bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of persistent COVID-19 symptoms on social life of female long haulers: A qualitative study
Authors: Aghaei Atefeh , Zhang Ran , Taylor Slone , Tam Cheuk-Chi , Yang Chih-Hsiang , Li Xiaoming , Qiao Shan
Published: January 2022

Introduction

Persistent COVID-19 symptoms (long COVID) may bring numerous challenges to long haulers’ social lives. Women may have to endure more profound impacts given their social roles and existing structural inequality. This study aims to explore the impacts of long COVID on various aspects of social life among female long haulers.

Methods

We conducted 15 semi-structured interviews with female long haulers in the United States purposely recruited from Facebook groups, Slack groups, and organization websites. The interviews were audio recorded after appropriate consent and transcribed verbatim. Inductive approach was applied in thematic analysis, which consists of six stages: becoming familiar with data, developing initial codes, extracting themes, refining themes, labeling themes, and reporting. The MAXQDA software was used in data analysis.

Results

Persistent COVID-19 symptoms negatively affected female long haulers’ social lives in many aspects including physical function, financial security, social relationship, conflict of social roles, and social stigma. Physical limitations changed their body image. Social isolation and work-family conflicts caused huge stress. They experienced internalization of stigma and job insecurities. Shifting to new methods of communication, especially social media may buffer the negative effects of social isolation because of long COVID.

Conclusion

Existing policies and intervention programs need to be adapted to address the challenges and barriers that long haulers face in returning to normal social life, especially for females. Tailored social life-related recommendations and social support are needed for female long haulers.
Piperlongumine (PL) conjugates induce targeted protein degradation
Authors: Pei Jing , Xiao Yufeng , Liu Xingui , Hu Wanyi , Sobh Amin , Yuan Yaxia , Zhou Shuo , Hua Nan , Mackintosh Samuel G , Zhang Xuan , Basso Kari B. , Kamat Manasi , Yang Qingping , Licht Jonathan D. , Zheng Guangrong , Zhou Daohong , Lv Dongwen
Published: January 2022

PROteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that degrade target proteins through recruiting E3 ligases. However, their application is limited in part because few E3 ligases can be recruited by known E3 ligase ligands. In this study, we identified piperlongumine (PL), a natural product, as a covalent E3 ligase recruiter, which induces CDK9 degradation when it is conjugated with SNS-032, a CDK9 inhibitor. The lead conjugate955can potently degrade CDK9 in a ubiquitin-proteasome-dependent manner and is much more potent than SNS-032 against various tumor cellsin vitro. Mechanistically, we identified KEAP1 as the E3 ligase recruited by955to degrade CDK9 through a TurboID-based proteomics study, which was further confirmed by KEAP1 knockout and the nanoBRET ternary complex formation assay. In addition, PL-Ceritinib conjugate can degrade EML4-ALK fusion oncoprotein, suggesting that PL may have a broader application as a covalent E3 ligase ligand in targeted protein degradation.
The architecture of the actin network can balance the pushing forces produced by growing microtubules
Authors: Yamamoto Shohei , Gaillard Jérémie , Vianay Benoit , Guerin Christophe , Orhant-Prioux Magali , Blanchoin Laurent , Théry Manuel
Published: January 2022

The position of centrosome, the main microtubule-organizing center (MTOC), is instrumental in the definition of cell polarity. It is defined by the balance of tension and pressure forces in the network of microtubules (MTs). As MTs polymerize against the cell periphery, pressure increases and produces pushing forces on the MTOC. How the mechanical interplay between MTs and the actin network is involved in the regulation of these forces remains poorly understood, in particular because its investigation is technically limited by the structural and biochemical complexity of the cell cytoplasm. Here, in a cell-free assay, we used purified proteins to reconstitute the interaction of an aster of dynamic MTs with actin networks of various compositions and architectures in cell-sized microwells. In the absence of actin filaments, the positioning of the MTOC was highly sensitive to variations in MT length. The presence of a bulk actin filament network limited MTs deformation and displacement, and MTOCs were hold in place. In contrast, the assembly of a dense and branched actin network along the edges of the wells centered the MTOCs by preventing MT slippage and thus maintaining an isotropic balance of pushing forces. In agreement with this, an asymmetric peripheral actin network caused the MTOC to decenter by creating an asymmetry in the pushing forces. Numerical simulations demonstrated that steric hindrance by actin networks, at the tip or along the entire length of MTs, can modulate MTOC positioning, as observed in the experiments. Overall, our results show that actin networks can limit the sensitivity of MTOC positioning to MT length and enforce robust MTOC centering or decentering depending on its architecture.
Mast cell-mediated inflammation relies on insulin-regulated aminopeptidase controlling cytokine export from the Golgi
Authors: Weimershaus Mirjana , Carvalho Caroline , Rignault Rachel , Waeckel-Enee Emmanuelle , Dussiot Michael , van Endert Peter , Maciel Thiago Trovati , Hermine Olivier
Published: January 2022

