bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beyond pathologist-level annotation of large-scale cancer histology for semantic segmentation using immunofluorescence restaining
Authors: Komura Daisuke , Onoyama Takumi , Shinbo Koki , Odaka Hiroto , Hayakawa Minako , Ochi Mieko , Herdiantoputri Ranny , Sakamoto Kei , Katoh Hiroto , Ikeda Tohru , Ushiku Tetsuo , Ishikawa Shumpei 
Published: May 2022

AbstractNumerous cancer histopathology specimens have been collected and digitised as whole slide images over the past few decades. A comprehensive evaluation of the distribution of various cells in a section of tumour tissue can provide valuable information for understanding cancer and making accurate cancer diagnoses. Deep learning is one of the most suitable techniques to achieve these goals; however, the collection of large, unbiased training data has been a barrier to producing accurate segmentation models. Here, we developed a pipeline to generate SegPath, the largest annotation dataset that is over one order of magnitude larger than publicly available annotations, for the segmentation of haematoxylin and eosin (H&E)-stained sections for eight major cell types. The pipeline used H&E-stained sections that were destained and subsequently immunofluorescence-stained with carefully selected antibodies. The results showed that SegPath is comparable to, or significantly outperforms, conventional pathologist annotations. Moreover, we revealed that annotations by pathologists are biased toward typical morphologies; however, the model trained on SegPath can overcome this limitation. Our results provide foundational datasets for the histopathology machine learning community.
Extended DNA binding interface beyond the canonical SAP domain contributes to SDE2 function at DNA replication forks
Authors: Weinheimer Alexandra S. , Paung YiTing , Rageul Julie , Khan Arafat , Ho Brian , Tong Michael , Alphonse Sébastien , Seeliger Markus A. , Kim Hyungjin 
Published: May 2022

ABSTRACTElevated DNA replication stress causes instability of the DNA replication fork and DNA mutations, which underlies tumorigenesis. The DNA replication stress regulator SDE2 binds to TIMELESS (TIM) of the fork protection complex (FPC) and enhances its stability, thereby supporting replisome activity at DNA replication forks. Here, we structurally and functionally characterize a new conserved DNA binding motif related to SAP (SAF-A/B, Acinus, PIAS) in human SDE2 and establish its preference for single-stranded DNA (ssDNA). The nuclear magnetic resonance solution structure of SDE2SAP reveals a helix-extended loop-helix core aligned parallel to each other, consistent with known canonical SAP folds. Notably, its DNA interaction extends beyond the core SAP domain and is augmented by two lysine residues in the C-terminal tail, which is uniquely positioned adjacent to SAP and conserved in the pre-mRNA splicing factor SF3A3. Mutation in the SAP domain with extended C-terminus not only disrupts ssDNA binding but also impairs TIM localization at replication forks, thus inhibiting efficient fork progression. Together, our study establishes SDE2SAP as an essential element for SDE2 to exert its role in preserving replication fork integrity via FPC regulation and highlights the structural diversity of the DNA-protein interactions achieved by a specialized DNA binding motif.
Evolution avoids a pathological stabilizing interaction in the immune protein S100A9
Authors: Harman Joseph L. , Reardon Patrick N. , Costello Shawn M. , Warren Gus D. , Phillips Sophia R. , Connor Patrick J. , Marqusee Susan , Harms Michael J. 
Published: May 2022

