cancer. Genomic studies of tumors have found that APOBEC mutational signatures are particularly enriched in the HER2 subtype of breast cancer and have been associated with immunotherapy response in diverse cancer types. However, the direct consequences of APOBEC mutagenesis on the tumor immune microenvironment have not been thoroughly investigated. To address this, we developed syngeneic murine mammary tumor models with inducible expression of APOBEC3B. We found that APOBEC activity induces an antitumor adaptive immune response and CD4+T cell-mediated tumor growth inhibition. While polyclonal APOBEC tumors had a moderate growth defect, clonal APOBEC tumors were almost completely rejected by the immune system, suggesting that APOBEC-mediated genetic heterogeneity limits the antitumor adaptive immune response. Consistent with the observed immune infiltration in APOBEC tumors, APOBEC activity sensitized HER2-driven breast tumors to checkpoint inhibition. In human breast cancers, the relationship between APOBEC mutagenesis and immunogenicity varied by breast cancer subtype and the frequency of subclonal mutations. This work provides a mechanistic basis for the sensitivity of APOBEC tumors to checkpoint inhibitors and suggests a rationale for using APOBEC mutational signatures as a biomarker predicting immunotherapy response in HER2-positive breast cancers.SIGNIFICANCEAPOBEC mutational signatures are observed in many cancers, yet the consequences of these mutations on the tumor immune microenvironment are not well understood. Using a novel mouse model, we show that APOBEC activity sensitizes HER2-driven mammary tumors to checkpoint inhibition and could inform immunotherapy treatment strategies for HER2-positive breast cancer patients.
Exon 9LEPRGene SNP Polymorphism of Hybrid Chickens F2KambroCrossbreeds of ♀ F1Kambrowith ♂ F1Kambro
Authors: Mahardhika I Wayan Swarautama , Daryono Budi Setiadi 
Published: February 2021

AbstractThe implementation of the T-ARMS PCR method in the detection of single nucleotide polymorphisms (SNPs) in theLEPRgene in chicken DNA samples has never been conducted. This research aims to design a specific protocol for exon 9LEPRgene SNPs detection and detectLEPRgene expression orLEPRSNPs inPelungchicken samples, F1Pelung, Layer, Broiler Cobb 500, F1Kambrochicken and F2Kambrochicken using the T-ARMS PCR method. Determination ofLEPRgene correlation degree on Body Weight (BT) and Egg Productivity (PT) in F1Kambro population and F2Kambro. Qualitative phenotype parameters showed six groups of segregated phenotypes compared to F1Kambrochicken. Growth of F2Kambrochicken weight reached 753.36 ± 155.31 grams in 8 weeks was not significant for F1Kambrochicken due to inbreeding depression (Fx = 25%, IR = 4.925%) and transversion of ALEPRallele mutations. Specific protocol detection of exon 9LEPRgene SNPs using the T-ARMS PCR method can detect C127ALEPRmutations with IP: OP ratio 10:1 pmol / µM, chicken DNA template concentration of 100 ng / µL with annealing temperature of 55.7° C / 30s. The transversion mutation of C127A ofLEPRexon 9 SNP were detected in DNA samples of F1Kambrohens (80%), F2Kambroroosters (20%), Broiler Cobb 500 hens (75%). The mutations were not detected in Layer,Pelung Blirik Hitamchicken and F1Pelungpopulations.
Phylogenomic subsampling and the search for phylogenetically reliable loci
Authors: Koch Nicolás Mongiardino 
Published: February 2021

AbstractPhylogenomic subsampling is a procedure by which small sets of loci are selected from large genome-scale datasets and used for phylogenetic inference. This step is often motivated by either computational limitations associated with the use of complex inference methods, or as a means of testing the robustness of phylogenetic results by discarding loci that are deemed potentially misleading. Although many alternative methods of phylogenomic subsampling have been proposed, little effort has gone into comparing their behavior across different datasets. Here, I calculate multiple gene properties for a range of phylogenomic datasets spanning animal, fungal and plant clades, uncovering a remarkable predictability in their patterns of covariance. I also show how these patterns provide a means for ordering loci by both their rate of evolution and their relative phylogenetic usefulness. This method of retrieving phylogenetically useful loci is found to be among the top performing when compared to alternative subsampling protocols. Relatively common approaches such as minimizing potential sources of systematic bias or increasing the clock-likeness of the data are found to fare worse than selecting loci at random. Likewise, the general utility of rate-based subsampling is found to be limited: loci evolving at both low and high rates are among the least effective, and even those evolving at optimal rates can still widely differ in usefulness. This study shows that many common subsampling approaches introduce unintended effects in off-target gene properties, and proposes an alternative multivariate method that simultaneously optimizes phylogenetic signal while controlling for known sources of bias.
Separate functional subnetworks of excitatory neurons show preference to periodic and random sound structures
Authors: Mehra Muneshwar , Mukesh Adarsh , Bandyopadhyay Sharba 
Published: February 2021