Upon activation, mast cells rapidly release preformed inflammatory mediators from large cytoplasmic granules via regulated exocytosis. This acute degranulation is followed by a late activation phase involving synthesis and secretion of cytokines, growth factors and other inflammatory molecules via the constitutive pathway that remains ill-defined. Here we describe a role for an insulin-responsive vesicle-like endosomal compartment, marked by insulin-regulated aminopeptidase (IRAP), in the secretion of TNF-α- and IL-6 in mast cells and macrophages. IRAP-deficient mice are protected from TNF-α-dependent kidney injury and inflammatory arthritis. In the absence of IRAP, TNF-α fails to be efficiently exported from the Golgi. Subsequently, reduced co-localization of VAMP3+ endosomes with Stx4 was observed, while VAMP8-dependent exocytosis of secretory granules was facilitated. Chemical targeting of IRAP+ endosomes reduced pro-inflammatory cytokine secretion thereby highlighting this compartment as a promising target for the therapeutic control of inflammation.
Hsa-miR-31-5p controls a metabolic switch in psoriatic keratinocytes that identifies therapeutic intervention
Authors: Wang Mao-Jie , Xu Yong-Yue , Vos HarmJan , Gulersonmez Can , Stigter Edwin , Gerritsen Johan , Gallego Marc Pages , van Es Robert , Li Li , Deng Hao , Han Ling , Huang Run-Yue , Lu Chuan-Jian , Burgering Boudewijn MT
Published: January 2022

Psoriasis is characterized by a combination of keratinocyte hyperproliferation and immune cell activation. Immune cell activation requires increased glucose consumption, consequently limiting glucose availability for other cell types like keratinocytes. In psoriasis Hsa-microRNA-31-5p (miR-31) is highly expressed in keratinocytes. Here we show that miR-31 expression in keratinocytes is induced by limited glucose availability and increases survival under limiting glucose conditions, by increasing glutamine metabolism. In addition, miR-31 induced glutamine metabolism results in secretion of specific metabolites (aspartate and glutamate) but also immuno-modulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibition of glutaminase (GLS) using CB-839 impedes miR31-induced metabolic rewiring and secretion of immuno-modulatory factors. Concordantly, pharmacological targeting of GLS alleviated psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.
Reproductive outcomes in sport horse commercial French breeding farms: clinical relevance of mares’ age, parity and lactating status
Authors: Derisoud Emilie , Grimard Bénédicte , Gourtay Clothilde , Auclair-Ronzaud Juliette , Chavatte-Palmer Pascale
Published: January 2022

Background

For a long time, important and progressive fertility decline is observed with mare age. Parity and yearly breeding, however, are controversial factors impacting fertility. Most of these studies were performed on race horses and before 2010, on data accumulated before. The cumulative effects of age and nulliparity/nursing with improved reproductive technologies and practices, often observed in sport horses, has not been investigated yet.

Objectives

To investigate the effect of age, parity and nursing, as well as reproductive management, on post-insemination inflammation and fertility in sports mares.

Study design

Age, parity, nursing status, follicular size before ovulation, estrus and/or ovulation induction, artificial insemination (AI) protocol, post-breeding inflammation and treatment, Day 14 pregnancies rates (PR) and number of embryos, as well as subsequent foaling the next year were recorded for 277 mares (506 cycles) over one breeding season in two French commercial studs.

Methods

Multivariate logistic regression models were used.

Results

PR was 41.9% per cycle and 76.5% at the end of the season. Post-insemination fluid accumulation risk was increased in >10-year-old, barren or July or August inseminated mares (p<0.0001, OR=3.29, 5.389 and 3.329, respectively). PR were reduced in mares >10-year-old vs younger or inseminated with frozen vs fresh or refrigerated semen (p<0.05, OR=0.622 and 0.582, respectively). More pregnancy on Day 14 were observed in mares with multiple ovulations compared to mono- ovulation (p<0.05, OR=1.791). Regardless the age, PR only tended to be improved in multiparous (p=0.07, OR=1.434 in parous vs nulliparous) but in >10-year-old mares, multiparity greatly increased PR (44.09% in parous vs 30.89% in nulliparous, p<0.05).

Main limitations

Limited number of mares.

Conclusion

In sport horse, maternal age was more important than parity and lactating status for reproductive success but cumulative effects of nulliparity and aging was deleterious on PR, demonstrating their importance in the management of sport mares.
On the hormonal control of posterior regeneration in the annelid Platynereis dumerilii
Authors: Álvarez-Campos Patricia , Planques Anabelle , Bideau Loïc , Vervoort Michel , Gazave Eve
Published: January 2022

Regeneration is the process by which many animals are able to restore lost or injured body parts. After amputation of the posterior part of its body, the annelid Platynereis dumerilii is able to regenerate the pygidium, the posteriormost part of its body that bears the anus, and a subterminal growth zone containing stem cells that allows the subsequent addition of new segments. The ability to regenerate their posterior part (posterior regeneration) is promoted in juvenile worms by a hormone produced by the brain and is lost when this hormonal activity becomes low at the time the worms undergo their sexual maturation. By characterizing posterior regeneration at the morphological and molecular levels in worms that have been decapitated, we show that the presence of the head is essential for multiple aspects of posterior regeneration, as well as for the subsequent production of new segments. We also show that methylfarnesoate, the molecule proposed to be the brain hormone, can partially rescue the posterior regeneration defects observed in decapitated worms. Our results are therefore consistent with a key role of brain hormonal activity in the control of regeneration and growth in P. dumerilii, and support the hypothesis of the involvement of methylfarnesoate in this control.
Tropical Origin, Global Diversification and Dispersal in the Pond Damselflies (Coenagrionoidea) Revealed by a New Molecular Phylogeny
Authors: Willink B. , Ware J. , Svensson E. I.
Published: January 2022

