bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep learning-based risk stratification of preoperative breast biopsies using digital whole slide images
Authors: Boissin Constance , Wang Yinxi , Sharma Abhinav , Weitz Philippe , Karlsson Emelie , Robertson Stephanie , Hartman Johan , Rantalainen Mattias 
Published: August 2023

AbstractIntroductionNottingham histological grade (NHG) is a well established prognostic factor in breast cancer histopathology. However, manual NHG assessment of biopsies is challenging and has a large inter-assessor variability with a large proportion being classified as NHG2 (intermediate grade). Here, we evaluate whether DeepGrade, a previously developed model for the risk stratification of resected tumour specimens, could be applied to risk-stratify biopsy specimens.MethodsA total of 11,943,905 tiles from 1171 whole slide images (WSIs) of preoperative biopsies from 897 patients diagnosed with breast cancer in Stockholm, Sweden, were included in this retrospective observational study. DeepGrade, a deep convolutional neural network model, was applied for classification of low and high risk tumours and evaluated against clinically assigned grades 1 and 3 using area under the operating curve (AUC). The prognostic value of the DeepGrade model in the biopsy setting was evaluated using time-to-event analysis.ResultsThe DeepGrade model classified resected tumour cases with grades NHG1 and NHG3 using only biopsy specimens with an AUC of 0.903 (95% CI: 0.88;0.93). The model could also classify the biopsy NHG (1 and 3) assessed on the biopsy of 186 patients with an AUC of 0.959 (95% CI: 0.93; 0.99). Furthermore, out of the 434 NHG2 tumours, 255 (59%) were classified as DeepGrade2-low, and 179 (41%) were classified as DeepGrade2-high. Using a multivariable Cox proportional hazards model the hazard ratio between low- and high-risk groups was estimated as 2.01 (p-value = 0.036).ConclusionsDeepGrade could predict the resected tumour grades NHG1 and NHG3 using only the biopsy specimen and sub-classify grade 2 tumours into low and high risks. The results demonstrate that the DeepGrade model can provide decision support for biopsy grading, and potentially provide decision support in the clinical setting to identifying high-risk tumours based on preoperative breast biopsies, thus improving information available for clinical treatment decisions.
SARS-CoV-2 shedding and evolution in immunocompromised hosts during the Omicron period: a multicenter prospective analysis
Authors: Raglow Zoe , Surie Diya , Chappell James D. , Zhu Yuwei , Martin Emily T. , Kwon Jennie H. , Frosch Anne E. , Mohamed Amira , Gilbert Julie , Bendall Emily E. , Bahr Auden , Halasa Natasha , Talbot H. Keipp , Grijalva Carlos G. , Baughman Adrienne , Womack Kelsey N. , Johnson Cassandra , Swan Sydney A. , Koumans Emilia , McMorrow Meredith L. , Harcourt Jennifer L. , Atherton Lydia J. , Burroughs Ashley , Thornburg Natalie J. , Self Wesley H. , Lauring Adam S. 
Published: August 2023

ABSTRACTBackgroundProlonged SARS-CoV-2 infections in immunocompromised hosts may predict or source the emergence of highly mutated variants. The types of immunosuppression placing patients at highest risk for prolonged infection and associated intrahost viral evolution remain unclear.MethodsAdults aged ≥18 years were enrolled at 5 hospitals and followed from 4/11/2022 – 2/1/2023. Eligible patients were SARS-CoV-2-positive in the previous 14 days and had a moderate or severely immunocompromising condition or treatment. Nasal specimens were tested by rRT-PCR every 2–4 weeks until negative in consecutive specimens. Positive specimens underwent viral culture and whole genome sequencing. A Cox proportional hazards model was used to assess factors associated with duration of infection.ResultsWe enrolled 150 patients with: B cell malignancy or anti-B cell therapy (n=18), solid organ or hematopoietic stem cell transplant (SOT/HSCT) (n=59), AIDS (n=5), non-B cell malignancy (n=23), and autoimmune/autoinflammatory conditions (n=45). Thirty-eight (25%) were rRT-PCR-positive and 12 (8%) were culture-positive ≥21 days after initial SARS-CoV-2 detection or illness onset. Patients with B cell dysfunction had longer duration of rRT-PCR- positivity compared to those with autoimmune/autoinflammatory conditions (aHR 0.32, 95% CI 0.15-0.64). Consensus (>50% frequency) spike mutations were identified in 5 individuals who were rRT-PCR-positive >56 days; 61% were in the receptor-binding domain (RBD). Mutations shared by multiple individuals were rare (<5%) in global circulation.ConclusionsIn this cohort, prolonged replication-competent Omicron SARS-CoV-2 infections were uncommon. Within-host evolutionary rates were similar across patients, but individuals with infections lasting >56 days accumulated spike mutations, which were distinct from those seen globally.
Comparative neuroimaging of sex differences in human and mouse brain anatomy
Authors: Guma Elisa , Beauchamp Antoine , Liu Siyuan , Levitis Elizabeth , Ellegood Jacob , Pham Linh , Mars Rogier B , Raznahan Armin , Lerch Jason P 
Published: August 2023

