bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel markers to detect HER2 amplification in Breast cancer
Authors: Mudgal Shikha , Kalra Arnav , Ravi Bina , Rao Shalinee , Chowdhury Nilotpal 
Published: November 2021

AbstractOverexpression of HER2 in breast cancer is an important prognostic and predictive biomarker, assessed using immunohistochemistry (IHC) and in situ hybridization (ISH). More than 20% of tumours are graded equivocal on IHC and is send for reflex testing via ISH. In situ hybridization (ISH) is an expensive assay and is not available widely in resource limiting areas. Therefore, we propose that genes found significantly co-expressed with HER2 in breast cancer can be used as surrogate markers for HER2 in breast cancer which can detect HER2 positivity on IHC itself. This hypothesis is based on analysis of publicly available datasets from the Gene Expression Omnibus (GEO) database. The genes found most significantly correlated with HER2 expression were PGAP3 (r = 0.85), GRB7 (r = 0.82), STARD3 (r = 0.78), CDK12 (r= 0.68), PSMD3 (r =0.67) and GSDMB (r = 0.63). We hypothesize that these identified surrogate markers for HER2 amplification which can be detected on IHC can detect HER2 amplification status in HER2 equivocal tumors based on IHC staining alone and will reduce the number of HER2 2+ (equivocal) category tumours.
Decidual immune response following COVID-19 during pregnancy varies by timing of maternal SARS-CoV-2 infection
Authors: Juttukonda Lillian J. , Wachman Elisha M. , Boateng Jeffery , Jain Mayuri , Benarroch Yoel , Taglauer Elizabeth S. 
Published: November 2021

AbstractWhile COVID-19 infection during pregnancy is common, fetal transmission is rare, suggesting that intrauterine mechanisms form an effective blockade against SARS-CoV-2. Key among these is the decidual immune environment of the placenta. We hypothesized that decidual leukocytes are altered by maternal SARS-CoV-2 infection in pregnancy and that this decidual immune resonse is shaped by the timing of infection during gestation. To address this hypothesis, we collected decidua basalis tissues at delivery from women with symptomatic COVID-19 during second (2nd Tri COVID, n=8) or third trimester (3rd Tri COVID, n=8) and SARS-CoV-2-negative controls (Control, n=8). Decidual natural killer (NK) cells, macrophages and T cells were evaluated using quantitative microscopy, and pro- and anti-inflammatory cytokine mRNA expression was evaluated using quantitative reverse transcriptase PCR (qRT-PCR). When compared with the Control group, decidual tissues from 3rd Tri COVID exhibited significantly increased macrophages, NK cells and T cells, whereas 2nd Tri COVID only had significantly increased T cells. In evaluating decidual cytokine expression, we noted that IL-6, IL-8, IL-10 and TNF-α were significantly correlated with macrophage cell abundance. However, in 2nd Tri COVID tissues, there was significant downregulation of IL-6, IL-8, IL-10, and TNF-α. Taken together, these results suggest innate and adaptive immune responses are present at the maternal-fetal interface in maternal SARS-CoV-2 infections late in pregnancy, and that infections earlier in pregnancy show evidence of a resolving immune response. Further studies are warranted to characterize the full scope of intrauterine immune responses in pregnancies affected by maternal COVID-19.
Visual Attention in The Fovea and The Periphery during Visual Search
Authors: Zhang Jie , Zhu Xiaocang , Wang Shanshan , Ma Zhengyu , Esteky Hossein , Tian Yonghong , Desimone Robert , Zhou Huihui 
Published: November 2021

SummaryVisual search depends on both the foveal and peripheral visual system, yet the foveal attention mechanisms is still lack of insights. We simultaneously recorded the foveal and peripheral activities in V4, IT and LPFC, while monkeys performed a category-based visual search task. Feature attention enhanced responses of Face-selective, House-selective, and Non-selective foveal cells in visual cortex. While foveal attention effects appeared no matter the peripheral attention effects, paying attention to the foveal stimulus dissipated the peripheral feature attentional effects, and delayed the peripheral spatial attentional effects. When target features appeared both in the foveal and the peripheral, feature attention effects seemed to occur predominately in the foveal, which might not distribute across the visual field according to common view of distributed feature attention effects. As a result, the parallel attentive process seemed to occur during distractor fixations, while the serial process predominated during target fixations in visual search.
Simplified, Shear Induced Generation of Double Emulsions for Robust Compartmentalization during Single Genome Analysis
Authors: Cowell Thomas W. , Dobria Andrew , Han Hee-Sun 
Published: November 2021