The processes responsible for the formation of Earth’s most conspicuous diversity pattern, the latitudinal diversity gradient (LDG), remain unexplored for many clades in the Tree of Life. Here, we present a densely-sampled and dated molecular phylogeny for the most speciose clade of damselflies worldwide (Odonata: Coenagrionoidea), and investigate the role of time, macroevolutionary processes and biome-shift dynamics in shaping the LDG in this ancient insect superfamily. We used process-based biogeographic models to jointly infer ancestral ranges and speciation times, and to characterise within-biome dispersal and biome-shift dynamics across the cosmopolitan distribution of Coenagrionoidea. We also investigated temporal and biome-dependent variation in diversification rates. Our results uncover a tropical origin of pond damselflies and featherlegs ∼ 105 Ma, while highligthing uncertainty of ancestral ranges within the tropics in deep time. Even though diversification rates have declined since the origin of this clade, global climate change and biome-shifts have slowly increased diversity in warm- and cold-temperate areas, where lineage turnover rates have been relatively higher. This study underscores the importance of biogeographic origin and time to diversify as important drivers of the LDG in pond damselflies and their relatives, while diversification dynamics have instead resulted in the formation of ephemeral species in temperate regions. Biome-shifts, although limited by tropical niche conservatism, have been the main factor reducing the steepness of the LDG in the last 30 Myr. With ongoing climate change and increasing northward range expansions of many damselfly taxa, the LDG may become less pronounced. Our results support recent calls to unify biogeographic and macroevolutionary approaches to increase our understanding of how latitudinal diversity gradients are formed and why they vary across time and among taxa.
Delimiting the cryptic diversity and host preferences of Sycophila parasitoid wasps associated with oak galls using phylogenomic data
Authors: Zhang Y. Miles , Sheikh Sofia I. , Ward Anna K.G. , Forbes Andrew A. , Prior Kirsten M. , Stone Graham N. , Gates Michael W. , Egan Scott P. , Zhang Linyi , Davis Charles , Weinersmith Kelly L. , Melika George , Lucky Andrea
Published: January 2022

Cryptic species diversity is a major challenge for the species-rich community of parasitoids attacking oak gall wasps due to a high degree of sexual dimorphism, morphological plasticity, small size, and poorly known biology. As such, we know very little about the number of species present, nor the evolutionary forces responsible for generating this diversity. One hypothesis is that trait diversity in the gall wasps, including the morphology of the galls they induce, has evolved in response to selection imposed by the parasitoid community, with reciprocal selection driving diversification of the parasitoids. Using a rare, continental-scale data set of Sycophila parasitoid wasps reared from 44 species of cynipid galls from 18 species of oak across the US, we combined mitochondrial DNA barcodes, Ultraconserved Elements (UCEs), morphological, and natural history data to delimit putative species. Using these results, we generate the first large-scale assessment of ecological specialization and host association in this species-rich group, with implications for evolutionary ecology and biocontrol. We find most Sycophila target specific subsets of available cynipid host galls with similar morphologies, and generally attack larger galls. Our results suggest that parasitoid wasps such as Sycophila have adaptations allowing them to exploit particular host trait combinations, while hosts with contrasting traits are resistant to attack. These findings support the tritrophic niche concept for the structuring of plant-herbivore-parasitoid communities.
NELL-1 regulates the matrisome to alter osteosarcoma disease progression
Authors: Qin Qizhi , Gomez-Salazar Mario , Tower Robert J. , Chang Leslie , Morris Carol D. , McCarthy Edward F. , Ting Kang , Zhang Xinli , James Aaron W.
Published: January 2022

Sarcomas produce abnormal extracellular matrix (ECM) which in turn provides instructive cues for cell growth and invasion. Neural EGF Like-Like molecule 1 (NELL1) is a secreted glycoprotein characterized by its non-neoplastic osteoinductive effects, yet highly expressed in skeletal sarcomas. Here, NELL1 gene deletion markedly reduced invasive behavior across human osteosarcoma (OS) cell lines. This resulted in reduced OS disease progression, inhibited metastatic potential and improved survival in a xenograft model. These observations were recapitulated with Nell1 conditional knockout in mouse models of p53/Rb driven sarcomagenesis, including reduced tumor frequency, and extended tumor free survival.

Transcriptomic and phospho-proteomic analysis demonstrated that NELL1 loss skews the expression of matricellular proteins associated with reduced FAK signaling. Culture on OS enriched matricellular proteins reversed phenotypic and signaling changes among NELL1 knockout sarcoma cells. These findings in mouse and human models suggest that NELL1 expression alters the sarcoma matrix, thereby modulating cellular invasive potential and prognosis. Disruption of NELL1 signaling may represent a novel therapeutic approach to short circuit sarcoma disease progression.
A Cyclisation and Docking Protocol for Cyclic Peptide-Protein Modelling using HADDOCK2.4
Authors: Charitou Vicky , van Keulen Siri C. , Bonvin Alexandre M.J.J.
Published: January 2022