ABSTRACTAuditory cortex (ACX) neurons are sensitive to spectro-temporal sound patterns and violations in patterns induced by rare stimuli embedded within streams of sounds. We investigate the auditory cortical representation of repeated presentations of sequences of sounds with standard stimuli (common) with an embedded deviant (rare) stimulus in two conditions – Periodic (Fixed deviant position) or Random (Random deviant position), using extracellular single-unit and 2-photon Ca+2imaging recordings in Layer 2/3 neurons of the mouse ACX. In the population average, responses increased over repetitions in the Random-condition and were suppressed or did not change in the Periodic-condition, showing irregularity preference. A subset of neurons also showed the opposite behavior, indicating regularity preference. Pairwise noise correlations were higher in Random-condition over Periodic-condition, suggesting the role of recurrent connections. 2-photon Ca+2imaging of excitatory (EX) and parvalbumin-positive (PV) and somatostatin-positive (SOM) inhibitory neurons, showed different categories of adaptation or change in response over repetitions (categorized by the sign of the slope of change) as observed with single units. However, the examination of functional connectivity between pairs of neurons of different categories showed that EX-PV connections behaved opposite to the EX-EX and EX-SOM pairs that show more functional connections outside category in Random-condition than Periodic-condition. Finally considering Regularity preference, Irregularity preference and no preference categories, showed that EX-EX and EX-SOM connections to be in largely separate functional subnetworks with the different preferences, while EX-PV connections were more spread. Thus separate subnetworks could underly the coding of periodic and random sound sequences.Significance StatementStudying how the ACX neurons respond to streams of sound sequences help us understand the importance of changes in dynamic acoustic noisy scenes around us. Humans and animals are sensitive to regularity and its violations in sound sequences. Psychophysical tasks in humans show that auditory brain differentially responds to periodic and random structures, independent of the listener’s attentional states. Here we show that mouse ACX L2/3 neurons detect a change and respond differentially to changing patterns over long-time scales. The differential functional connectivity profile obtained in response to two different sound contexts, suggest the stronger role of recurrent connections in the auditory cortical network. Furthermore, the excitatory-inhibitory neuronal interactions can contribute to detecting the changing sound patterns.
Newly developedad hocmolecular assays show how eDNA can witness and anticipate the monk seal recolonization of central Mediterranean
Authors: Valsecchi Elena , Coppola Emanuele , Pires Rosa , Parmegiani Andrea , Casiraghi Maurizio , Galli Paolo , Bruno Antonia 
Published: February 2021

ABSTRACTThe monk sealMonachus monachusis the most endangered pinniped worldwide and the only one found in the Mediterranean, where its distribution and abundance have suffered a drastic decline in the last few decades. Data on its status are scattered due to both its rarity and evasiveness, and records are biased towards occasional, mostly coastal, encounters. Nowadays molecular techniques allow us to detect and quantify minute amounts of DNA traces released in the environment (eDNA) by any organism. We present three qPCR-assays targeting the monk seal mitogenome. The assays were soundly tested on an extensive and diversified sample set (n=73), including positive controls from Madeira breeding population collected during the peak of abundance, and two opportunistic Mediterranean eDNA-sample collections (offshore/coastal) from on-going projects. Monk seal DNA was detected in 47.2% and 66.7% of the samples collected in the Tyrrhenian from a ferry platform (2018-2019) and in the Pelagie archipelago -Strait of Sicily- (2020) respectively, anticipating (up to 2 year) visual observations occurred subsequently in proximity of the sampled areas. In the Tyrrhenian, detection occurrence increased between 2018 and 2019. Monk seal DNA recoveries were commoner in night-time ferry-samples, suggesting nocturnal predatory activity in pelagic waters. The proposed technique provides a non-invasive and yet highly-sensitive tool for defining the monk seal actual distribution and home range, its recovery rate and pinpoint coastal/offshore localities where prioritizing conservation, research, citizen science and education initiatives.
Characterizing white matter alterations in drug-naïve de novo Parkinson’s disease with diffusion MRI
Authors: Xiao Yiming , Peters Terry M. , Khan Ali R. 
Published: February 2021

AbstractParkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by a range of motor and non-motor symptoms, often with the motor dysfunction initiated unilaterally. Knowledge regarding disease-related alterations in white matter pathways can effectively help improve the understanding of the disease and propose targeted treatment strategies. Microstructural imaging techniques, including diffusion tensor imaging (DTI), allows inspection of white matter integrity to study the pathogenesis of various neurological conditions. Previous voxel-based analyses with DTI measures, such as fractional anisotropy and mean diffusivity have uncovered changes in brain regions that are associated with PD, but the conclusions were inconsistent, partially due to small patient cohorts and the lack of consideration for clinical laterality onset, particularly in early PD. Fixel-based analysis (FBA) is a recent framework that offers tract-specific insights regarding white matter health, but very few FBA studies on PD exist. We present a study that reveals strengthened and weakened white matter integrity that is subject to symptom laterality in a large drug-naïvede novoPD cohort using complementary DTI and FBA measures. The findings suggest that the disease gives rise to both functional degeneration and the creation of compensatory networks in the early stage.
Structure and mechanistic analyses of the gating mechanism of elongating ketosynthases
Authors: Mindrebo Jeffrey T. , Chen Aochiu , Kim Woojoo E. , Re Rebecca N. , Davis Tony D. , Noel Joseph P. , Burkart Michael D. 
Published: February 2021

AbstractKetosynthases (KSs) catalyze carbon-carbon bond forming reactions in fatty acid synthases (FASs) and polyketide synthases (PKSs). KSs utilize a two-step ping pong kinetic mechanism to carry out an overall decarboxylative thio-Claisen condensation that can be separated into the transacylation and condensation reactions. In both steps, an acyl carrier protein (ACP) delivers thioester tethered substrates to the active sites of KSs. Therefore, protein-protein interactions (PPIs) and KS-mediated substrate recognition events are required for catalysis. Recently, crystal structures ofEscherichia colielongating type II FAS KSs, FabF and FabB, in complex withE. coliACP, AcpP, revealed distinct conformational states of two active site KS loops. These loops were proposed to operate via a gating mechanism to coordinate substrate recognition and delivery followed by catalysis. Here we interrogate this proposed gating mechanism by solving two additional high-resolution structures of substrate engaged AcpP-FabF complexes, one of which provides the missing AcpP-FabF gate-closed conformation. Clearly defined interactions of one of these active site loops with AcpP are present in both the open and closed conformations, suggesting AcpP binding triggers or stabilizes gating transitions, further implicating PPIs in carrier protein-dependent catalysis. We functionally demonstrate the importance of gating in the overall KS condensation reaction and provide experimental evidence for its role in the transacylation reaction. Furthermore, we evaluate the catalytic importance of these loops using alanine scanning mutagenesis and also investigate chimeric FabF constructs carrying elements found in type I PKS KS domains. These findings broaden our understanding of the KS mechanism which advances future engineering efforts in both FASs and evolutionarily related PKSs.
Constructing local Cell Sepcific Networks from Single Cell Data
Authors: Wang Xuran , Choi David , Roeder Kathryn 
Published: February 2021

AbstractSingle-cell RNA sequencing facilitates investigations of gene co-expression networks at the cellular level potentially yielding unique biological insights, but the estimation problem is challenging. We develop a non-parametric approach to estimate cell-specific networks for each cell and cell type and propose novel downstream analyses. The individual networks preserve the cellular heterogeneity and facilitate testing for differences between cell groups. To further our understanding of autism spectrum disorder, we examine the evolution of gene networks in fetal brain cells and compare the gene networks of cells sampled from case and control subjects to reveal patterns in gene co-expression.