ABSTRACTDrop microfluidics has driven innovations for high throughput, low input analysis techniques such as single-cell RNA-seq. However, the instability of single emulsion (SE) drops occasionally causes significant merging during drop processing, limiting most applications to single-step reactions in drops. Here, we show that double emulsion (DE) drops address this critical limitation and completely prevent content mixing, which is essential for single entity analysis. DEs show excellent stability during thermal cycling. More importantly, DEs undergo rupture into the continuous phase instead of merging, preventing content mixing and eliminating unstable drops from the downstream analysis. Due to the lack of drop merging, the monodispersity of drops is maintained throughout a workflow, enabling the deterministic manipulation of drops downstream. We also developed a simple, one-layer fabrication method for DE drop makers. This design is powerful as it allows robust production of single-core DEs at a wide range of flow rates and better control over the shell thickness, both of which have been significant limitations of conventional two-layer devices. This approach makes the fabrication of DE devices much more accessible, facilitating its broader adoption. Finally, we show that DE droplets effectively maintain the compartmentalization of single virus genomes during PCR-based amplification and barcoding, while SEs mixed contents due to merging. With their resistance to content mixing, DE drops have key advantages for multistep reactions in drops, which is limited in SEs due to merging and content mixing.
Sampling the conformational landscapes of transporters and receptors with AlphaFold2
Authors: del Alamo Diego , Sala Davide , Mchaourab Hassane S. , Meiler Jens 
Published: November 2021

ABSTRACTEquilibrium fluctuations and triggered conformational changes often underlie the functional cycles of membrane proteins. For example, transporters mediate the passage of molecules across cell membranes by alternating between inward-facing (IF) and outward-facing (OF) states, while receptors undergo intracellular structural rearrangements that initiate signaling cascades. Although the conformational plasticity of these proteins has historically posed a challenge for traditional de novo protein structure prediction pipelines, the recent success of AlphaFold2 (AF2) in CASP14 culminated in the modeling of a transporter in multiple conformations to high accuracy. Given that AF2 was designed to predict static structures of proteins, it remains unclear if this result represents an underexplored capability to accurately predict multiple conformations and/or structural heterogeneity. Here, we present an approach to drive AF2 to sample alternative conformations of topologically diverse transporters and G-protein coupled receptors (GPCRs) that are absent from the AF2 training set. Whereas models generated using the default AF2 pipeline are conformationally homogeneous and nearly identical to one another, reducing the depth of the input multiple sequence alignments (MSAs) by stochastic subsampling led to the generation of accurate models in multiple conformations. In our benchmark, these conformations spanned the range between two experimental structures of interest, with models at the extremes of these conformational distributions observed to be among the most accurate (average template modeling (TM)-score of 0.94). These results suggest a straightforward approach to identifying native-like alternative states, while also highlighting the need for the next generation of deep learning algorithms to be designed to predict ensembles of biophysically relevant states.
Induction and inhibition of Drosophila X chromosome gene expression are both impeded by the dosage compensation complex
Authors: Meisel Richard P. , Asgari Danial , Schlamp Florencia , Unckless Robert L. 
Published: November 2021