ABSTRACTStability constrains evolution. While much is known about constraints on destabilizing mutations, less is known about the constraints on stabilizing mutations. We recently identified a mutation in the innate immune protein S100A9 that provides insight into such constraints. When introduced into human S100A9, M63F simultaneously increases the stability of the protein and disrupts its natural ability to activate Toll-like receptor 4. Using chemical denaturation, we found that M63F stabilizes a calcium-bound conformation of hS100A9. We then used NMR to solve the structure of the mutant protein, revealing that the mutation distorts the hydrophobic binding surface of hS100A9, explaining its deleterious effect on function. Hydrogen deuterium exchange (HDX) experiments revealed stabilization of the region around M63F in the structure, notably Phe37. In the structure of the M63F mutant, the Phe37 and Phe63 sidechains are in contact, plausibly forming an edge-face ν-stack. Mutating Phe37 to Leu abolished the stabilizing effect of M63F as probed by both chemical denaturation and HDX. It also restored the biological activity of S100A9 disrupted by M63F. These findings reveal that Phe63 creates a “molecular staple” with Phe37 that stabilizes a non-functional conformation of the protein, thus disrupting function. Using a bioinformatic analysis, we found that S100A9 proteins from different organisms rarely have Phe at both positions 37 and 63, suggesting that avoiding a pathological stabilizing interaction indeed constrains S100A9 evolution. This work highlights an important evolutionary constraint on stabilizing mutations: they must avoid inappropriately stabilizing non-functional protein conformations.SIGNIFICANCE STATEMENTProtein stability constrains protein evolution. While much is known about evolutionary constraints on destabilizing mutations, less is known about the constraints on stabilizing mutations. We recently found a mutation to an innate immune protein that increases its stability but disrupts its function. Here we show, through careful biophysical and functional studies, that this mutation stabilizes a nonfunctional form of the protein through a direct interaction with another amino acid. We find that specific amino acids can be tolerated at each of the interacting positions individually, but not at both simultaneously. This pattern has been conserved over millions of years of evolution. Our work highlights an underappreciated evolutionary constraint on stabilizing mutations: they must avoid inappropriately stabilizing non-functional protein conformations.
Computational modeling of TGF-β2:TβRI:TβRII receptor complex assembly as mediated by the TGF-β co-receptor betaglycan
Authors: Ingle Michelle , Madamanchi Asakiran , Hinck Andrew P. , Umulis David 
Published: May 2022

AbstractTransforming growth factor-β1, -β2, and -β3 (TGF-β1, -β2, and -β3) are secreted signaling ligands that play essential roles in tissue development, tissue maintenance, immune response, and wound healing. TGF-β homodimers signal by assembling a heterotetrameric complex comprised of two type I receptor (TβRI):type II receptor (TβRII) pairs. TGF-β1 and TGF-β3 signal with high potency due to their high affinity for TβRII, which engenders high affinity binding of TβRI through a composite TGF-β:TβRII binding interface. However, TGF-β2 binds TβRII 200-500 more weakly than TβRII and signals with lower potency compared to TGF-β1 and -β3. Remarkably, potency of TGF-β2 is increased to that of TGF-β1 and -β3 in the presence of an additional membrane-bound co-receptor, known as betaglycan (BG), even though betaglycan does not directly participate in the signaling mechanism and is displaced as the signaling receptors, TβRI and TβRII, bind. To determine the role of betaglycan in the potentiation of TGF-β2 signaling, we developed deterministic computational models with different modes of betaglycan binding and varying cooperativity between receptor subtypes. The models, which were developed using published kinetic rate constants for known quantities and optimization to determine unknown quantities, identified conditions for selective enhancement of TGF-β2 signaling. The models provide support for additional receptor binding cooperativity that has been hypothesized, but not evaluated in the literature. The models further showed that betaglycan binding to TGF-β2 ligand through two domains provides an effective mechanism for transfer to the signaling receptors that has been tuned to efficiently promote assembly of the TGF-β2(TβRII)2(TβRI)2 signaling complex.
Evolutionary ecology of microbial populations inhabiting deep sea sediments associated with cold seeps
Authors: Dong Xiyang , Peng Yongyi , Wang Muhua , Woods Laura , Wu Wenxue , Wang Yong , Xiao Xi , Li Jiwei , Jia Kuntong , Greening Chris , Shao Zongze , Hubert Casey R.J. 
Published: May 2022

