bluuebunny/crossref_metadata_2025 huggingface dataset:
Mosaic patterns of selection in genomic regions associated with diverse human traits
Authors: Abraham Abin , LaBella Abigail L. , Capra John A. , Rokas Antonis
Published: May 2022

Natural selection shapes the genetic architecture of many human traits. However, the prevalence of different modes of selection on genomic regions associated with variation in traits remains poorly understood. To address this, we developed an efficient computational framework to calculate enrichment of different evolutionary measures among regions associated with complex traits. We applied the framework to summary statistics from >900 genome-wide association studies (GWASs) and 11 evolutionary measures of sequence constraint, population differentiation, and allele age while accounting for linkage disequilibrium, allele frequency, and other potential confounders. We demonstrate that this framework yields consistent results across GWASs with variable sample sizes, numbers of trait-associated SNPs, and analytical approaches. The resulting evolutionary atlas maps diverse signatures of selection on genomic regions associated with complex human traits on an unprecedented scale. We detected positive enrichment for sequence conservation among trait-associated regions for the majority of traits (>77% of 290 high power GWASs), which was most dominant in reproductive traits. Many traits also exhibited substantial enrichment for population differentiation and recent positive selection, especially among hair, skin, and pigmentation traits. In contrast, we detected widespread negative enrichment for balancing selection (51% GWASs) and no evidence of enrichment for selection signals in regions associated with late-onset Alzheimer’s disease. These results support a pervasive role for negative selection on regions of the human genome that contribute to variation in complex traits, but also demonstrate where diverse modes of selection have shaped trait-associated loci. This atlas of signatures of different modes of natural selection across the diversity of available GWASs will enable exploration of the relationship between the genetic architecture and selection in the human genome.
Effects of larval and adult crowding on fitness components in Drosophila populations adapted to larval crowding experienced under different combinations of food amount and egg number
Authors: Pandey Neha , Malhotra Rishabh , Joshi Amitabh
Published: May 2022

Since the realization in the 1970s that simple discrete-time population growth models can show complex unstable dynamics of population size, many explanations were proposed for the evolution of enhanced population stability. The most plausible of these was density-dependent selection, suggested to favour greater stability due to r-K trade-offs. However, the first experiment aimed at testing this prediction revealed that Drosophila melanogaster populations adapted to larval crowding did not evolve greater constancy stability than their ancestral controls. A subsequent study showed that D. ananassae populations adapted to larval crowding had evolved greater constancy and persistence than ancestral controls. These D. ananassae populations had experienced chronic larval crowding in conditions of very low amounts of food, whereas the earlier studied D. melanogaster populations had experienced chronic larval crowding at fairly high food amounts. Further theoretical work also suggested that populations adapting to crowding could evolve greater stability even in the absence of r-K trade-offs. Most recently, studies in our laboratory showed that two sets of crowding adapted D. melanogaster populations, derived from a common ancestral lineage, which differed in the food amounts at which they experienced larval crowding, evolved different patterns of constancy and persistence stability. These two sets of populations also differed in the traits, e.g. larval feeding rate, that evolved as they became more competitive. Here, we examine the response of key fitness components to larval and adult densities in these two sets of populations, to see whether differences in their stability attributes can be explained by variation in how their life-histories respond to crowding at different life stages. Of all traits examined, only pre-adult survivorship responded differently to larval density across the two sets of populations. The populations that adapted to larval crowding at low food amounts showed reduced sensitivity of pre-adult survivorship to larval density, compared to those that adapted to larval crowding at high food amounts. We discuss our results in the context of different ways in which density-dependent selection may facilitate the evolution of greater constancy or persistence, depending on the ecological details of how crowding was experienced.
A data-driven approach to quantifying meal characteristics influencing energy intake
Authors: Fazzino Tera L. , Courville Amber B. , Guo Juen , Hall Kevin D.
Published: May 2022