ABSTRACTSex chromosomes frequently differ from the autosomes in the frequencies of genes with sexually dimorphic or tissue-specific expression. Multiple hypotheses have been put forth to explain the unique gene content of the X chromosome, including selection against male-beneficial X-linked alleles, expression limits imposed by the haploid dosage of the X in males, and interference by the dosage compensation complex (DCC) on expression in males. Here, we investigate these hypotheses by examining differential gene expression in Drosophila melanogaster following several treatments that have widespread transcriptomic effects: bacterial infection, viral infection, and abiotic stress. We found that genes that are induced (up-regulated) by these biotic and abiotic treatments are frequently under-represented on the X chromosome, but so are those that are repressed (down-regulated) following treatment. We further show that whether a gene is bound by the DCC in males can largely explain the paucity of both up- and down-regulated genes on the X chromosome. Specifically, genes that are bound by the DCC, or close to a DCC high-affinity site, are unlikely to be up- or down-regulated after treatment. This relationship, however, could partially be explained by a correlation between differential expression and breadth of expression across tissues. Nonetheless, our results suggest that DCC binding, or the associated chromatin modifications, inhibit both up- and down-regulation of X chromosome gene expression within specific contexts. We propose multiple possible mechanisms of action for the effect, including a role of Males absent on the first (Mof), a component of the DCC, as a dampener of gene expression variance in both males and females. This effect could explain why the Drosophila X chromosome is depauperate in genes with tissue-specific or induced expression, while the mammalian X has an excess of genes with tissue-specific expression.
Co-Delivery of Synergistic Antimicrobials with Polyelectrolyte Nanocomplexes to Treat Bacterial Biofilms and Lung Infections
Authors: Finbloom Joel A. , Raghavan Preethi , Kwon Michael , Kharbikar Bhushan N. , Yu Michelle A. , Desai Tejal A. 
Published: November 2021

AbstractNew approaches are needed to treat bacterial biofilm infections, particularly those of Pseudomonas aeruginosa (PA), which have high rates of antimicrobial resistance and are commonly found in chronic wound and cystic fibrosis lung infections. Combination therapeutics that act synergistically can overcome resistance; however, the delivery of multiple therapeutics at relevant dosages remains a challenge. We therefore developed a new nanoscale drug carrier for antimicrobial co-delivery by combining approaches from polyelectrolyte nanocomplex (NC) formation and layer-by-layer electrostatic self-assembly. This strategy led to NC drug carriers loaded with tobramycin antibiotics and antimicrobial silver nanoparticles (AgTob-NCs). AgTob-NCs displayed synergistic enhancements in antimicrobial activity against both planktonic and biofilm PA cultures, with positively charged NCs leading to complete biofilm eradication. NCs were evaluated in mouse models of lung infection, leading to reduced bacterial burden and improved survival outcomes. This approach therefore shows promise for nanoscale therapeutic co-delivery to overcome antimicrobial resistant bacterial infections.
Mechanically induced nuclear shuttling of β-catenin requires co-transfer of actin
Authors: Sen Buer , Xie Zhihui , Howard Sean , Styner Maya , van Wijnen Andre J , Uzer Gunes , Rubin Janet 
Published: November 2021

AbstractMesenchymal stem cells (MSC) respond to environmental forces with both cytoskeletal re-structuring and activation of protein chaperones of mechanical information, β-catenin and Yes-Associated Protein 1 (YAP1). To function, MSCs must differentiate between dynamic forces such as cyclic strains of extracellular matrix due to physical activity and static strains due to ECM stiffening. To delineate how MSCs recognize and respond differently to both force types, we compared effects of dynamic (200 cycles x 2%) and static (1 × 2% hold) strain on nuclear translocation of β-catenin and YAP1 at 3h after force application. Dynamic strain induced nuclear accumulation of β-catenin, and increased cytoskeletal actin structure and cell stiffness, but had no effect on nuclear YAP1 levels. Critically, both nuclear actin and nuclear stiffness increased along with dynamic strain-induced β-catenin transport. Augmentation of cytoskeletal structure using either static strain or lysophosphatidic acid (LPA) did not increase nuclear content of β–catenin or actin, but induced robust nuclear increase in YAP1. As actin binds β-catenin, we considered whether β-catenin, which lacks a nuclear localization signal, was dependent on actin to gain entry to the nucleus. Knockdown of cofilin-1 (Cfl1) or importin-9 (Ipo9), which co-mediate nuclear transfer of G-actin, prevented dynamic strain-mediated nuclear transfer of both β-catenin and actin. In sum, dynamic strain induction of actin re-structuring promotes nuclear transport of G-actin, concurrently supporting nuclear access of β-catenin via mechanisms utilized for actin transport. Thus, dynamic and static strain activate alternative mechanoresponses reflected by differences in the cellular distributions of actin, β-catenin and YAP1.Significance statementCells integrate both static and dynamic mechanical signals through the actin cytoskeleton which is attached to the nuclear envelope, affecting nuclear transport of β-catenin and YAP1. Dynamic strain induces nuclear translocation of β-catenin, but not YAP1, while static strain causes nuclear translocation of YAP1, but not β-catenin. Importantly, nuclear transport of actin is induced by dynamic but not static force. Furthermore, nuclear import of β-catenin depends on cofilin/importin-9 dependent actin transport mechanisms. Thus the presence of β-catenin and YAP1 in the nucleus represent specific responses to regulatory mechanical signals.
Beetle bioluminescence outshines aerial predators
Authors: Powell Gareth S. , Saxton Natalie A. , Pacheco Yelena M. , Stanger-Hall Kathrin F. , Martin Gavin J. , Kusy Dominik , Da Silveira Luiz Felipe Lima , Bocak Ladislav , Branham Marc A. , Bybee Seth M. 
Published: November 2021

