bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantifying political influence on COVID-19 fatality in Brazil
Authors: de Almeida Leandro , Carelli Pedro V. , Cavalcanti Nara G. , Nascimento José-Dias do , Felinto Daniel
Published: February 2022

The COVID-19 pandemic was severely aggravated in Brazil due to its politicization by the country’s central government. However, the impact of diffuse political forces on the fatality of an epidemic is commonly hard to quantify. Here we introduce a method to measure this effect in the Brazilian case, based on the inhomogeneous distribution throughout the national territory of political support to the central government. The correlation between fatality rate and political support grows as the government’s misinformation campaign is developed, leading to the dominance of such political factor for the pandemic impact in Brazil in 2021. Once this dominance is established, this correlation allows for an estimation of the total number of deaths due to political influence as 350 ± 70 thousands up to the end of 2021.
“Investigating the effect of obesity on adipose-derived stem cells (ASCs) using Göttingen Minipigs”
Authors: Meyhoff-Madsen Maria , Østrup Esben , Fredholm Merete , Cirera Susanna
Published: February 2022

Obesity is associated with low grade inflammation, which may adversely impact the biological functions of adipose tissue and consequently of adipose-derived stem cells (ASCs). Studies in humans and rodents have described that obesity alters ASC properties and functionality, compromising their therapeutic prospects. The Göttingen Minipig (GM) is a commonly used obesity model. Nevertheless, there are no studies investigating the effect of obesity on ASCs from GM, which could constitute a valuable addition to both obesity modelling and adult stem cells investigations.

In this study, we isolated subcutaneous ASCs from lean and obese GM to investigate the effect of obesity on cell behavior and differentiation capacity. During culturing, we observed an inherent difference in cell morphology between lean and obese ASCs. Upon adipogenic induction, obese-ASCs readily differentiated, developing significantly larger amounts of adipocytes than corresponding lean-ASCs, hinting at a predisposition towards adipogenic differentiation. Expression profiling of obesity-related genes in cell cultures, before and after adipogenic differentiation, revealed a tendency towards up-regulation in differentiated obese-cultures. Altogether, our results indicate that stem cells from obese donors could display different therapeutic properties. In summary, our results point towards GM as a valuable model for future ASCs investigations in healthy and obese states.
Getting Personal with Epigenetics: Towards Machine-Learning-Assisted Precision Epigenomics
Authors: Hawkins-Hooker Alex , Visonà Giovanni , Narendra Tanmayee , Rojas-Carulla Mateo , Schölkopf Bernhard , Schweikert Gabriele
Published: February 2022

Epigenetic modifications are dynamic control mechanisms involved in the regulation of gene expression. Unlike the DNA sequence itself, they vary not only between individuals but also between different cell types of the same individual. Exposure to environmental factors, somatic mutations, and ageing contribute to epigenomic changes over time, which may constitute early hallmarks or causal factors of disease. Epigenetic changes are reversible and, therefore, promising therapeutic targets. However, mapping efforts to determine an individual’s cell-type-specific epigenome are constrained by experimental costs. We developed eDICE, an attention-based deep learning model, to impute epigenomic tracks. eDICE achieves improved overall performance compared to previous models on the reference Roadmap epigenomes. Furthermore, we present a proof of concept for the imputation of personalised epigenomic measurements on the ENTEx dataset, where eDICE correctly predicts individual- and cell-type-specific epigenetic patterns. This case study constitutes an important step towards robustly employing machine-learning-based approaches for personalised epigenomics.
In-vivo estimation of axonal morphology from MRI and EEG data
Authors: Oliveira Rita , Pelentritou Andria , Domenicantonio Giulia Di , De Lucia Marzia , Lutti Antoine
Published: February 2022

Purpose

We present a novel approach that allows the estimation of morphological features of axonal fibers from data acquired in-vivo in humans. This approach allows the assessment of white matter microscopic properties non-invasively with improved specificity.

Theory

The proposed approach is based on a biophysical model of Magnetic Resonance Imaging (MRI) data and of axonal conduction velocity estimates obtained with Electroencephalography (EEG). In a white matter tract of interest, these data depend on 1) the distribution of axonal radius – P(r)– and 2) the g-ratio of the individual axons that compose this tract – g(r). P(r)is assumed to follow a Gamma distribution with mode and scale parameters, M and θ, and g(r) is described by a power-law with parameters α and β.

Methods

MRI and EEG data were recorded from 14 healthy volunteers. MRI data were collected with a 3T scanner. MRI g-ratio maps were computed and sampled along the visual transcallosal tract. EEG data were recorded using a 128-lead system with a visual Poffenberg paradigm. The interhemispheric transfer time and axonal conduction velocity were computed from the EEG current density at the group level. Using the MRI and EEG measures and the proposed model, we estimated morphological properties of axons in the visual transcallosal tract.

Results

The estimated interhemispheric transfer time was 11.72±2.87 ms, leading to an average conduction velocity across subjects of 13.22±1.18 m/s. Out of the 4 free parameters of the proposed model, we estimated θ – the width of the right tail of the axonal radius distribution and β – the scaling factor of the axonal g-ratio, a measure of fiber myelination. Across subjects, the parameter θ was 0.40±0.07 µm and the parameter β was 0.67±0.02 µm−α.