An emerging class of therapeutic molecules are cyclic peptides with over 40 cyclic peptide drugs currently in clinical use. Their mode of action is, however, not fully understood, impeding rational drug design. Computational techniques could positively impact their design but modeling them and their interactions remains challenging due to their cyclic nature and their flexibility. This study presents a step-by-step protocol for generating cyclic peptide conformations and docking them to their protein target using HADDOCK2.4. A dataset of 30 cyclic peptide-protein complexes was used to optimize both cyclisation and docking protocols. It supports peptides cyclized via an N- and C-terminus peptide bond and/or a disulfide bond. An ensemble of cyclic peptide conformations is then used in HADDOCK to dock them onto their target protein using knowledge of the binding site on the protein side to drive the modeling. The presented protocol predicts at least one acceptable model according to CAPRI criteria (Critical Assessment of Prediction of Interaction) for each complex of the dataset when the top 10 HADDOCK-ranked single structures are considered (100% success rate top10) both in the bound and unbound docking scenario. Moreover, its performance in both bound and fully unbound docking, is similar to the state-of-the-art software in the field, Autodock CrankPep. The presented cyclisation and docking protocol should make HADDOCK a valuable tool for rational cyclic peptide-based drug design and high-throughput screening.
EFA6R suppresses ovarian cancer cell migration and invasion
Authors: Tamaddon-Jahromi Salman , Murphy Kate , Walker William , Kanamarlapudi Venkateswarlu
Published: January 2022

Exchange factor for ADP-ribosylation factor (Arf)6 (EFA6)R expression loss in ovarian cancer has shown to decrease patient survival. EFA6R contains the catalytic Sec7, pleckstrin homology (PH), and coiled-coil (CC) domains. To gain further insight into the role of EFA6R, this study further investigated EFA6R expression in OC and its putative role as a metastatic suppressor. EFA6R mRNA expression, assessed by RT-qPCR, was significantly downregulated in OC tissues and cell lines. OC tissue microarray staining with EFA6R antibody showed that loss of protein expression correlated with increased cancer grade. Furthermore, EFA6R protein levels, assessed by immunoblotting, were significantly reduced in OC tissues and cell lines. Treatment of SKOV-3 cells with 5-aza-2’deoxycytidine, an epigenetic regulator, restored EFA6R expression and attenuated functional cell migration and invasion, which was reversed by siRNA-mediated knockdown of EFA6R expression. This study also revelated that exogenously expressed EFA6R localises to the plasma membrane, through its PH domain, and thereby inhibits cell migration and invasion in the CC domain-dependent and an Arf6-independent manner. EFA6R loss-of-function involves epigenetic mechanisms in which downregulation increases OC tumour cell migration and invasion.

Summary statement

EFA6R expression is epigenetically regulated in ovarian cancer cells and loss of expression correlates with increased tumour grade and enhanced tumour cell migration. EFA6R appears to mediate these effects independently of Arf6.
Within and among population differences in cuticular hydrocarbons in the seabird tick Ixodes uriae
Authors: Dupraz Marlène , Leroy Chloe , Thórarinsson Thorkell Lindberg , d’Ettorre Patrizia , McCoy Karen D.
Published: January 2022

Abstract

The hydrophobic layer of the arthropod cuticle acts to maintain water balance, but can also serve to transmit chemical signals via cuticular hydrocarbons (CHC), essential mediators of arthropod behavior. CHC signatures typically vary qualitatively among species, but also quantitatively among populations within a species, and have been used as taxonomic tools to differentiate species or populations in a variety of taxa. Most work in this area to date has focused on insects, with little known for other arthropod groups such as ticks. The worldwide distribution and extensive host-range of the seabird tick Ixodes uriae make it a good model to study the factors influencing CHC composition. Genetically differentiated host-races of I. uriae have evolved across the distribution of this species but the factors promoting sympatric population divergence are still unknown. To test for a potential role of host-associated CHC in population isolation, we collected I. uriae specimens from two of its seabird hosts, the Atlantic puffin (Fratercula arctica) and the common guillemot (Uria aalge) in different colonies in Iceland. Using gas-chromatography and mass-spectrometry, we detected a complex cuticular mixture of 22 hydrocarbons, including n-alkanes, methyl-alkanes and alkenes ranging from 17 to 33 carbons in length. We found that each population had a distinct CHC profile. The host group explained the greatest amount of population divergence, with long-chain hydrocarbons being more abundant in puffin tick populations compared to guillemot tick populations. Future work will now be required to test whether the different CHC signals reinforce assortative mating, thereby playing a role in generating I. uriae population divergence patterns, and to evaluate diverse hypotheses on the origin of distinct population signatures.
The role of rice SOG1 and SOG1-like in DNA damage response
Authors: Nishizawa-Yokoi Ayako , Motoyama Ritsuko , Tanaka Tsuyoshi , Mori Akiko , Iida Keiko , Toki Seiichi
Published: January 2022