AbstractBioluminescence is found across the tree of life and has many functions. Yet we understand very little about its timing and origins, particularly as a predator avoidance strategy. Understanding the timing between bioluminescence and predator origins has yet to be examined and can help elucidate the evolution of this ecologically important aposematic signal. Using the most prevalent bioluminescent group, fireflies, where bioluminescence primarily functions as aposematic and sexual signals, the timing for the origins of both potential predators of fireflies and bioluminescence is explored. Divergence time estimations were performed using genomic-scale phylogenetic reconstructions, and multiple fossil calibration points, allowing for a robust estimate for the origin of lampyrid bioluminescence as a terrestrial and as an aerial signal. Our results recover the origins of terrestrial beetle bioluminescence at 141.17 (122.63–161.17) mya and firefly aerial bioluminescence at 133.18 (117.86–152.47) mya with a large dataset focused on Lampyridae; and terrestrial bioluminescence as 148.03 (130.12–166.80) mya, with the age of aerial bioluminescence at 104.97 (99.00–120.90) mya with a complementary broad Elateroidea dataset. These ages predate the origins of all known extant aerial predators (i.e., bats and birds) and support the much older terrestrial predators (assassin bugs, frogs, ground beetles, lizards, snakes, hunting spiders, and harvestmen) as the most likely drivers of terrestrial bioluminescence in beetles, and sexual signaling likely being the original function in aerial fireflies.
Electrophysiological correlates of confidence differ across correct and erroneous perceptual decisions
Authors: Feuerriegel Daniel , Murphy Mackenzie , Konski Alexandra , Mepani Vinay , Sun Jie , Hester Robert , Bode Stefan 
Published: November 2021

AbstractEvery decision we make is accompanied by an estimate of the probability that our decision is accurate or appropriate. This probability estimate is termed our degree of decision confidence. Recent work has uncovered event-related potential (ERP) correlates of confidence both during decision formation and after a decision has been made. However, the interpretation of these findings is complicated by methodological issues related to ERP amplitude measurement that are prevalent across existing studies. To more accurately characterise the neural correlates of confidence, we presented participants with a difficult perceptual decision task that elicited a broad range of confidence ratings. We identified a frontal ERP component within an onset prior to the behavioural response, which exhibited more positive-going amplitudes in trials with higher confidence ratings. This frontal effect also biased measures of the centro-parietal positivity (CPP) component at parietal electrodes via volume conduction. Amplitudes of the error positivity (Pe) component that followed each decision were negatively associated with confidence for trials with decision errors, but not for trials with correct decisions, with Bayes factors providing moderate evidence for the null in the latter case. We provide evidence for both pre- and post-decisional neural correlates of decision confidence that are observed in trials with correct and erroneous decisions, respectively. Our findings suggest that certainty in having made a correct response is associated with frontal activity during decision formation, whereas certainty in having committed an error is instead associated with the post-decisional Pe component. These findings also highlight the possibility that some previously reported associations between decision confidence and CPP/Pe component amplitudes may have been a consequence of ERP amplitude measurement-related confounds. Re-analysis of existing datasets may be useful to test this hypothesis more directly.Highlights–We mapped the event-related potential correlates of decision confidence–A frontal component was associated with confidence during decision formation–The error positivity component was associated with confidence in error trials–The error positivity was not associated with confidence in correct response trials
Chronic Physical and Vicarious Psychosocial Stress Alter Fentanyl Consumption and Nucleus Accumbens Rho GTPases in Male and Female C57BL/6 Mice
Authors: Franco Daniela , Wulff Andreas B , Lobo Mary Kay , Fox Megan E 
Published: November 2021