Conclusions

The estimates of axonal radius and myelination are consistent with histological findings, illustrating the feasibility of this approach. The proposed method allows the measurement of the distribution of axonal radius and myelination within a white matter tract, opening new avenues for the combined study of brain structure and function, and for in-vivo histological studies of the human brain.
Intercontinental movement of H5 2.3.4.4 Highly Pathogenic Avian Influenza A(H5N1) to the United States, 2021
Authors: Bevins Sarah N. , Shriner Susan A. , Cumbee James C. , Dilione Krista E. , Douglass Kelly E. , Ellis Jeremy W. , Killian Mary Lea , Torchetti Mia K. , Lenoch Julianna B.
Published: February 2022

Eurasian-origin highly pathogenic avian influenza A(H5N1) belonging to the Gs/GD lineage, clade 2.3.4.4b, was detected in two Atlantic states in wild waterfowl in the United States in January 2022. Bird banding data show widespread movement of waterfowl both within the Atlantic Flyway and between neighboring flyways and northern breeding grounds.
Discovery of Flaviviridae-derived endogenous viral elements in shrew genomes provide novel insights into Pestivirus ancient history
Authors: Li YQ , Bletsa M , Zisi Z , Boonen I , Gryseels S , Kafetzopoulou L , Webster JP , Catalano S , Pybus OG , Van de Perre F , Li HT , Li YY , Li YC , Abramov A , Lymberakis P , Lemey P , Lequime S
Published: February 2022

As viral genomic imprints in host genomes, endogenous viral elements (EVEs) shed light on the deep evolutionary history of viruses, ancestral host ranges, and ancient viral-host interactions. In addition, they may provide crucial information for calibrating viral evolutionary timescales. In this study, we conducted a comprehensive in silico screening of a large dataset of available mammalian genomes for EVEs deriving from members of the viral family Flaviviridae, an important group of viruses including well-known human pathogens. We identified two novel pestivirus-like EVEs in the reference genome of the Indochinese shrew (Crocidura indochinensis). Homologs of these novel EVEs were subsequently detected in vivo by molecular detection and sequencing in 27 shrew species, including 26 species representing a wide distribution within the Crocidurinae subfamily and one in the Soricinae subfamily. Based on this wide distribution, we estimate that the integration event occurred before the last common ancestor of the subfamily, about 10.8 million years ago, attesting to an ancient origin of pestiviruses and Flaviviridae in general. Moreover, we provide the first description of Flaviviridae-derived EVEs in mammals even though the family encompasses numerous mammal-infecting members, including major human pathogens such as Zika, dengue, or hepatitis C viruses. This also suggests that shrews were past and perhaps also current natural reservoirs of pestiviruses. Taken together, our results expand the current known Pestivirus host range and provide novel insight into the ancient evolutionary history of pestiviruses and the Flaviviridae family in general.
Cryo-EM structures reveal ubiquinone-10 binding to mitochondrial complex I and conformational transitions associated with Q-site occupancy
Authors: Chung Injae , Wright John J. , Bridges Hannah R. , Ivanov Bozhidar S. , Biner Olivier , Pereira Caroline S. , Arantes Guilherme M. , Hirst Judy
Published: February 2022

Mitochondrial complex I is a central metabolic enzyme that uses the reducing potential of NADH to reduce ubiquinone-10 (Q10) and drive four protons across the inner mitochondrial membrane, powering oxidative phosphorylation. Although many complex I structures are now available, structures of Q10-bound states have remained elusive. Here, we reconstitute mammalian complex I into phospholipid nanodiscs with exogenous Q10. Using cryo-EM, we reveal a Q10 molecule occupying the full length of the Q-binding site in the ‘active’ (ready-to-go) resting state (plus a matching substrate-free structure) and apply molecular dynamics simulations to propose how the charge states of key residues influence the Q10 binding pose. By comparing ligand-bound and ligand-free forms of the ‘deactive’ resting state (that require reactivating to catalyse), we begin to define how substrate binding restructures the deactive Q-binding site, providing insights into its physiological and mechanistic relevance.
Functional characterization of Atlantic salmon (Salmo salar L.) PepT2 transporters
Authors: Vacca Francesca , Gomes Ana S. , Murashita Koji , Cinquetti Raffella , Roseti Cristina , Barca Amilcare , Rønnestad Ivar , Verri Tiziano , Bossi Elena
Published: February 2022

The high-affinity/low-capacity system Slc15a2 (PepT2) is responsible for the reuptake of di/tripeptides from the renal proximal tubule, but it also operates in many other tissues/organs. Information regarding PepT2 in teleost fish is limited and to date functional data are available from the zebrafish (Danio rerio) only. Here, we report the identification of two slc15a2 genes in the Atlantic salmon (Salmo salar) genome, namely slc15a2a and slc15a2b. The two encoded PepT2 proteins share 87% identity and resemble both structurally and functionally to the canonical vertebrate PepT2 system. The mRNA tissue distribution analyses reveal a widespread distribution of slc15a2a transcripts, being more abundant in the brain and gills, while slc15a2b transcripts are mainly expressed in kidney and distal part of gastrointestinal tract. The function of the two transporters was investigated by heterologous expression in Xenopus laevis oocytes and two- electrode voltage-clamp recordings of transport and presteady-state currents. Both PepT2a and PepT2b in the presence of Gly-Gln elicit pH-dependent and Na+ independent inward currents. The biophysical and kinetic analysis of the recorded currents defined the transport properties, confirming that the two Atlantic salmon PepT2 proteins behave as high-affinity/low-capacity transporters. The recent structures and the previous kinetic schemes of rat and human PepT2 qualitatively account for the characteristics of the two Atlantic salmon proteins. This study is the first to report on the functional expression of two PepT2-type transporters that operate in the same vertebrate organism as a result of (a) gene duplication process(es).