Higher plants are constantly exposed to environmental stresses, and therefore complicated defense systems, including DNA damage response (DDR) and DNA repair systems, have developed to protect plant cells. InArabidopsis, the transcription factor SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1) has been reported to play a key role in DDR. Here, we focus on DDR in rice—thought to be a simpler system compared withArabidopsisdue to lack of induction of endocycle even under DNA damage stress. Rice SOG1 (OsSOG1) and SOG1-like (OsSGL) were identified as putative AtSOG1 orthologs with complete or partial conservation of the serine-glutamine (SQ) motifs involved in activation via phosphorylation. In addition to OsSOG1- or OsSGL-knockout mutants, OsSOG1 non-phosphorylatable mutants (OsSOG1-7A) were generated by homologous recombination-mediated gene targeting. Based on DNA damage susceptibility and transcriptome analysis using these mutants, we demonstrated that OsSOG1, but not OsSGL, plays a central role in the DDR and DNA repair. OsSOG1 regulated target genes via CTT (N)7AAG motifs reported previously as AtSOG1 recognition sites. The loss of transcription activities and DNA damage tolerance of OsSOG1-7A was not complete compared with OsSOG1-knockout mutants, raising the possibility that another phosphorylation site might be involved in the activation of OsSOG1. Furthermore, our findings have highlighted differences in SOG1-mediated DDR between rice andArabidopsis, especially regarding induction of cell-cycle arrest and endocycle arrest, revealing rice-specific DDR mechanisms.

One sentence summary

Rice transcription factor SUPPRESSOR OF GAMMA RESPONSE 1 controls DNA damage response and DNA repair through activation via phosphorylation and the direct regulation of expression of numerous genes.
New insights into tomato CLE peptide repertoire and perception mechanisms
Authors: Carbonnel Samy , Falquet Laurent , Hazak Ora
Published: January 2022

Precision in sensing the environmental cues and adjusting the growth and the physiology of the root system are necessary for plant robustness. Plants achieve their phenotypic plasticity by tightly controlling and buffering developmental decisions. In addition to the classical plant hormones that mediate plant development and stress responses, the CLE peptides constitute an additional crucial level of regulation. While the CLV3-CLV1 module appears to be highly conserved to control the proliferation of the shoot apical meristem stem cells, we do not yet fully understand the function of the additionalCLEgenes and whether they act in a similar way across the plant species, including tomato. Due to the small gene size and high sequence variability, it is extremely difficult to precisely annotateCLEgenes in plant genomes. Here we present our analysis of theCLEfamily in tomato, based on a combination of iterative tBLASTn and Hidden-Markov-Model (HMM), which allowed us to identify thirty-seven newSlCLEs in addition to the fifteen reported previously. We could confirm the biological activities of selected SlCLEs in suppressing root meristematic cell divisions. We show that root response is mediated bySlCLAVATA2, indicating the conservation of CLE perception mechanism.

One-sentence summary

Using a combination of iterative tBLASTn and Hidden-Markov-Model approaches, we uncovered 37 new tomatoCLEgenes predominantly expressed in roots, and we showed a conserved effect on root meristem arrest, that wasSlCLAVATA2-dependent.

Highlights

We applied a combined approach of iterative tBLASTn and Hidden-Markov-Model to identify fifty-two tomatoSlCLEgenes, including thirty-seven new genes

All identified genes encode for pre-propeptides with a single CLE-domain containing conserved residues similar to Arabidopsis

Analyzing the publicly available RNAseq datasets, we could confirm the expression ofSlCLEgenes that was often associated specifically with root or shoot, a certain developmental stage of the fruit, or with drought stress conditions

Remarkably, the majority ofSlCLEgenes are predominantly expressed in the root tissues

We showed the conserved inhibitory effect on the root meristem and columella cells division for the selected SlCLE peptides that wereSlCLAVATA2-dependent.
Crosstalk of Histone Modifications in the Healthy Human Immune System
Authors: Dermadi Denis , Kalesinskas Laurynas , Ganesan Ananthakrishnan , Kuo Alex , Cheung Peggie , Cheng Sarah , Dvorak Mei , Scriba Thomas J. , Habtezion Aida , Donato Michele , Utz Paul J. , Khatri Purvesh
Published: January 2022

Chromatin remodeling through post-translational modifications of histone tails (HPTM) is fundamental for regulation and maintenance of DNA-centered processes. Systems level understanding of coordination and interactions between HPTMs and their impact on the functional state of the immune cells remain unexplored due to the technical reasons. We leveraged large biologically heterogeneous data (>27 million cells), comprising of primary human immune cells profiled for 33 HPTMs and 4 histone variants at the single-cell level using high-dimensional mass cytometry (EpiTOF), to discover and map relations between HPTMs at the systems level. Briefly, we elucidated a comprehensive epigenetic network of HPTM interactions, discovered a novel subset of hematopoietic progenitors with distinct epigenetic profile, and revealed hitherto undescribed associations between a decrease in global methylations, modulation of one-carbon metabolism, and immune cell life span. Ultimately our work lays a foundation for future studies aimed at understanding complexity of HPTM interactions in immune response in infectious or autoimmune diseases, cancers, and vaccination.
Computed cancer interactome explains the effects of somatic mutations in cancers
Authors: Zhang Jing , Pei Jimin , Durham Jesse , Bos Tasia , Cong Qian
Published: January 2022