AbstractIn vivo neuroimaging studies have established several reproducible volumetric sex differences in the human brain, but the causes of such differences are hard to parse. While mouse models are useful for understanding the cellular and mechanistic bases of sex-biased brain development in mammals, there have been no attempts to formally compare mouse and human sex differences across the whole brain to ascertain how well they translate. Addressing this question would shed critical light on use of the mouse as a translational model for sex differences in the human brain and provide insights into the degree to which sex differences in brain volume are conserved across mammals. Here, we use cross-species structural magnetic resonance imaging to carry out the first comparative neuroimaging study of sex-biased neuroanatomical organization of the human and mouse brain. In line with previous findings, we observe that in humans, males have significantly larger and more variable total brain volume; these sex differences are not mirrored in mice. After controlling for total brain volume, we observe modest cross-species congruence in the volumetric effect size of sex across 60 homologous brain regions (r=0.30; e.g.: M>F amygdala, hippocampus, bed nucleus of the stria terminalis, and hypothalamus and F>M anterior cingulate, somatosensory, and primary auditory cortices). This cross-species congruence is greater in the cortex (r=0.33) than non-cortex (r=0.16). By incorporating regional measures of gene expression in both species, we reveal that cortical regions with greater cross-species congruence in volumetric sex differences also show greater cross-species congruence in the expression profile of 2835 homologous genes. This phenomenon differentiates primary sensory regions with high congruence of sex effects and gene expression from limbic cortices where congruence in both these features was weaker between species. These findings help identify aspects of sex-biased brain anatomy present in mice that are retained, lost, or inverted in humans. More broadly, our work provides an empirical basis for targeting mechanistic studies of sex-biased brain development in mice to brain regions that best echo sex-biased brain development in humans.
Multi-scale model of axonal and dendritic polarization by transcranial direct current stimulation in realistic head geometry
Authors: Aberra Aman S. , Wang Ruochen , Grill Warren M. , Peterchev Angel V. 
Published: August 2023

1.AbstractBackgroundTranscranial direct current stimulation (tDCS) is a non-invasive brain stimulation modality that can alter cortical excitability. However, it remains unclear how the subcellular elements of different neuron types are polarized by specific electric field (E-field) distributions.ObjectiveTo quantify neuronal polarization generated by tDCS in a multi-scale computational model.MethodsWe embedded layer-specific, morphologically-realistic cortical neuron models in a finite element model of the E-field in a human head and simulated steady-state polarization generated by conventional primary-motor-cortex–supraorbital (M1–SO) and 4×1 high-definition (HD) tDCS. We quantified somatic, axonal, and dendritic polarization of excitatory pyramidal cells in layers 2/3, 5, and 6, as well as inhibitory interneurons in layers 1 and 4 of the hand knob.ResultsAxonal and dendritic terminals were polarized more than the soma in all neurons, with peak axonal and dendritic polarization of 0.92 mV and 0.21 mV, respectively, compared to peak somatic polarization of 0.07 mV for 1.8 mA M1–SO stimulation. Both montages generated regions of depolarization and hyperpolarization beneath the M1 anode; M1–SO produced slightly stronger, more diffuse polarization peaking in the central sulcus, while 4×1 HD produced higher peak polarization in the gyral crown. Simulating polarization by uniform local E-field approximated the spatial distribution of tDCS polarization but produced large errors in some regions.ConclusionsPolarization of pre- and postsynaptic compartments of excitatory and inhibitory cortical neurons may play a significant role in tDCS neuromodulation. These effects cannot be predicted from the E-field distribution alone but rather require calculation of the neuronal response.
Conditioned pain modulation of pressure pain is associated with reduced activation in the parietal operculum and posterior insula
Authors: Ojala Karita E. , Chu Ying , Finsterbusch Jürgen , Büchel Christian 
Published: August 2023