Key points summary

Two slc15a2-type genes, slc15a2a and slc15a2b coding for PepT2-type peptide transporters were found in the Atlantic salmon.

slc15a2a transcripts, widely distributed in the fish tissues, are abundant in brain and gills, while slc15a2b transcripts are mainly expressed in kidney and distal gastrointestinal tract.

Amino acids involved in vertebrate Slc15 transport function are conserved in PepT2a and PepT2b proteins.

Detailed kinetic analysis indicates that both PepT2a and PepT2b operate as high-affinity transporters.

The kinetic schemes and structures proposed for the mammalian models of PepT2 are suitable to explain the function of the two Atlantic salmon transporters.
Conifer leaves have a peroxisomal oxidative decarboxylation path in the photorespiratory pathway
Authors: Miyazawa Shin-Ichi , Miyama Takafumi , Tahara Ko , Ujino-Ihara Tokuko , Tobita Hiroyuki , Suzuki Yuji , Nishiguchi Mitsuru
Published: February 2022

The photorespiratory pathway consists of enzymes operating in chloroplasts, mitochondria, and peroxisomes. Conifer leaves lack one of them, chloroplastic Gln synthetase, which questioned the current belief that the photorespiratory mechanism is identical between angiosperm C3 species and conifers. A photorespiratory-metabolite analysis of the leaves of 13 conifer and 14 angiosperm tree species revealed significant differences in the mean metabolite concentrations between the two taxonomic groups: the glycerate content on chlorophyll basis in conifer leaves was <1/10 that detected in angiosperm leaves, whereas the glycolate content was 1.6 times higher in conifer leaves. Glycerate is produced from Ser through an intermediate, hydroxypyruvate. To investigate the lower glycerate levels observed in conifer leaves, we performed experiments of 13C-labeled Ser feeding to the detached shoots of a conifer (Cryptomeria japonica) via the transpiration stream, and compared the labeling patterns of photorespiratory metabolites with those of an angiosperm (Populus nigra). Glycerate was most labeled in P. nigra, whereas glycolate was more labeled than glycerate in C. japonica. The photorespiration pathway involves H2O2-scavenging and H2O2-generating enzymes, catalase (CAT) and glycolate oxidase (GLO), respectively, which are the peroxisomal targeting enzymes in angiosperms. In contrast, database analyses of the peroxisomal targeting signal motifs and analyses of the peroxisomal fractions isolated from C. japonica leaves indicated that the conifer peroxisomes were not a major localization of CAT. These results suggest that the conifer photorespiration pathway has a bypass from Ser to glycolate via the decarboxylation of hydroxypyruvate, because of an imbalance between CAT and GLO activities in peroxisomes.

One sentence summary

Conifer peroxisome is not a major localization of catalase and yields a unique oxidative decarboxylation path in the photorespiratory pathway.
WlzWarp: An Open-Source Tool for Complex Alignment of Spatial Data
Authors: Hill Bill , Husz Zsolt , Armit Chris , Davidson Duncan R. , Murphy Paula , Baldock Richard A.
Published: February 2022

Background

The spatio-temporal organisation of many biological processes such as gene-expression and neuronal activity is critical to understanding the overall biological behaviour, phenotype and disease. This is especially true during embryonic development. During development spatial patterns of gene expression are key to segmentation, tissue differentiation and organ development. In situ techniques can reveal the activity of genes and the presence of proteins to a very high sub-cellular resolution but typically at high resolution only a few probes can be used on any sample therefore to compare many such patterns requires mapping of image-based data to a standard spatial framework. Once mapped those data can be collated, queried and analysed in purely spatial terms to reveal unknown combinatorial gene-activity that could not be discovered any other way. Mapping spatial data to image domains with systematic variation in shape and pose, such as embryos or elongated organs, presents special problems. Automated techniques available for more constrained systems can not deliver the mapping fidelity required to analyse these data therefore we have developed a manual editing tool, WlzWarp, for mapping 3D image data using the constrained distance transform (CDT) which uniquely can deliver the complex transforms required.

Results

We have implemented a fully open-source tool (available on GitHub), WlzWarp to provide interactive complex spatial mapping of 3D image data. We have applied WlzWarp to map a set of gene-expression patterns in the developing mouse embryo that could not be mapped by any other technique. The transform procedure was tested by using multiple images of the same gene from independent samples and thereby testing the full end-to-end mapping process. WlzWarp is implemented in C++ using open-source packages Qt, Coin and SIMVoleon for cross-architecture compatibility. It has been developed under Linux but also tested on Mac OSX and MS Windows.