Protein-protein interactions (PPIs) are involved in almost all essential cellular processes. Perturbation of PPI networks plays critical roles in tumorigenesis, cancer progression and metastasis. While numerous high-throughput experiments have produced a vast amount of data for PPIs, these datasets suffer from high false positive rates and exhibit a high degree of discrepancy. Coevolution of amino acid positions between protein pairs has proven to be useful in identifying interacting proteins and providing structural details of the interaction interfaces with the help of deep learning methods like AlphaFold (AF). In this study, we applied AF to investigate the cancer protein-protein interactome. We predicted 1,798 PPIs for cancer driver proteins involved in diverse cellular processes such as transcription regulation, signal transduction, DNA repair and cell cycle. We modeled the spatial structure for the predicted binary protein complexes, 1,087 of which lacked previous 3D structure information. Our predictions offer novel structural insight into many cancer-related processes such as the MAP kinase cascade and Fanconi anemia pathway. We further investigated the cancer mutation landscape by mapping somatic missense mutations (SMMs) in cancer to the predicted PPI interfaces and performing enrichment and depletion analyses. Interfaces enriched or depleted with SMMs exhibit different preferences for functional categories. Interfaces enriched in mutations tend to function in pathways that are deregulated in cancers and they may help explain the molecular mechanisms of cancers in patients; interfaces lacking mutations appear to be essential for the survival of cancer cells and thus may be future targets for PPI modulating drugs.
Bacteria-mediated stabilization of murine norovirus
Authors: Budicini Melissa R. , Pfeiffer Julie K.
Published: January 2022

Enteric viruses encounter various bacteria in the host which can impact infection outcomes. The interactions between noroviruses and enteric bacteria are not well understood. Previous work determined that murine norovirus (MNV), a model norovirus, had decreased replication in antibiotic-treated mice compared with conventional mice. Although this suggests that microbiota promote MNV infection, the mechanisms are not completely understood. Additionally, prior work with other enteric viruses such as poliovirus and coxsackievirus B3 demonstrated that virions bind bacteria, and exposure to bacteria stabilizes viral particles and limits premature RNA release. Therefore, we examined interactions between MNV and specific bacteria and the consequences of these interactions. We found that the majority of Gram-positive bacteria tested stabilized MNV, while Gram-negative bacteria did not stabilize MNV. Both Gram-positive and Gram-negative bacteria bound to MNV. However, bacterial binding alone was not sufficient for virion stabilization since Gram-negative bacteria bound MNV but did not stabilize virions. Additionally, we found that bacterial conditioned media also stabilized MNV and this stabilization may be due to a small heat stable molecule. Overall this work identifies specific bacteria and bacterial components that stabilize MNV and may impact virion stability in the environment.

Importance

Enteric viruses are exposed to a wide variety of bacteria in the intestine, but effects of bacteria on viral particles are incompletely understood. We found that murine norovirus (MNV) virion stability is enhanced in the presence of several Gram-positive bacterial strains. Virion stabilizing activity was also present in bacterial culture medium, and activity was retained upon heat or protease treatment. These results suggest that certain bacteria and bacterial products may promote MNV stability in the environment, which could influence viral transmission.
A characteristic cerebellar biosignature for bipolar disorder, identified with fully automatic machine learning
Authors: Thomaidis Georgios V. , Papadimitriou Konstantinos , Michos Sotirios , Chartampilas Evangelos , Tsamardinos Ioannis
Published: January 2022

Backround

Transcriptomic profile differences between patients with bipolar disorder and healthy controls can be identified using machine learning and can provide information about the potential role of the cerebellum in the pathogenesis of bipolar disorder.With this aim, user-friendly, fully automated machine learning algorithms can achieve extremely high classification scores and disease-related predictive biosignature identification, in short time frames and scaled down to small datasets.

Method

A fully automated machine learning platform, based on the most suitable algorithm selection and relevant set of hyper-parameter values, was applied on a preprocessed transcriptomics dataset, in order to produce a model for biosignature selection and to classify subjects into groups of patients and controls. The parent GEO datasets were originally produced from the cerebellar and parietal lobe tissue of deceased bipolar patients and healthy controls, using Affymetrix Human Gene 1.0 ST Array.

Results

Patients and controls were classified into two separate groups, with no close-to-the-boundary cases, and this classification was based on the cerebellar transcriptomic biosignature of 25 features (genes), with Area Under Curve 0.929 and Average Precision 0.955. Using 6 of the characteristic features (genes) discovered during the selection process, 99,6% of predictive performance was achieved. The 3 genes contributing most to the predictive power of the model (92,7% predictive performance) are also deregulated in temporal lobe epilepsy. KEGG analysis revealed participation of 4 identified features in 6 pathways which have been associated with bipolar disorder.

Conclusion

93% Area Under Curve, 96% Average Precision, and complete separation between unaffected controls and patients with bipolar disorder, were achieved in ∼2 hours. The cerebellar transcriptomic biosignature suggests a potential genetic overlap with temporal lobe epilepsy and new genetic contributions to the pathogenesis of bipolar disorder.
Expert Surgeons and Deep Learning Models Can Predict the Outcome of Surgical Hemorrhage from One Minute of Video
Authors: Pangal Dhiraj J , Kugener Guillaume , Zhu Yichao , Sinha Aditya , Unadkat Vyom , Cote David J , Strickland Ben , Rutkowski Martin , Hung Andrew , Anandkumar Animashree , Han X.Y. , Papyan Vardan , Wrobel Bozena , Zada Gabriel , Donoho Daniel A
Published: January 2022

Background

Major vascular injury resulting in uncontrolled bleeding is a catastrophic and often fatal complication of minimally invasive surgery. At the outset of these events, surgeons do not know how much blood will be lost or whether they will successfully control the hemorrhage (achieve hemostasis). We evaluate the ability of a deep learning neural network (DNN) to predict hemostasis control ability using the first minute of surgical video and compare model performance with human experts viewing the same video.