AbstractChronic stress can increase the risk of developing a substance use disorder in vulnerable individuals. Numerous models have been developed to probe the underlying neurobiological mechanisms, however most prior work has been restricted to male rodents, conducted only in rats, or introduces physical injury that can complicate opioid studies. Here we sought to establish how chronic psychosocial stress influences fentanyl consumption in male and female C57BL/6 mice. We used chronic social defeat stress (CSDS), or the modified vicarious chronic witness defeat stress (CWDS), and used social interaction to stratify mice as stress-susceptible or resilient. We then subjected mice to a 15 day fentanyl drinking paradigm in the home cage that consisted of alternating forced and choice periods with increasing fentanyl concentrations. Male mice susceptible to either CWDS or CSDS consumed more fentanyl relative to unstressed mice, and exhibited increased preference for fentanyl. CWDS-susceptible female mice did not differ from unstressed mice during the forced periods, but showed increased preference for fentanyl. We also found decreased expression of nucleus accumbens Rho GTPases in male, but not female mice following stress and fentanyl drinking. We also compare fentanyl drinking behavior in mice that had free access to plain water throughout. Our results indicate that stress-sensitized fentanyl consumption is dependent on both sex and behavioral outcomes to stress.
Comparative analysis of Bacillus cereus group isolates’ resistance using disk diffusion and broth microdilution and the correlation between resistance phenotypes and genotypes
Authors: Mills Emma , Sullivan Erin , Kovac Jasna 
Published: November 2021

ABSTRACTA collection of 85 Bacillus cereus group isolates were screened for phenotypic resistance to nine antibiotics using disk diffusion and broth microdilution. The broth microdilution antimicrobial results were interpreted using the CLSI M45 breakpoints for Bacillus spp. Due to the lack of Bacillus spp. disk diffusion breakpoints, the results obtained with the disk diffusion assay were interpreted using the CLSI M100 breakpoints for Staphylococcus spp. We identified significant (p < 0.05) discrepancies in resistance interpretation between the two methods for ampicillin, gentamicin, rifampicin, tetracycline, and trimethoprim/sulfamethoxazole. Antimicrobial resistance genes were detected using unassembled and assembled whole-genome sequences with Ariba and Abricate, respectively, to assess the sensitivity and specificity for predicting phenotypic resistance based on the presence of antimicrobial resistance genes. We found antimicrobial resistance gene presence to be a poor indicator for phenotypic resistance, calling for further investigation of mechanisms underlying antimicrobial resistance in the B. cereus group. Genes with poor sensitivity and/or specificity, as determined based on broth microdilution results included rph (rifampicin, 0%, 95%), mph genes (erythromycin, 0%, 96%), and all van genes (vancomycin, 100%, 35%). However, Bc (ampicillin, 64%, 100%) and tet genes (tetracycline, 67%, 100%) were highly specific, albeit moderately sensitive indicators of phenotypic resistance based on broth microdilution results. Only beta-lactam resistance genes (Bc, BcII, and blaTEM) were highly sensitive (94%) and specific (100%) markers of resistance to ceftriaxone based on the disk diffusion results, providing further evidence of these beta-lactams’ role in nonsusceptibility of Bacillus cereus group isolates to ceftriaxone.IMPORTANCEBacillus cereus group includes human pathogens that can cause severe infections requiring antibiotic treatment. Screening of environmental and food isolates for antimicrobial resistance can provide insight into what antibiotics may be more effective therapeutic options based on the lower prevalence of resistance. Currently, interpretation of antimicrobial susceptibility testing results using the disk diffusion method is complicated by the fact that there are no standard disk diffusion resistance breakpoints defined for Bacillus spp. Hence, the breakpoints for Staphylococcus are often used in research studies. By comparing the results of disk diffusion interpreted using the Staphylococcus spp. breakpoints against broth microdilution interpreted using Bacillus spp. breakpoints, this study demonstrated that disk diffusion results interpretation with Staphylococcus spp. breakpoints are inconsistent. This study also provides new insight into the poor associations between antimicrobial resistance genotypes and phenotypes for the B. cereus group.