Conclusions

WlzWarp is a freely available software tool for non-linear registration and alignment of complex 2D & 3D spatial patterns from one image to another or to an atlas model. It has been tested in the context of embryo data but can be used for any 3D or 2D image registration problem.
Characterization of the Interaction of Nanobubble Ultrasound Contrast Agents with Human Blood Components
Authors: Cooley Michaela B. , Abenojar Eric C. , Wegierak Dana , Gupta Anirban Sen , Kolios Michael C. , Exner Agata A.
Published: February 2022

Nanoscale ultrasound contrast agents, or nanobubbles, are being explored in preclinical applications ranging from vascular and cardiac imaging to targeted drug delivery in cancer. These sub-micron particles are approximately 10x smaller than clinically available microbubbles. This allows them to effectively traverse compromised physiological barriers and circulate for extended periods of time. While various aspects of nanobubble behavior have been previously examined, their behavior in human whole blood has not yet been explored. Accordingly, herein we examined, for the first time, the short and long-term effects of blood components on nanobubble acoustic response. We observed differences in the kinetics of backscatter from nanobubble suspensions in whole blood compared to bubbles in phosphate buffered saline (PBS), plasma, or red blood cell solutions (RBCs). Specifically, after introducing nanobubbles to fresh human whole blood, signal enhancement gradually increased by 22.8 ± 13.1% throughout our experiment, with peak intensity reached within 145 seconds. In contrast, nanobubbles in PBS had a stable signal with negligible change in intensity (−1.7 ± 3.2%) over 8 minutes. Under the same conditions, microbubbles made with the same lipid formulation showed a −56.8 ± 6.1% decrease in enhancement. Subsequent confocal, fluorescent, and scanning electron microscopy analysis revealed attachment of the nanobubbles to the surface of RBCs, suggesting that direct interactions, or hitchhiking, of nanobubbles on RBCs in the presence of plasma may be a possible mechanism for the observed effects. This phenomenon could be key to extending nanobubble circulation time and has broad implications in drug delivery, where RBC interaction with nanoparticles could be exploited to improve delivery efficiency.
Neurophysiological Measures of Auditory Sensory Processing are Associated with Adaptive Behavior in Children with Autism Spectrum Disorder
Authors: Cotter Mairin , Tikir Seydanur , Francisco Ana Alves , Oakes Leona , Crosse Michael J. , Foxe John J. , Molholm Sophie
Published: February 2022

Background

Atypical auditory cortical processing is consistently found in scalp electrophysiological and magnetoencephalographic studies of Autism Spectrum Disorder (ASD), and may provide a marker of neuropathological brain development. However, the relationship between atypical cortical processing of auditory information and adaptive behavior in ASD is not yet well understood.

Methods

We sought to test the hypothesis that early auditory processing in ASD is related to everyday adaptive behavior through the examination of auditory event-related potentials (AEPs) in response to simple tones and Vineland Adaptive Behavior Scales in a large cohort of children with ASD (N=89), aged 6-17, and in age- and IQ-matched neurotypically (NT) developing controls (N=120).

Results

Statistical analyses revealed significant group differences in early AEPs over temporal scalp regions. Whereas the expected rightward lateralization of the AEP to tonal stimuli occurred in both groups, lateralization of the AEP was only significantly associated with adaptive functioning, in the domains of communication and daily living, in the ASD group.

Conclusions

These results lend support to the hypothesis that atypical processing of sensory information is related to everyday adaptive behavior in autism.
Vaccine-elicitation of cross-group neutralizing protective antibodies to influenza A viruses
Authors: Moin Syed M. , Boyington Jeffrey C. , Boyoglu-Barnum Seyhan , Gillespie Rebecca A. , Cerutti Gabriele , Cheung Crystal Sao-Fong , Cagigi Alberto , Gallagher John R. , Brand Joshua , Prabhakaran Madhu , Tsybovsky Yaroslav , Stephens Tyler , Fisher Brian E. , Creanga Adrian , Ataca Sila , Rawi Reda , Corbett Kizzmekia S. , Crank Michelle C. , Gorman Jason , McDermott Adrian B. , Harris Audray K. , Zhou Tongqing , Kwong Peter D. , Shapiro Lawrence , Mascola John R. , Graham Barney S. , Kanekiyo Masaru
Published: February 2022

Current influenza vaccines predominantly induce immunity to the hypervariable viral hemagglutinin (HA) head, requiring frequent vaccine reformulation. Conversely, antigenic sites on the conserved HA stem are subdominant and harbor a supersite which is targeted by broadly neutralizing antibodies (bnAbs), making it a prime target for universal vaccines. Here, we show that co-immunization of two stem immunogens derived from influenza A group 1 and 2 HAs elicits cross-group protective immunity and neutralizing antibody responses in mice, ferrets, and nonhuman primates (NHPs). Immunized mice were protected from multiple group 1 and 2 viruses, and all animal models showed broad serum neutralizing activity. A bnAb isolated from an immunized NHP broadly neutralized and conferred protection from viruses including H5N1 and H7N9. Genetic and structural analyses revealed a remarkable convergent evolution between macaque and human bnAbs, illustrating the biophysical constraints for acquiring immunoglobulins with cross-group specificity. Co-immunization of stem immunogens elicits not only group-specific protective immunity, but also cross-group bnAb responses, and represents a step towards broadly protective influenza vaccines.
An optimized method to infer relatedness up to the 5th degree from low coverage ancient human genomes
Authors: Nyerki Emil , Kalmár Tibor , Schütz Oszkár , Lima Rui M. , Neparáczki Endre , Török Tibor , Maróti Zoltán
Published: February 2022