We used a data-driven approach to determine the influence of energy density, hyper-palatability, protein content, and eating rate on ad libitum non-beverage energy intake during 2733 meals consumed by 35 inpatient adults who participated in two 28-day feeding studies. All four meal characteristics significantly contributed to energy intake, but their relative importance varied by the prevailing dietary pattern according to macronutrient composition and degree of processing.
Searching for mates may shape the immune response and parental investments
Authors: Sevgili Hasan
Published: May 2022

In the sexual reproduction model, a wide variety of strategies have emerged in different animal species for individuals to pursue the opposite sex for mating purposes. Many ways (such as chemical signals and calling songs) are utilized to stimulate or invite the other sex. This may lead to differential evolution of sexes in a species. For example, the limitations in signal production or perception of one of the sexes can make this sex sedentary, therefore strategies in pursuing mates evolve diversely among sexes. In this context, McCartney et al. (2012) proposed a theory to explain the differentiation of the mate-searching system in some species of Poecilimon bushcrickets and the reasons for the change in the sexual roles in the search. The aim of the present study was the testing of this theory proposed by McCartney et al. (2012) for Poecilimon species on spermatophore investment, with two species (P. sureyanus-female searching and P. inflatus- male searching), which have different strategies in terms of females’ response to male calling songs. Reproductive effort and physiological activities are both costly for the organism, and these traits belie a trade-off due to the limited energetic resources. Therefore, some immune parameters (Phenoloxidase and lytic activities) of these two species were compared within the context of the allocation of resources resulting from the trade-off between reproductive functions and immune defence. Immune activities are much more plastic in nature than the differentiation of reproductive traits among sexes. The results of this study showed that a mate searching strategy difference, based on the female’s ability to respond to male call sounds -which must acoustically communicate for reproduction-may play a decisive role in both spermatophore and immune activities. On the other hand, the findings also indicated that there may be trade-offs between the costs related to reproduction and the immune system. In addition, it has been revealed that there may be a trade-off between the immune activities and the differences between sexes. On the other hand, our data indicated that the duration of morphogenesis did not have a decisive role on spermatophore and sperm allocation in bushcrickets.
Characterization of a nanobody-epitope tag interaction and its application for receptor engineering
Authors: Cabalteja Chino C. , Sachdev Shivani , Cheloha Ross W.
Published: May 2022

Peptide epitope tags offer a valuable means for detection and manipulation of protein targets for which high quality detection reagents are not available. Most commonly used epitope tags are bound by conventional, full-size antibodies (Abs). The complex architecture of Abs complicates their application in protein engineering and intracellular applications. To address these shortcomings, single domain antibodies (nanobodies, Nbs) that recognize short peptide epitopes have become increasingly prized. Here we characterize the interaction between a Nb (Nb6E) and a 14-mer peptide epitope. We identify residues in the peptide epitope essential for high affinity binding. Using this information in combination with computational modeling we propose a mode of interaction between Nb6E and this epitope. We apply this nanobody-epitope pair to augment the potency of a ligand at an engineered adenosine A2A receptor. This characterization of the nanobody-epitope pair opens the door to diverse applications including mechanistic studies of G protein-coupled receptor function.
Imprinted antibody responses against SARS-CoV-2 Omicron sublineages
Authors: Park Young-Jun , Pinto Dora , Walls Alexandra C. , Liu Zhuoming , De Marco Anna , Benigni Fabio , Zatta Fabrizia , Silacci-Fregni Chiara , Bassi Jessica , Sprouse Kaitlin R. , Addetia Amin , Bowen John E. , Stewart Cameron , Giurdanella Martina , Saliba Christian , Guarino Barbara , Schmid Michael A. , Franko Nicholas , Logue Jennifer , Dang Ha V. , Hauser Kevin , di Iulio Julia , Rivera William , Schnell Gretja , Rajesh Anushka , Zhou Jiayi , Farhat Nisar , Kaiser Hannah , Montiel-Ruiz Martin , Noack Julia , Lempp Florian A. , Janer Javier , Abdelnabi Rana , Maes Piet , Ferrari Paolo , Ceschi Alessandro , Giannini Olivier , Dias de Melo Guilherme , Kergoat Lauriane , Bourhy Hervé , Neyts Johan , Soriaga Leah , Purcell Lisa A. , Snell Gyorgy , Whelan Sean P.J. , Lanzavecchia Antonio , Virgin Herbert W. , Piccoli Luca , Chu Helen , Pizzuto Matteo Samuele , Corti Davide , Veesler David
Published: May 2022

SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters result in potent plasma neutralizing activity against Omicron BA.1 and BA.2 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1 and BA.2 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity. While most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant antibody, that is unaffected by any Omicron lineage spike mutations and is a strong candidate for clinical development.
Secreted cytokines provide local immune tolerance for human stem cell-derived islets
Authors: Gerace Dario , Zhou Quan , Kenty Jennifer Hyoje-Ryu , Sintov Elad , Wang Xi , Boulanger Kyle R , Li Hongfei , Melton Douglas A
Published: May 2022

Immunological protection of transplanted stem cell-derived islet (SC-islet) cells is yet to be achieved without chronic immunosuppression or encapsulation. Existing genetic engineering approaches to produce hypoimmunogenic SC-islet cells have so far shown variable results. Here, we show that targeting the human leukocyte antigens (HLAs) and PD-L1 alone do not sufficiently protect SC-islet cells from xeno- or allo-rejection. As an addition to these approaches, we genetically engineered SC-islet cells to secrete the cytokines IL-10, TGF-β and modified IL-2 such that they promote a tolerogenic local microenvironment by activating and expanding regulatory T cells (Tregs). These cytokine-secreting human SC-islet cells prevented xeno-rejection for up to 9 weeks post-transplantation in B6/albino mice. Thus, hESCs engineered to induce a tolerogenic local microenvironment may represent a source of replacement SC-islet cells that do not require encapsulation or immunosuppression for diabetes cell replacement therapy.
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

Numerous 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

Elevated 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

Stability 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 STATEMENT

Protein 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

Transforming 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

Deep 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

De 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

Objectives

Family 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 Methods

We 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.

Results

Congruent 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.

Discussion

We 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 Highlights

Ancient 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

The 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

Lyme 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 summary

The 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

Behavioral 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

In 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

While 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

In 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.
DistilProtBert: A distilled protein language model used to distinguish between real proteins and their randomly shuffled counterparts
Authors: Geffen Yaron , Ofran Yanay , Unger Ron
Published: May 2022

Recently, Deep Learning models, initially developed in the field of Natural Language Processing (NLP), were applied successfully to analyze protein sequences. A major drawback of these models is their size in terms of the number of parameters needed to be fitted and the amount of computational resources they require. Recently, “distilled” models using the concept of student and teacher networks have been widely used in NLP. Here, we adapted this concept to the problem of protein sequence analysis, by developing DistilProtBert, a distilled version of the successful ProtBert model. Implementing this approach, we reduced the size of the network and the running time by 50%, and the computational resources needed for pretraining by 98% relative to ProtBert model. Using two published tasks, we showed that the performance of the distilled model approaches that of the full model. We next tested the ability of DistilProtBert to distinguish between real and random protein sequences. The task is highly challenging if the composition is maintained on the level of singlet, doublet and triplet amino acids. Indeed, traditional machine learning algorithms have difficulties with this task. Here, we show that DistilProtBert preforms very well on singlet, doublet, and even triplet-shuffled versions of the human proteome, with AUC of 0.92, 0.91, and 0.87 respectively. Finally, we suggest that by examining the small number of false-positive classifications (i.e., shuffled sequences classified as proteins by DistilProtBert) we may be able to identify de-novo potential natural-like proteins based on random shuffling of amino acid sequences.