Methods

The publicly available SOCAL dataset contains 147 videos of attending and resident surgeons managing hemorrhage in a validated, high-fidelity cadaveric simulator. Videos are labeled with outcome and blood loss (mL). The first minute of 20 videos was shown to four, blinded, fellowship trained skull-base neurosurgery instructors, and to SOCALNet (a DNN trained on SOCAL videos). SOCALNet architecture included a convolutional network (ResNet) identifying spatial features and a recurrent network identifying temporal features (LSTM). Experts independently assessed surgeon skill, predicted outcome and blood loss (mL). Outcome and blood loss predictions were compared with SOCALNet.

Results

Expert inter-rater reliability was 0.95. Experts correctly predicted 14/20 trials (Sensitivity: 82%, Specificity: 55%, Positive Predictive Value (PPV): 69%, Negative Predictive Value (NPV): 71%). SOCALNet correctly predicted 17/20 trials (Sensitivity 100%, Specificity 66%, PPV 79%, NPV 100%) and correctly identified all successful attempts.

Expert predictions of the highest and lowest skill surgeons and expert predictions reported with maximum confidence were more accurate. Experts systematically underestimated blood loss (mean error −131 mL, RMSE 350 mL, R20.70) and fewer than half of expert predictions identified blood loss > 500mL (47.5%, 19/40). SOCALNet had superior performance (mean error −57 mL, RMSE 295mL, R20.74) and detected most episodes of blood loss > 500mL (80%, 8/10).

In validation experiments, SOCALNet evaluation of a critical on-screen surgical maneuver and high/low-skill composite videos were concordant with expert evaluation.

Conclusion

Using only the first minute of video, experts and SOCALNet can predict outcome and blood loss during surgical hemorrhage. Experts systematically underestimated blood loss, and SOCALNet had no false negatives. DNNs can provide accurate, meaningful assessments of surgical video. We call for the creation of datasets of surgical adverse events for quality improvement research.
Impact of accelerating booster vaccination amidst Omicron surge in the United States
Authors: Sah Pratha , Vilches Thomas N , Moghadas Seyed M. , Fitzpatrick Meagan C. , Schneider Eric C , Galvani Alison P.
Published: January 2022

COVID-19 infections driven by the Omicron variant are sweeping across the United States. Although early evidence suggests that the Omicron variant may cause less severe disease than previous variants, the explosive spread of infections threatens to drive hospitalizations and deaths to unprecedented high levels, swamping already overburdened hospitals. Booster vaccination appears to be effective at preventing severe illness and hospitalization. However, the pace of booster vaccination in the US has been slow despite the available infrastructure to administer doses at a much higher rate.

We used an age-stratified, multi-variant agent-based model to project the reduction in COVID-related deaths and hospitalizations that could be achieved by accelerating the current daily pace of booster vaccination in the US. We found that doubling the rate of booster vaccination would prevent over 400,000 hospitalizations and 48,000 deaths. Tripling the booster vaccination rate would avert over 600,000 hospitalizations and save 70,000 lives during the first four months of 2022.
The positive dimension of schizotypy is associated with a reduced attenuation and precision of self-generated touch
Authors: Asimakidou Evridiki , Job Xavier , Kilteni Konstantina
Published: January 2022

The brain predicts the sensory consequences of our movements and uses these predictions to attenuate the perception of self-generated sensations. Accordingly, self-generated touch feels weaker than externally generated touch of identical intensity. In schizophrenia, this somatosensory attenuation is substantially reduced, suggesting that patients with positive symptoms fail to accurately predict and process self-generated touch. Here we hypothesized that a similar impairment might exist in healthy nonclinical individuals with high positive schizotypal traits. One hundred healthy participants (53 female) scored for schizotypal traits and underwent a well-established psychophysics force discrimination task to quantify how they perceived self-generated and externally generated touch. The perceived intensity of tactile stimuli delivered to their left index finger (magnitude) and the ability to discriminate the stimuli (precision) were measured. We observed that higher positive schizotypal traits were associated with reduced somatosensory attenuation and poorer somatosensory precision of self-generated touch. These effects were specific to positive schizotypy and were not observed for the negative or disorganized dimensions of schizotypy. The results suggest that positive schizotypal traits are associated with a reduced ability to predict and process self-generated tactile stimuli. Given that the positive dimension of schizotypy represents the analogue of positive psychotic symptoms of schizophrenia, deficits in processing self-generated tactile information could indicate increased liability to schizophrenia.
Plant longevity, drought and island isolation favoured rampant evolutionary transitions towards insular woodiness
Authors: Zizka Alexander , Onstein Renske E. , Rozzi Roberto , Weigelt Patrick , Kreft Holger , Steinbauer Manuel J. , Bruelheide Helge , Lens Frederic
Published: January 2022