Background

Current state of art kinship analysis is capable to infer relatedness up to the 5-6th degree from deeply sequenced DNA if the proper reference population is known. Low coverage, partially genotyped, degraded archaic (or forensic) DNA and often unavailable or unknown reference population poses additional challenges, hence kinship analysis from low coverage archaic sequences so far has been possible up to the second degree with large uncertainties.

Results

We performed extensive simulations to identify and correct the main factors of bias in kinship analysis from low coverage data. As a result, we introduce a new metric for correction and offer a guideline, which overcomes the difficulties associated with low coverage samples. We validated our methodology on experimental modern and archaic data with widely different genome coverages (0.12x-11.9x) using samples with known family relations and known or unknown population structure. Out of 2526 ancient individuals from the REICH data set we confirmed all 96 indicated, and identified 303 new relatives additionally.

Conclusion

With the proposed workflow we provide the necessary additional tools to calculate the corrected kinship coefficient from the commonly used genome data formats. Our methodology allows to reliably identify relatedness up to the 4-5th degree from variable/low coverage archaic (or badly degraded forensic) WGS genome data.
Sequence-Dependent Backbone Dynamics of Intrinsically Disordered Proteins
Authors: Dey Souvik , MacAinsh Matthew , Zhou Huan-Xiang
Published: February 2022

For intrinsically disordered proteins (IDPs), a pressing question is how sequence codes for function. Dynamics serves as a crucial link, reminiscent of the role of structure in sequence-function relations of structured proteins. To define general rules governing sequence-dependent backbone dynamics, we carried out long molecular dynamics simulations of eight IDPs. Blocks of residues exhibiting large amplitudes in slow dynamics are rigidified by local inter-residue interactions or secondary structures. A long region or an entire IDP can be slowed down by long-range contacts or secondary- structure packing. On the other hand, glycines promote fast dynamics and either demarcate rigid blocks or facilitate multiple modes of local and long-range inter-residue interactions. The sequence-dependent backbone dynamics endows IDPs with versatile response to binding partners, with some blocks recalcitrant while others readily adapting to intermolecular interactions.
Substrate Binding and Inhibition of the Anion Exchanger 1 Transporter
Authors: Capper Michael J. , Yang Shifan , Stone Alexander C. , Vatansever Sezen , Zilberg Gregory , Mathiharan Yamuna Kalyani , Habib Raul , Hutchinson Keino , Schlessinger Avner , Mezei Mihaly , Osman Roman , Zhang Bin , Wacker Daniel
Published: February 2022

Anion Exchanger 1 (AE1, SLC4A1) is the primary bicarbonate (HCO3-) transporter expressed in erythrocyte membranes where it mediates transport of CO2between lungs and other tissues via import/export of bicarbonate. It is also a key regulator of erythrocyte structure and antigenic recognition. Previous biochemical studies, and a low-resolution crystal structure of the transmembrane domain have provided initial insight into AE1 structure and function. However, key questions remain regarding substrate binding and transport as well as the mechanism of inhibition. The orientation of the intracellular domain as well as the localization of lipid and sterol binding sites also remain enigmatic. We herein present seven novel high resolution cryo-EM structures of the full length human transporter in the apo, bicarbonate-bound, and several inhibitor-bound states combined with uptake- and computational studies. To our knowledge, these studies represent the first full length human, and substrate bound, SLC4 transporter structure. Our results reveal important molecular details about substrate binding and transport, as well as the diverse mechanisms of AE1 inhibition by both research chemicals and prescription drugs. We also provide novel insights into the full-length transporter architecture, identify the conformational space of the Diego blood antigen system and elucidate multiple lipid and sterol binding sites.
TheDrosophilachemokine-like Orion bridges phosphatidylserine and Draper in phagocytosis of neurons
Authors: Ji Hui , Wang Bei , Shen Yifan , Labib David , Lei Joyce , Chen Xinchen , Sapar Maria , Boulanger Ana , Dura Jean-Maurice , Han Chun
Published: February 2022

Phagocytic clearance of degenerating neurons is triggered by “eat-me” signals exposed on the neuronal surface. The conserved neuronal eat-me signal phosphatidylserine (PS) and the engulfment receptor Draper (Drpr) mediate phagocytosis of degenerating neurons inDrosophila. However, how PS is recognized by Drpr-expressing phagocytesin vivoremains poorly understood. Using multiple models of dendrite degeneration, we show that theDrosophilachemokine-like protein Orion can bind to PS and is responsible for detecting PS exposure on neurons; it is supplied cell-non-autonomously to coat PS-exposing dendrites and to mediate interactions between PS and Drpr, thus enabling phagocytosis. As a result, the accumulation of Orion on neurons and on phagocytes produces opposite outcomes by potentiating and suppressing phagocytosis, respectively. Moreover, the Orion dosage is a key determinant of the sensitivity of phagocytes to PS exposed on neurons. Lastly, mutagenesis analyses show that the sequence motifs shared between Orion and human immunomodulatory proteins are important for Orion function. Thus, our results uncover a missing link in PS-mediated phagocytosis inDrosophilaand imply conserved mechanisms of phagocytosis of neurons.