AbstractDeep sea cold seep sediments host abundant and diverse bacterial and archaeal populations that significantly influence biogeochemical cycles. While numerous studies have revealed the community structure and functional capabilities of cold seep microbiomes, little is known about their genetic heterogeneity within species. Here, we examined intraspecies diversity patterns of 39 abundant species identified in sediment layers down to 4.3 mbsf across six cold seep sites from around the world. These species were predicted to participate in methane oxidation and sulfate reduction, and based on their metabolic capabilities, grouped as aerobic methane-oxidizing bacteria (MOB), anaerobic methanotrophic archaea (ANME) and sulfate-reducing bacteria (SRB). These physiologically and phylogenetically diverse MOB, ANME and SRB display different degrees of intrapopulation sequence divergence and different evolutionary trajectories. Populations were in general characterized by low rates of homologous recombination and strong purifying selection with most of the nucleotide variation being synonymous. Functional genes related to methane (pmoAandmcrA) and sulfate (dsrA) metabolisms were found to be under strong purifying selection in the vast majority of species investigated, although examples of active positive selection were also observed. These genes differed in evolutionary trajectories across phylogenetic clades but are functionally conserved across cold seep sites. Intrapopulation diversification of MOB, ANME and SRB species as well as theirmcrAanddsrAgenes was observed to be depth-dependent and undergo divergent selection pressures throughout the sediment column. These results highlight the role of the interplay between ecological processes and the evolution of key bacteria and archaea in deep sea cold seep sediments and shed light on how microbial populations adapt in the subseafloor biosphere.
Design guidelines for α-helical peptides that self-assemble into transmembrane barrel pores killing antibiotic-resistant bacteria
Authors: Deb Rahul , Kabelka Ivo , Přibyl Jan , Vreeker Edo , Maglia Giovanni , Vácha Robert 
Published: May 2022

ABSTRACTDe novo design of peptides that self-assemble into transmembrane barrel-like nanopore structures is challenging due to the complexity of several competing interactions involving peptides, lipids, water, and ions. Here, we develop a computational approach for the de novo design of α-helical peptides that self-assemble into stable and large transmembrane barrel pores with a central nano-sized functional channel. We address the lack of existing design guidelines for the de novo pore-forming peptides and propose 52 sequence patterns, each of which can be tailored for different applications using the identified role of its residues. Atomic force microscopy, channel electrical recording, leakage of small fluorescent molecule and transport of macromolecule experiments confirm that the designed peptides form stable, large, and functional barrel-shaped nanopores in model membranes. The custom-designed peptides act as potent antimicrobial agents able to kill even antibiotic-resistant ESKAPE bacteria at micromolar concentrations, while exhibiting low toxicity to human cells. Peptides and their assembled nanopore structures can be similarly fine-tuned for other medical and biotechnological applications.
Genomic detection of a secondary family burial in a single jar coffin in early Medieval Korea
Authors: Lee Don-Nyeong , Jeon Chae Lin , Kang Jiwon , Burri Marta , Krause Johannes , Woo Eun Jin , Jeong Choongwon 
Published: May 2022

AbstractObjectivesFamily relationship is a key to understand the structure of past societies but its archaeological reconstruction mostly stays circumstantial. Archaeogenetic information, especially genome-wide data, provide an objective approach to accurately reconstruct the familial relationship of ancient individuals, thus allowing a robust test of an archaeology-driven hypothesis of kinship. In this study, we applied this approach to disentangle the genetic relationship of early Medieval individuals from Korea, who were secondarily co-buried in a single jar coffin.Materials and MethodsWe obtained genome-wide data of six early Medieval Korean individuals from a jar coffin. We inferred the genetic relatedness between these individuals and characterized their genetic profiles using well-established population genetics methods.ResultsCongruent with the unusual pattern of multiple individuals in a single jar coffin, genome-wide analysis of these individuals shows that they form an extended family, including a couple, their two children and both paternal and maternal relatives. We show that these early Medieval Koreans have a genetic profile similar to present-day Koreans.DiscussionWe show that an unusual case of a secondary multiple burial in a single jar coffin reflects family relationship among the co-buried individuals. We find both paternal and maternal relatives coburied with the nuclear family, which may suggest a family structure with limited gender bias. We find the genetic profile of early Medieval Koreans similar to that of present-day Koreans, suggesting no substantial genetic shift in the Korean peninsula for the last 1,500 years.Research HighlightsAncient genome-wide data find a family buried together in a jar coffin in early Medieval Korea.These early Medieval Koreans have a genetic profile similar to present-day Koreans.
Flexible cognition in context-modulated reservoir networks
Authors: Masse Nicolas Y. , Rosen Matthew C. , Tsao Doris Y. , Freedman David J. 
Published: May 2022