AbstractConditioned pain modulation (CPM) is the phenomenon of pain inhibiting further pain. CPM is impaired in patients suffering from various chronic pain conditions and may resemble a pro-nociceptive profile. A possible neural mechanism for CPM is descending control from cortical regions via brainstem that modulates neural activity at the level of the dorsal horn of the spinal cord where noxious input first arrives. We studied the involvement of the descending pain modulatory pathway by simultaneous functional imaging of the brain, brainstem, rostral medulla, and cervical spinal cord during CPM with pressure cuff algometry in 42 healthy human participants. Subjective CPM as measured by decreased pain ratings developed over the experiment with application of repeated short test stimuli for long conditioning pain compared with non-painful conditioning. Test stimuli paired with painful conditioning were associated with decreased BOLD fMRI activity in the parietal operculum (secondary somatosensory cortex) and posterior insula, as well as increased responses in bilateral primary somatosensory cortices. Subjective CPM reflected in pain ratings was associated with decreased test stimulus responses in somatosensory and pain-responsive brain regions such as the anterior and posterior insula and the parietal operculum. Conditioning pain and test pain were associated with increased neural activity in stimulus-ipsilateral spinal cord dorsal horn at segment C6 and C4, respectively. No evidence for neural correlates of CPM or associations with subjective CPM was observed in the spinal cord. Functional connectivity between the brain and spinal cord was altered during both conditioning and test pain but did not depend on conditioning intensity. Taken together, we observed neural activity associated with both negative (CPM) and positive modulation of pain in different somatosensory and pain-associated brain regions, and an association of these and other neural responses with subjective CPM. While we found that painful stimuli altered the connectivity along the descending pain modulatory pathway, we did not find evidence for a modulation by conditioning intensity nor neural correlates of CPM in the spinal cord.
Green Index: a widely accessible method to quantify greenness of photosynthetic organisms
Authors: Signorelli Santiago , Casaretto Esteban , Millar A. Harvey 
Published: August 2023

AbstractPlant phenotyping involves the quantitative determination of complex plant traits using image analysis. One important parameter is how green plant tissues appear to the observer, which is indicative of their health and developmental stage. Various formulas have been developed to quantify this by calculating leaf greenness scores. We have developed a revised formula called “Green Index” (GI) devised out of the need to quantitatively assess how the apparent greenness of seedlings changes during de-etiolation. The GI calculation is simple, uses widely available RGB values of pixels in images as input, and does not require commercial software platforms or advanced computational skills. In this study we describe the conception of the GI formula, compare it with other widely used greenness formulas, and test its wider application in plant phenotyping using the open source free software platform RawTherapee. We demonstrate the utility of the GI in addressing common issues encountered in assessing plant biology experiments, underscoring its potential as a reliable and accessible tool. Finally, we explore the correlation between GI and chlorophyll content, assess its reliance on different types of photography, and summarizes the key steps for its effective utilization.
Considerations for the use of laboratory-based and field-based estimates of environmental tolerance in water management decisions for an endangered salmonid
Authors: Zeug Steven C. , Constandache Alex , Cavallo Bradley , Sciences Cramer Fish 
Published: August 2023

AbstractWater infrastructure development and operation provides essential functions for human economic activity, health, and safety, yet this infrastructure can impact native fish populations resulting in legal protections that can, in turn, alter operations. Conflict over water allocation for ecological function and human use has come to the forefront at Shasta Reservoir, the largest water storage facility in California, USA. Shasta Reservoir supports irrigation for a multibillion-dollar agricultural industry, provides water for urban and domestic use, provides flood protection for downstream communities, and power generation as part of the larger Central Valley Project in California. Additionally, an endangered run of Chinook Salmon relies on cold water management at the dam for successful spawning and egg incubation. Tradeoffs between these uses can be explored through application of models that assess biological outcomes associated with flow and temperature management scenarios. However, the utility of models for management decisions are contingent on their characteristics, data used to construct them, and data collected to evaluate their predictions. We evaluated laboratory and field data currently available to parameterize temperature-egg survival models for winter run Chinook Salmon that are used to inform Shasta Dam operations. Models based on both laboratory and field data types had poor predictive performance which limits their value for management decisions. The sources of uncertainty that led to poor performance were different for each data type (field or laboratory) but were rooted in the fact that neither data set was collected with the intention to be used in a predictive model. Our findings suggest that if a predictive model is desired to evaluate operational tradeoffs, data must be collected for the specific variables desired, over an appropriate range of values, and at sufficient frequency to achieve the needed level of precision to address the modeling objective.
Domain-PFP: Protein Function Prediction Using Function-Aware Domain Embedding Representations
Authors: Ibtehaz Nabil , Kagaya Yuki , Kihara Daisuke 
Published: August 2023

AbstractDomains are functional and structural units of proteins that govern various biological functions performed by the proteins. Therefore, the characterization of domains in a protein can serve as a proper functional representation of proteins. Here, we employ a self-supervised protocol to derive functionally consistent representations for domains by learning domain-Gene Ontology (GO) co-occurrences and associations. The domain embeddings we constructed turned out to be effective in performing actual function prediction tasks. Extensive evaluations showed that protein representations using the domain embeddings are superior to those of large-scale protein language models in GO prediction tasks. Moreover, the new function prediction method built on the domain embeddings, named Domain-PFP, significantly outperformed the state-of-the-art function predictors. Additionally, Domain-PFP demonstrated competitive performance in the CAFA3 evaluation, achieving overall the best performance among the top teams that participated in the assessment.
α-Synuclein emulsifies TDP-43 prion-like domain – RNA liquid droplets to promote heterotypic amyloid fibrils
Authors: Dhakal Shailendra , Mondal Malay , Mirzazadeh Azin , Banerjee Siddhartha , Ghosh Ayanjeet , Rangachari Vijayaraghavan 
Published: August 2023