SIGNIFICANCE STATEMENT

Phagocytes efficiently clear sick or damaged neuronal branches by engulfing them, while leaving healthy branches untouched. How phagocytes recognize degenerating neurites remains poorly understood. Here, we identified a key role for the secreted protein Orion in the detection and engulfment of degenerating neurites inDrosophila. Using multiple models of dendrite degeneration, we found that Orion acts as a bridging molecule between the neuronal “eat-me” signal phosphatidylserine and the engulfment receptor Draper on phagocytes, enabling phagocytosis. Our study reveals a missing link in phosphatidylserine-mediated phagocytosisin vivo, sheds light on factors determining the sensitivity of phagocytes, and implies the potential for manipulating the detection of neuronal “eat-me” signals in neurodegenerative diseases.
Kinase Suppressor of Ras 2 promotes self-renewal and clonogenicity of small-cell lung carcinoma
Authors: Huisman Dianna H. , Chatterjee Deepan , Svoboda Robert A. , Vieira Heidi M. , Ireland Abbie S. , Skupa Sydney , Askew James W. , Frodyma Danielle E. , Girard Luc , Fisher Kurt W. , Kareta Michael S. , Minna John D. , Oliver Trudy G. , Lewis Robert E.
Published: February 2022

Small-cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. Here, we show that Kinase Suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells (PNECs) was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony forming ability of tumor propagating cells (TPCs)in vitroand their tumor initiating capacityin vivo.The effect of KSR2 depletion on self-renewal and clonogenicity is dependent on the interaction of KSR2 with ERK. These data indicate that the expression of KSR2 is an essential driver of SCLC-A tumor propagating cell function, and therefore may play a role in SCLC tumor initiation. These findings shed light on a novel effector promoting initiation of ASCL1-subtype SCLC tumors, and a potential subtype-specific therapeutic target.

Statement of Implication

Manipulation of the molecular scaffold KSR2 in ASCL1-subtype small-cell lung cancer cells reveals its contribution to self-renewal, clonogenicity, and tumor initiation.
Blockade of ghrelin receptor signaling enhances conditioned passive avoidance and context-associated neural circuit activation in fasted male rats
Authors: Edwards Caitlyn M. , Guerrero Inge Estefania , Dolezel Tyla , Zheng Huiyuan , Rinaman Linda
Published: February 2022

Interoceptive feedback to the brain regarding the body’s physiological state plays an important role in guiding motivated behaviors. For example, a state of negative energy balance tends to increase exploratory/food-seeking behaviors while reducing avoidance behaviors. We recently reported that overnight food deprivation reduces conditioned passive avoidance behavior in male (but not female) rats. Since fasting increases circulating levels of ghrelin, we hypothesized that ghrelin signaling contributes to the ability of fasting to reduce conditioned avoidance. To test this,ad libitum-fed male rats were trained in a passive avoidance procedure using mild footshock. Later, following overnight food deprivation, the same rats were pretreated with ghrelin receptor antagonist (GRA) or saline vehicle 30 min before avoidance testing. GRA restored passive avoidance in fasted rats as measured both by latency to enter and time spent in the shock-paired context. In addition, compared to vehicle-injected fasted rats, fasted rats that received GRA before re-exposure to the shock-paired context displayed more activation of prolactin-releasing peptide (PrRP)-positive noradrenergic neurons in the caudal nucleus of the solitary tract, accompanied by more activation of downstream neurons in the bed nucleus of the stria terminalis and paraventricular nucleus of the hypothalamus. These results support the view that ghrelin signaling contributes to the inhibitory effect of fasting on learned passive avoidance behavior, perhaps by suppressing recruitment of PrRP-positive noradrenergic neurons and their downstream hypothalamic and limbic forebrain targets.
In vivo calcium imaging identifies functionally and molecularly distinct subsets of tongue-innervating mechanosensory neurons
Authors: Moayedi Yalda , Xu Shan , Obayashi Sophie K , Hoffman Benjamin U , Gerling Gregory J , Lumpkin Ellen A
Published: February 2022