Insular woodiness (IW)—the evolutionary transition from herbaceousness towards woodiness on islands—is one of the most iconic features of island floras. Since pioneering work by Darwin and Wallace, five IW drivers have been proposed: (i) favourable aseasonal climate and (ii) lack of large native herbivores promote plant longevity that (iii) results in prolonged flowering favouring outcrossing. Alternatively, (iv) competition for sunlight requires taller and stronger stems, and (v) drought favours woodiness to safeguard root-to-shoot water transport. However, information on the occurrence of IW is fragmented, hampering tests of these potential drivers. Here, we identify 1,097 insular woody species (IWS) on 375 islands, and infer at least 175 evolutionary transitions on 31 archipelagos, concentrated in six angiosperm families. Structural equation models reveal that the IWS richness on oceanic islands correlates with aseasonal favourable climate, followed by increased drought and island isolation (approximating competition). When continental islands are included, reduced herbivory pressure by large native mammals, increased drought and island isolation are most relevant. The repeated evolution of IW opens promising avenues to disentangle the variation in gene regulatory networks triggering wood formation, and emphasize individual archipelagos as laboratories of evolution, where similar environmental conditions replicate convergent evolution of similar traits.
Single-Cell Transcriptomics reveals relaxed evolutionary constraint of spermatogenesis in two passerine birds as compared to mammals
Authors: Segami J. Carolina , Semon Marie , Cunha Catarina , Bergin Claudia , Mugal Carina F , Qvarnström Anna
Published: January 2022

Spermatogenesis is a complex process where spermatogonia develop into haploid, mobile sperm cells. The genes guiding this process are subject to an evolutionary trade-off between preserving basic functions of sperm while acquiring new traits ensuring advantages in competition over fertilization of female gametes. In species with XY sex chromosomes, the outcome of this trade-off is found to vary across the stages of spermatogenesis but remains unexplored for species with ZW sex chromosomes. Here we characterize avian spermatogenesis at single cell resolution from testis of collared and pied flycatchers. We find evidence for relaxed evolutionary constraint of genes expressed in spermatocyte cells going through meiosis. An overrepresentation of Z-linked differentially expressed genes between the two species at this stage suggests that this relaxed constraint is associated with the lack of sex-chromosome silencing during meiosis. We conclude that the high throughput of bird spermatogenesis, at least partly, is explained by relaxed developmental constraint.
Alteration of myocardial structure and function in RAF1-associated Noonan syndrome: Insights from cardiac disease modeling based on patient-derived iPSCs
Authors: Nakhaei-Rad Saeideh , Bazgir Farhad , Dahlmann Julia , Busley Alexandra Viktoria , Buchholzer Marcel , Haghighi Fereshteh , Schänzer Anne , Hahn Andreas , Kötter Sebastian , Schanze Denny , Anand Ruchika , Funk Florian , Borchardt Andrea , Kronenbitter Annette Vera , Scheller Jürgen , Piekorz Roland P. , Reichert Andreas S. , Volleth Marianne , Wolf Matthew J. , Cirstea Ion Cristian , Gelb Bruce D. , Tartaglia Marco , Schmitt Joachim , Krüger Martina , Kutschka Ingo , Cyganek Lukas , Zenker Martin , Kensah George , Ahmadian Mohammad R.
Published: January 2022

Noonan syndrome (NS), the most common among the RASopathies, is caused by germline variants in genes encoding components of the RAS-MAPK pathway. Distinct variants, including the recurrent Ser257Leu substitution in RAF1, are associated with severe hypertrophic cardiomyopathy (HCM). Here, we investigated the elusive mechanistic link between NS-associated RAF1S257L and HCM using three-dimensional cardiac bodies and bioartificial cardiac tissues generated from patient-derived induced pluripotent stem cells (iPSCs) harboring the pathogenic RAF1 c.770C>T missense change. We characterize the molecular, structural and functional consequences of aberrant RAF1 –associated signaling on the cardiac models. Ultrastructural assessment of the sarcomere revealed a shortening of the I-bands along the Z disc area in both iPSC-derived RAF1S257L cardiomyocytes, and myocardial tissue biopsies. The disease phenotype was partly reverted by using both MEK inhibition, and a gene-corrected isogenic RAF1L257S cell line. Collectively, our findings uncovered a direct link between a RASopathy gene variant and the abnormal sarcomere structure resulting in a cardiac dysfunction that remarkably recapitulates the human disease. These insights represent a basis to develop future targeted therapeutic approaches.
Tracing 3D apoplasmic complexity in vascular tissue of live conifer needles by X-ray computed tomography
Authors: Gao Chen , Marker Sean J. V. , Gundlach Carsten , Poulsen Henning F. , Bohr Tomas , Schulz Alexander
Published: January 2022

Architecture and conducting area of vascular elements along conifer needles are fundamentally different from broad leaves. We hypothesised that the needles’ unique transfusion tissue offers different mechanisms for water allocation and used multimodal imaging to dissect the critical water exchange interfaces in this xerophytic leaf type. Our study examined intact conifer needles with X-ray computed tomography (μXCT) and water-soluble tracers, allowing to render the functional 3D structure of the water-filled apoplast and the complementary symplasmic domain inside the bundle sheath. Segmentation of these data, together with fluorescence and electron microscopy of axial phloem and xylem elements along the needle, enabled quantification of the dimensions of the conducting tissue complex. The transfusion tracheid system between the endodermis-type bundle sheath and the axial venation formed a sponge-like apoplast domain. Transfusion parenchyma cell chains bridged this domain not directly but as tortuous symplasmic pathways between bundle sheath and axial phloem, which is nearly exclusively accessible at flanks. The transfusion tissue extends the plasma membrane surface for phloem loading and provides a large volume space. We discuss that this unique tissue plays an important role in the subtle interplay between water uptake/storage and sugar transport that has evolved to cope with desiccation stress.