AbstractThe brains of all animals are plastic, allowing us to form new memories, adapt to new environments, and to learn new tasks. What is less clear is how much plasticity is required to perform these cognitive functions: does learning require widespread plasticity across the brain, or can learning occur with more rigid networks, in which plasticity is highly localized? Here, we use biologically-inspired recurrent neural network (RNN) models to show that rapid multitask learning can be accomplished in reservoir-style networks, in which synaptic plasticity is sparse and highly localized. Crucially, only RNNs initialized with highly specific combinations of network properties, such as topology, normalization and reciprocal connection strength, are capable of such learning. Finally, we show that this rapid learning with localized plasticity can be accomplished with purely local error signals, without backpropagation, using a reinforcement learning setup. This work suggests that rapid learning in artificial (and potentially biological) agents can be accomplished with mostly-rigid networks, in which synaptic plasticity is highly constrained.
Lyme Disease IgG N-linked Glycans Contrast the Canonical Inflammatory Signature
Authors: Haslund-Gourley Benjamin Samuel , Grauzam Stéphane , Mehta Anand S. , Wigdahl Brian , Comunale Mary Ann 
Published: May 2022

AbstractLyme disease (LD) infection is caused byBorrelia burgdorferisensulato. Due to the limited presence of this pathogen in the bloodstream in humans, diagnosis of LD relies on seroconversion. Immunoglobulins produced in response to infection are differentially glycosylated to promote or inhibit downstream inflammatory responses by the immune system. IgG N-glycan responses to LD have not been characterized. In this study, we analyzed IgG N-glycans from cohorts of healthy controls, acute LD patient serum, and serum collected after acute LD patients completed a 2- to 3-week course of antibiotics and convalesced for 70-90 days. Results indicate that during the acute phase of Bb infection, IgG shifts its glycosylation profile to include structures that are not associated with the classic proinflammatory IgG N-glycan signature. This unexpected result is in direct contrast to what is reported for other inflammatory diseases. Furthermore, IgG N-glycans detected during acute LD infection discriminated between control, acute, and treated cohorts with a sensitivity of 75-100% and specificity of 94.7-100%.Author summaryThe causative agent of Lyme disease (LD), Borrelia burgdorferi sensu lato (Bb), is transmitted from an infected Ixodes tick into the human host dermis during the tick’s blood meal. Currently, LD is the most prevalent vector-borne disease in the US, with an estimated 476,000 annual cases. LD diagnostics rely on patient seroconversion against Bb antigens, and these tests cannot distinguish between an acute patient compared to a patient previously treated for LD. With the goal of identifying novel biomarkers associated specifically with LD infections, we analyzed the glycoprotein Immunoglobulin G (IgG) N-glycan signatures from healthy control, acute LD, and a second time point composed of the same LD patients after antibiotic therapy. We found acute LD IgG N-glycan signatures were significantly different from the canonical pro-inflammatory profile associated with most inflammatory diseases. The dramatic shifts observed in the acute LD time point were further altered at the treated time point. IgG N-glycan signature data was employed to discriminate between acute LD and healthy controls. In addition, IgG N-glycan signatures distinguished patients who completed antibiotic therapy from the acute LD timepoint. Our study will contribute to the accurate and prompt treatment of LD patients and reveals a new research avenue of immune dysregulation associated with LD.Graphical Abstract
Primate mothers promote proximity between their offspring and infants who look like them
Authors: Charpentier Marie J. E. , Poirotte Clémence , Roura-Torres Berta , Amblard-Rambert Paul , Willaume Eric , Kappeler Peter M. , Rousset François , Renoult Julien P. 
Published: May 2022