Mechanosensory neurons in the mouth provide essential information to guide feeding and speech. How classes of oral mechanoreceptors contribute to oral behaviors is not well understood; in particular, the functional properties of lingual mechanoreceptors remain elusive. Previous work identified putative mechanosensory endings in the tongue with novel morphologies; how these fit into current knowledge of mechanosensory neuron classification is not known. To identify functional classes of lingual mechanosensory neurons, we used in vivo calcium imaging of trigeminal ganglia. We first investigated calcium responses of tongue-innervating trigeminal neurons to thermal and mechanical stimulation (e.g., pressure, fluid flow, temperature changes). We found that around 17% of neurons responded to pressure, and that these pressure responders were significantly larger than neurons that only responded to temperature changes. To further investigate the cadre of functionally distinct mechanosensory neurons, we tested responses to brushing and sustained pressures and found that brush-sensitive neurons comprise the majority of tongue-innervating mechanosensory trigeminal neurons. Qualitatively, mechanosensory neurons responded to pressure with distinct kinetics, suggesting the presence of multiple classes of mechanoreceptors. To determine the number of classes, we developed an unbiased multi-layer hierarchical clustering approach to classify calcium response characteristics to pressure stimulation. This approach revealed that mechanosensory neurons displayed five distinct stimulus-response profiles to pressure. Classes include neuronal populations with sustained, transient, high-threshold, and negative responses to force as well as neurons that responded only to brushing. Analysis of cluster representation in transgenic animals with only subsets of labeled neurons reveals molecular markers of clusters and end organ structures. These studies are amongst the first to determine the functional properties of low-threshold mechanosensory neurons innervating the mouse tongue.
A Self-attention Graph Convolutional Network for Precision Multi-tumour Early Diagnostics with DNA Methylation Data
Authors: Jiang Xue , Li Zhiqi , Mehmood Aamir , Wang Heng , Wang Qiankun , Chu Yanyi , Mao Xueying , Zhao Jing , Jiang Mingming , Zhao Bowen , Lin Guanning , Wang Edwin , Wei Dongqing
Published: February 2022

DNA methylation data-based precision tumor early diagnostics is emerging as state of the art technology, which could capture the signals of cancer occurrence 3∼5 years in advance and clinically more homogenous groups. At present, the sensitivity of early detection for many tumors is about 30%, which needs to be significantly improved. Nevertheless, based on the genome wide DNA methylation information, one could comprehensively characterize the entire molecular genetic landscape of the tumors and subtle differences among various tumors. With the accumulation of DNA methylation data, we need to develop high-performance methods that can model and consider more unbiased information. According to the above analysis, we have designed a self-attention graph convolutional network to automatically learn key methylation sites in a data-driven way for precision multi-tumor early diagnostics. Based on the selected methylation sites, we further trained a multi-class classification support vector machine. Large amount experiments have been conducted to investigate the performance of the computational pipeline. Experimental results demonstrated the effectiveness of the selected key methylation sites which are highly relevant for blood diagnosis.
The UCLA ATLAS Community Health Initiative: promoting precision health research in a diverse biobank
Authors: Johnson Ruth , Ding Yi , Bhattacharya Arjun , Chiu Alec , Lajonchere Clara , Geschwind Daniel H. , Pasaniuc Bogdan
Published: February 2022

The UCLA ATLAS Community Health Initiative (ATLAS) has an initial target to recruit 150,000 participants from across the UCLA Health system, with the goal of creating a genomic database to accelerate precision medicine efforts in California. This initiative includes a biobank embedded within the UCLA Health system that comprises de-identified genomic data linked to electronic health records (EHR). The first freeze of data from September 2020 contains 27,987 genotyped samples imputed to 7.9 million SNPs across the genome and is linked with a de-identified EHR extract. This database enables the study of numerous clinically-related phenotypes within the same medical system. Here we describe a centralized repository of the genotype data and provide tools and pipelines to perform genome-wide and phenome-wide association studies across a wide range of EHR-derived phenotypes and genetic ancestry groups. We demonstrate the utility of this resource through the analysis of 7 well-studied traits and recapitulate many previous genetic and phenotypic associations.
Divergence amid recurring gene flow: complex demographic histories for two North American pines (Pinus pungens and P. rigida) fit growing expectations among forest trees
Authors: Bolte Constance E. , Faske Trevor M. , Friedline Christopher J. , Eckert Andrew J.
Published: February 2022

Long-lived species of trees, especially conifers, often display weak patterns of reproductive isolation, but clear patterns of local adaptation and phenotypic divergence. Discovering the evolutionary history of these patterns is paramount to a generalized understanding of speciation for long-lived plants. We focus on two closely related yet phenotypically divergent pine species, Pinus pungens and P. rigida, that co-exist along high elevation ridgelines of the southern Appalachian Mountains. In this study, we performed historical species distribution modeling (SDM) to form hypotheses related to population size change and gene flow to be tested in a demographic inference framework. We further sought to identify drivers of divergence by associating climate and geographic variables with genetic structure within and across species boundaries. Population structure within each species was absent based on genome-wide RADseq data. Signals of admixture were present range-wide, however, and species-level genetic differences associated with precipitation seasonality and elevation. When combined with information from contemporary and historical species distribution models, these patterns are consistent with a complex evolutionary history of speciation influenced by Quaternary climate. This was confirmed using inferences based on the multidimensional site- frequency spectrum, where demographic modeling inferred recurring gene flow since divergence (2.74 million years ago) and population size reductions that occurred during the last glacial period (∼35.2 thousand years ago). This suggests that phenotypic and genomic divergence, including the evolution of divergent phenological schedules leading to partial reproductive isolation, as previously documented for these two species, can happen rapidly, even between long-lived species of pines.
The Role of Glycocalyx Steric Effects on Viral Endocytosis*
Authors: Buckley Joseph , Battaglia Giuseppe
Published: February 2022