AbstractMany neurodegenerative diseases including frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA), etc., show colocalized deposits of TDP-43 and α-synuclein (αS) aggregates. To understand whether these colocalizations are driven by specific molecular interactions between the two proteins, we previously showed that the prion-like C-terminal domain of TDP-43 (TDP-43PrLD) and αS synergistically interact to form neurotoxic heterotypic amyloids in homogeneous buffer conditions. However, it remains unclear whether and how αS modulates TDP-43 present within liquid droplets and biomolecular condensates called stress granules (SGs). Here, using cell culture and in vitro TDP-43PrLD – RNA liquid droplets as models along with microscopy, nanoscale spatially-resolved spectroscopy, and other biophysical analyses, we uncover the interactions of αS with phase-separated droplets. We learn that αS acts as a Pickering agent by forming clusters on the surface of TDP-43PrLD – RNA droplets and emulsifying them. The ‘hardening’ of the droplets that follow by αS aggregates on the periphery, nucleates the formation of heterotypic TDP-43PrLD amyloid fibrils with structures distinct from those derived from homogenous solutions. Together, these results reveal an intriguing property of αS as a Pickering agent in interacting with SGs and unmask the hitherto unknown role of αS in modulating TDP-43 proteinopathies.
Gut microbiome remains stable following COVID-19 vaccination in healthy and immuno-compromised individuals
Authors: Boston Rebecca H. , Guan Rui , Kalmar Lajos , Beier Sina , Horner Emily C. , Beristain-Covarrubias Nonantzin , Yam-Puc Juan Carlos , Gerber Pehuén Pereyra , Faria Luisa , Kuroshchenkova Anna , Lindell Anna E. , Blasche Sonja , Correa-Noguera Andrea , Elmer Anne , Saunders Caroline , Bermperi Areti , Jose Sherly , Kingston Nathalie ,   CITIID-NIHR COVID-19 BioResource Collaboration, Grigoriadou Sofia , Staples Emily , Buckland Matthew S. , Lear Sara , Matheson Nicholas J. , Benes Vladimir , Parkinson Christine , Thaventhiran James E. D. , Patil Kiran R. 
Published: August 2023

AbstractThe bidirectional interaction between the immune system and the gut microbiota is a key contributor to various host physiological functions. Immune-associated diseases such as cancer and autoimmunity, as well as the efficacy of immunomodulatory therapies, have been linked to microbiome variation. While COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immunomodulating therapies. We find that the gut microbiome remained remarkably stable post-vaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results indicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings encourage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection.
Designing Efficient Enzymes: Eight Predicted Mutations Convert a Hydroxynitrile Lyase into an Efficient Esterase
Authors: Casadevall Guillem , Pierce Colin , Guan Bo , Iglesias-Fernandez Javier , Lim Huey-Yee , Greenberg Lauren R. , Walsh Meghan E. , Shi Ke , Gordon Wendy , Aihara Hideki , Evans Robert L. , Kazlauskas Romas , Osuna Sílvia 
Published: August 2023

AbstractHydroxynitrile lyase from rubber tree (HbHNL) shares 45% identical amino acid residues with the homologous esterase from tobacco, SABP2, but the two enzymes catalyze different reactions. The x-ray structures reveal a serine-histidine-aspartate catalytic triad in both enzymes along with several differing amino acid residues within the active site. Previous exchange of three amino acid residues in the active site ofHbHNL with the corresponding amino acid residue in SABP2 (T11G-E79H-K236M) created variant HNL3, which showed low esterase activity toward p-nitrophenyl acetate. Further structure comparison reveals additional differences surrounding the active site.HbHNL contains an improperly positioned oxyanion hole residue and differing solvation of the catalytic aspartate. We hypothesized that correcting these structural differences would impart good esterase activity on the corresponding HbHNL variant. To predict the amino acid substitutions needed to correct the structure, we calculated shortest path maps for bothHbHNL and SABP2, which reveal correlated movements of amino acids in the two enzymes. Replacing four amino acid residues (C81L-N104T-V106F-G176S) whose movements are connected to the movements of the catalytic residues yielded variant HNL7TV (stabilizing substitution H103V was also added), which showed an esterase catalytic efficiency comparable to that of SABP2. The x-ray structure of an intermediate variant, HNL6V, showed an altered solvation of the catalytic aspartate and a partially corrected oxyanion hole. This dramatic increase in catalytic efficiency demonstrates the ability of shortest path maps to predict which residues outside the active site contribute to catalytic activity.