AbstractBehavioral discrimination of kin is a key process structuring social relationships in animals. In this study, we provide a first example of discrimination towards non-kin by third-parties through a mechanism of phenotype matching. In mandrills, we recently demonstrated increased facial resemblance among paternally-related juvenile and adult females indicating adaptive opportunities for paternal kin recognition. Here, we hypothesize that mothers use offspring’s facial resemblance with other infants to guide offspring’s social opportunities towards similarly-looking ones. Using deep learning for face recognition in 80 wild mandrill infants, we first show that infants born to the same father or conceived during the tenure of the same alpha male resemble each other the most, independently of their age, sex or maternal origin, extending previous results to the youngest age class. Using long-term behavioral observations on association patterns and controlling for matrilineal origin, maternal relatedness and infant age and sex, we then demonstrate that, as hypothesized, mothers are spatially closer to infants that resemble their own offspring more, thereby facilitating associations among similar-looking infants. Using theoretical modeling, we describe a plausible evolutionary process whereby mothers gain fitness benefits by promoting nepotism among paternally related infants. This mechanism, that we call “second-order kin selection”, may extend beyond mother-infant interactions and has the potential to explain cooperative behaviors among non-kin in social species, including humans.
Insulin regulates systemic lipid traffic in starving animals
Authors: Trautenberg Laura Christin , Fedorova Maria , Brankatschk Marko 
Published: May 2022

AbstractIn periods of malnutrition starving organisms initiate the reorganization and degradation of cellular lipids. Yet, the build-up of lipid stores is reported in animals entering early starvation stages. Anabolic lipid metabolism is regulated by many circuits including the insulin/insulin- like growth factor signaling (IIS) cascade. The regulative role of IIS ligands in food deprived animals is often neglected, since supporting evidence for this notion is largely missing.Here we show that in starving adult Drosophila melanogaster IIS is required to stabilize the transport of circulating lipids and sugars, and is essential for the initial increase of lipid stores in fat body cells. Further, we demonstrate that the Drosophila insulin-like peptides (dIlp) 2 and 5 regulate the cellular IIS cascade differentially. To its end we speculate that each hormone initiates complementary measures that increase the starvation resistance of adult flies.
FunOMIC: Pipeline with built-in Fungal Taxonomic and Functional Databases for Human Mycobiome Profiling
Authors: Xie Zixuan , Manichanh Chaysavanh 
Published: May 2022

AbstractWhile analysis of the bacterial microbiome has become routine, that of the fungal microbiome is still hampered by the lack of robust databases and bioinformatic pipelines. Here, we present FunOMIC, a pipeline with built-in taxonomic (1.6 million marker genes) and functional (3.4 million non-redundant fungal proteins) databases for the identification of fungi. Applied to more than 2,600 human metagenomic samples, the tool revealed fungal species associated with geography, body sites, and diseases. Correlation network analysis provided new insights into inter-kingdom interactions. With this pipeline and two of the most comprehensive fungal databases, we foresee a fast-growing resource for mycobiome studies.
Mesocosm experiments reveal the loss of migratory tendencies in a recently isolated population of three-spined sticklebacks
Authors: Ramesh A. , Gismann J. , Groothuis T.G.G. , Weissing F.J. , Nicolaus M. 
Published: May 2022

AbstractIn the 1970s, water management in the Netherlands resulted in numerous isolated populations of three-spined sticklebacks, which can no longer migrate from freshwater to the sea. We tested whether ∼50 years of isolation resulted in reduced migratory tendencies in these ‘resident’ sticklebacks. Lab-based individual testing showed behavioural divergence between residents and migrants, but also produced counter-intuitive results, especially with regards to movement tendencies. To detect differences in migration tendencies, we set up a semi-natural mesocosm, consisting of connected ponds, where movements of numerous individuals could continually be tracked at larger spatial scales. We found that wild-caught residents and migrants exhibited no differences in movement tendencies ‘within ponds’, but residents moved significantly less ‘between ponds’ than migrants. Between-pond movements were consistent and the observed differences were robust across contexts (changes in water flow and group size). Our study reveals that larger-scale movement tendencies can diverge over short time scales in response to human-induced isolation, and highlights the importance of observing behaviour in ecologically relevant setups that bridge the gap between lab and field studies.