Availability

https://github.com/yarongef/DistilProtBert

Contact

yaron.geffen@biu.ac.il
Derivation of the Relationship Between the Mass and Lifespan of Living Organisms
Authors: Shyian Anatolii
Published: May 2022

Annotation

The relation p=1-a between exponents, by which the dependencies of lifespan p and growth intensity a on masses of living organisms are described, is obtained and testified.
Rapid covalent labeling of a GPCR on living cells using a nanobody-epitope tag pair to interrogate receptor pharmacology
Authors: Cabalteja Chino C. , Cheloha Ross W.
Published: May 2022

Synthetic molecules that form a covalent bond upon binding to a targeted biomolecule (proximity-induced reactivity) are the subject of intense biomedical interest for the unique pharmacological properties imparted by irreversible binding. However, off-target covalent labeling and the lack of molecules with sufficient specificity limit more widespread applications. We describe the first example of a crosslinking platform that uses a synthetic peptide epitope and a single domain antibody (or nanobody) pair to form a covalent linkage rapidly and specifically. The rate of the crosslinking reaction between peptide and nanobody is faster than most other biocompatible crosslinking reactions, and it can be used to label live cells expressing receptor-nanobody fusions. The rapid kinetics of this system allowed us to probe the consequences on signaling for ligand crosslinking to the A2A-adenosine receptor. Our method may be generally useful to site-specifically link synthetic molecules to receptors on mammalian cell surfaces.
Fin ray branching is defined by TRAP+ osteolytic tubules
Authors: Cardeira-da-Silva João , Bensimon-Brito Anabela , Tarasco Marco , Brandão Ana S. , Rosa Joana , Almeida Paulo J. , Jacinto António , Cancela M. Leonor , Gavaia Paulo J. , Stainier Didier Y. R. , Laizé Vincent
Published: May 2022

The shaping of bone structures relies on various cell types and signalling pathways. Here, we use the zebrafish bifurcating fin rays during regeneration to investigate bone patterning. We found that the regenerating fin rays form via two mineralization fronts that undergo an osteoblast-dependent fusion/stitching until the branchpoint, and that bifurcation is not simply the splitting of one unit into two. We identified tartrate-resistant acid phosphatase-positive (TRAP+) osteolytic tubular structures at the branchpoints, here named osteolytic tubules (OLTs). Chemical inhibition of their bone-resorbing activity strongly impairs ray bifurcation, indicating that OLTs counteract the stitching process. Finally, by testing different osteoactive compounds, we show that the position of the branchpoint depends on the balance between bone mineralization and resorption activities. Overall, these findings provide a new perspective on fin ray formation and bifurcation, and reveal a key role for OLTs in defining the proximo-distal position of the branchpoint.

Graphical summary
Single-molecule architecture and heterogeneity of human telomeric DNA and chromatin
Authors: Dubocanin Danilo , Sedeno Cortes Adriana E. , Ranchalis Jane , Real Taylor , Mallory Ben , Stergachis Andrew B.
Published: May 2022

Telomeres are essential for linear genomes, yet their repetitive DNA content and somatic variability has hindered attempts to delineate their chromatin architectures. We performed single-molecule chromatin fiber sequencing (Fiber-seq) on human cells with a fully resolved genome, enabling nucleotide-precise maps of the genetic and chromatin structure of all telomeres. Telomere fibers are predominantly comprised of three distinct chromatin domains that co-occupy individual DNA molecules – multi- kilobase telomeric caps, highly accessible telomeric-subtelomeric boundary elements, and subtelomeric heterochromatin. Extended G-rich telomere variant repeats (TVRs) punctuate nearly all telomeres, and telomere caps imprecisely bridge these degenerate repeats. Telomeres demonstrate pervasive somatic alterations in length, sequence, and chromatin composition, with TVRs and adjacent CTCF-bound promoters impacting their stability and composition. Our results detail the structure and function of human telomeres.

One sentence summary

We use single-molecule chromatin fiber sequencing to detail the structure and function of human telomeric DNA and chromatin.
Persistent serum protein signatures define an inflammatory subset of long COVID
Authors: Talla Aarthi , Vasaikar Suhas V. , Szeto Gregory Lee , Lemos Maria P. , Czartoski Julie L. , MacMillan Hugh , Moodie Zoe , Cohen Kristen W. , Fleming Lamar B. , Thomson Zachary , Okada Lauren , Becker Lynne A. , Coffey Ernest M. , De Rosa Stephen C. , Newell Evan W. , Skene Peter J. , Li Xiaojun , Bumol Thomas F. , McElrath M. Juliana , Torgerson Troy R.
Published: May 2022

Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a clinical syndrome featuring diverse symptoms that can persist for months after acute SARS-CoV-2 infection. The etiologies are unknown but may include persistent inflammation, unresolved tissue damage, or delayed clearance of viral protein or RNA. Attempts to classify subsets of PASC by symptoms alone have been unsuccessful. To molecularly define PASC, we evaluated the serum proteome in longitudinal samples from 55 PASC individuals with symptoms lasting ≥60 days after onset of acute infection and compared this to symptomatically recovered SARS-CoV-2 infected and uninfected individuals. We identified subsets of PASC with distinct signatures of persistent inflammation. Type II interferon signaling and canonical NF-κB signaling (particularly associated with TNF), were the most differentially enriched pathways. These findings help to resolve the heterogeneity of PASC, identify patients with molecular evidence of persistent inflammation, and highlight dominant pathways that may have diagnostic or therapeutic relevance.

One Sentence Summary

Serum proteome profiling identifies subsets of long COVID patients with evidence of persistent inflammation including key immune signaling pathways that may be amenable to therapeutic intervention.
A marine probiotic treatment against the bacterial pathogenVibrio coralliilyticusto improve the performance of Pacific (Crassostrea gigas) and Kumamoto (C. sikamea) oyster larvae
Authors: Madison David , Schubiger Carla , Lunda Spencer , Mueller Ryan S. , Langdon Chris
Published: May 2022

Oyster larvae reared in hatcheries on the U.S. West coast often experience severeVibrio coralliilyticus-related mortalities early in their development. Current treatment options for these molluscs are either not available or feasible; however, for decades, probiotics have been successfully used in finfish and crustacean shellfish culture. Consequently, the objectives of this work were to 1) isolate marine bacteria from oysters and evaluate their protective activity againstVibrio coralliilyticusinfection of Pacific oyster (Crassostrea gigas) larvae, and 2) to determine the long-term effects of probiotic additions on growth and metamorphosis of larval Pacific and Kumamoto oysters (C. sikamea). A combination of three probiotic strains applied once 24 hours post-fertilization was more effective in improving survival of larvalC. gigasexposed to lethal concentrations ofV. coralliilyticusstrain RE22, compared with separate additions of individual probiotics. In addition, a single application of the probiotic combination to one-day-old larvae increased the larval metamorphosis success ofC. sikameaand both the Midori and Myiagi stocks ofC. gigas. These results suggest that probiotics are effective at preventing bacterial infections and can significantly improve performance of oyster larvae, using a single application early in their development.

Highlights

• A combination of marine bacteria improved survival of Pacific oyster larvae exposed to virulentV. coralliilyticus.

• Metamorphosis was increased after adding a single dose of probiotics to one-day-old larvae.

• Repetitive dosing after each water change was not superior to a single dose one day post egg-fertilization.

• A single dose of the probiotic combination resulted in larger size on day 12.
SIRT3 deficiency decreases oxidative-metabolism capacity but increases lifespan under caloric restriction
Authors: Dhillon Rashpal S , Qin Yiming (Amy) , van Ginkel Paul R , Fu Vivian X , Vann James M , Lawton Alexis J , Green Cara L , Manchado-Gobatto Fúlvia B , Gobatto Claudio A , Lamming Dudley W , Prolla Tomas A , Denu John M
Published: May 2022

Mitochondrial NAD+-dependent protein deacetylase Sirtuin3 (SIRT3) has been proposed to mediate calorie restriction (CR)-dependent metabolic regulation and lifespan extension. Here, we investigated the role of SIRT3 in CR-mediated longevity, mitochondrial function, and aerobic fitness. We report that SIRT3 is required for whole-body aerobic capacity but is dispensable for CR-dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3-/-) yielded a longer overall and maximum lifespan as compared to Sirt3+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3-/- CR mice exhibit lower physical activity and favor fatty acid oxidation during the postprandial period, leading to a pseudo-fasting condition that extends the fasting period. This study shows uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity), and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.