Understanding the mechanisms of viral entry is key to aiding the development of effective anti-viral treatments. In this work, we produce a simple thermodynamic model of viral entry, which is able to predict the differences between viruses. We also show that the glycocalyx, which is often neglected in studies of cell-entry, plays a key role, and the density and structure of the glycocalyx can determine whether or not a virus can enter the cell. We further find that co-receptors play not only a signalling role, but an important thermodynamic role in viral entry. We then show that this model can be used to calculate the cell-entry probabilities of a given virus, which can shine a light on the clinical observations associated with a virus.
Mentalizing in an economic games context is associated with enhanced activation and connectivity in left temporoparietal junction
Authors: Chang Li-Ang , Warns Lotte , Armaos Konstantinos , Ma de Sousa Ava Q. , Paauwe Femke , Scholz Christin , Engelmann Jan B.
Published: February 2022

Studies in Social Neuroeconomics have consistently reported activation in social cognition regions during interactive economic games suggesting mentalizing during economic choice. It remains important to test the involvement of neural activity associated with mentalizing in an economic games context within the same sample of participants performing the same task. We designed a novel version of the classic false-belief task in which participants observed interactions between agents in the ultimatum and trust games and were subsequently asked to infer the agents’ beliefs. We compared activation patterns during the economic-games false-belief task to those during the classic false-belief task using conjunction analyses. We find significant overlap in left TPJ, and dmPFC, as well as temporal pole during two task phases: belief formation and belief inference. Moreover, gPPI analyses show that during belief formation right TPJ is a target of both left TPJ and right temporal pole (TP) seed regions, while during belief inferences all seed regions show interconnectivity with each other. These results indicate that across different task types and phases, mentalizing is associated with activation and connectivity across central nodes of the social cognition network. Importantly, this is the case in the context of the novel economic-games and classic false-belief tasks.
Genetic analysis ofC. elegansHaspin-like genes shows thathasp-1plays multiple roles in the germline
Authors: Macaraeg Jommel , Reinhard Isaac , Ward Matthew , Carmeci Danielle , Stanaway Madison , Moore Amy , Hagmann Ethan , Brown Katherine , Wynne David J
Published: February 2022

Haspin is a histone kinase that promotes error-free chromosome segregation by recruiting the Chromosomal Passenger Complex (CPC) to mitotic and meiotic chromosomes. Haspin remains less well studied than other M-phase kinases and the models explaining Haspin function have been developed primarily in mitotic cells. Here, we generate new mutations in theC. elegansHaspin homologshasp-1andhasp-2and characterize their phenotypes. We show thathasp-1is responsible for all predicted functions of Haspin and that loss of function ofhasp-1using classical and conditional alleles produces defects in germline stem cell proliferation, spermatogenesis, and confirms its role in oocyte meiosis. Genetic analysis suggestshasp-1acts downstream of the Polo-like kinaseplk-2and shows synthetic interactions betweenhasp-1and two genes expected to promote recruitment of the CPC by a parallel pathway that depends on the kinase Bub1. This work adds to the growing understanding of Haspin function by characterizing a variety of roles in an intact animal.

Summary statement

We characterize new mutations in theC. eleganshomologs of the histone kinase Haspin and show roles in spermatogenesis, germline proliferation and genetic interactions during oocyte meiosis.
Shrimp vaccination with insect-adapted yellow head virus (YHV) extends survival upon YHV challenge
Authors: Gangnonngiw Warachin , Kanthong Nipaporn
Published: February 2022

This short paper on yellow head virus Type1 (YHV-1) describes preliminary research worthy of further study. YHV-1 disease outbreaks can cause severe mortality in the cultivated shrimp Penaeus (Penaeus) monodon and Penaeus (Litopenaeus) vannamei. No practical preventative treatment such as vaccination has been reported. However, it has been shown that C6/36 mosquito cell cultures can adapt to YHV-1 and become persistently immunopositive for the virus after 30 split-cell passages or more. Shrimp injection with homogenates from low passages caused yellow head disease (YHD) but from high passages did not, even though injection resulted in immunopositive hemocytes in the injected shrimp. This suggested YHV-1 attenuation during insect cell passaging and the possibility of using cell homogenates as a vaccine to protect shrimp against virulent YHV-1. To test this hypothesis, we injected shrimp with 30th passage homogenates to test for protection against YHD upon subsequent challenge with virulent YHV-1. Results confirmed earlier work that hemocytes of the infected shrimp became both reverse transcriptase PCR positive and immunopositive for YHV-1 but exhibited no mortality. Similarly, there was no mortality in the control group injected with homogenate from YHV-1 negative insect cells. When subsequently challenged with YHV-1, shrimp in the positive control group injected with homogenate from naïve insect cells gave 100 percent mortality within 7 days post challenge while total mortality in the group injected with YHV-1 homogenate did not occur until day 9 post challenge. Kaplan-Meier log-rank survival analysis revealed that survival curves for the two groups were significantly different (p<0.001) and that the mean survival time for the test group (6.5 days) was significantly longer than that in the positive control group (5.4 days). The results confirmed that shrimp injection with YHV-1 immunopositive insect-cell homogenate gave transient resistance to YHV infection and that further research into the possible use of insect cell lines to produce shrimp antiviral vaccines is warranted.