bluuebunny/crossref_metadata_2025 huggingface dataset:
PARG establishes a functional module with BRCA1-BARD1 that controls DNA repair pathway choice during gametogenesis
Authors: Trivedi Shalini , Blazicková Jitka , Silva Nicola
Published: June 2022

During meiosis, accurate chromosome segregation relies on the formation of programmed DNA double-strand breaks (DSBs). These are in turn repaired by homologous recombination (HR), generating physical attachments between the parental chromosomes called crossovers (COs). Fewer breaks yield recombinant outcomes, while CO-independent mechanisms are employed for repairing the majority of lesions. The balance between different repair pathways is crucial to ensure genome fidelity and to preserve its integrity. We show that Caenorhabditis elegans BRC-1/BRCA1-BRD-1/BARD1 and PARG-1/PARG form a complex in vivo, that is essential for accurate DNA repair in the germline. Contemporary depletion of BRC-1 and PARG-1 causes synthetic lethality due to reduced CO formation and impaired DSB repair, as evidenced by hindered RPA-1 removal and presence of aberrant chromatin bodies in diakinesis nuclei, whose formation depends on spo-11 function. These factors largely co-localize and undergo independent loading in developing oocytes, consistent with operating in different pathways. Abrogation of KU- or Theta-mediated end joining elicits opposite effects in brc-1; parg-1 doubles, highlighting differential involvement of DNA repair pathways and suggesting a profound impact in influencing DNA repair pathway choice by BRC-1-PARG-1. Importantly, lack of PARG-1 catalytic activity suppresses untimely accumulation of RAD-51 foci in brc-1 mutants but is only partially required to maintain fertility. Altogether, our data show that BRC-1/BRD-1-PARG-1 joined function is essential to keep genome integrity in meiotic cells by regulating multiple DNA repair pathways.
Hamilton’s rule, the evolution of behavior rules and the wizardry of control theory
Authors: Lehmann Laurent
Published: June 2022

This paper formalizes selection on a quantitative trait affecting the evolution of behavior (or development) rules through which individuals act and react with their surroundings. Combining Hamilton’s marginal rule for selection on scalar traits and concepts from optimal control theory, a necessary first-order condition for the evolutionary stability of the trait in a group-structured population is derived. The model, which is of intermediate level of complexity, fills a gap between the formalization of selection on evolving traits that are directly conceived as actions (no phenotypic plasticity) and selection on evolving traits that are conceived as strategies or function valued actions (complete phenotypic plasticity). By conceptualizing individuals as open deterministic dynamical systems expressing incomplete phenotypic plasticity, the model captures selection on a large class of phenotypic expression mechanisms, including developmental pathways and learning under life-history trade-offs. As an illustration of the results, a first-order condition for the evolutionary stability of behavior response rules from the social evolution literature is re-derived, strengthened, and generalized. All results of the paper also generalize directly to selection on multidimensional quantitative traits affecting behavior rule evolution, thereby covering neural and gene network evolution.
Early-Life Stress Impairs Perception and Neural Encoding of Rapid Signals in the Auditory Pathway
Authors: Ye Yi , Mattingly Michelle M. , Sunthimer Matthew J. , Gay Jennifer D. , Rosen Merri J.
Published: June 2022

In children, early ear infections are a risk factor for later speech perception deficits. This is likely because auditory deprivation during a developmental critical period (CP) induces long-lasting deficits in perception and ACx encoding of temporally-varying sounds. CPs also create susceptibility to early-life stress (ELS) in neural regions involved with cognition and anxiety. As CP mechanisms are shared by sensory cortices and higher neural regions, ACx and temporal encoding may also be susceptible to ELS. To examine the effects of ELS on temporal processing, we developed a model of ELS in the Mongolian gerbil, a well-established model for auditory processing. ELS induction impaired the behavioral detection of short gaps in sound, which are critical for speech perception. This was accompanied by reduced neural responses to gaps in ACx, the auditory periphery, and auditory brainstem. These ELS effects presumably degrade the fidelity of sensory representations available to higher regions, and could contribute to ELS-induced problems with cognition.
Distinct hippocampal and cortical contributions in the representation of hierarchies
Authors: Scholz Robert , Villringer Arno , Martins Mauricio J.D.
Published: June 2022

Humans generate complex hierarchies across a variety of domains, including language and music, and this capacity is often associated with activity in inferior frontal gyrus (IFG). Non-human animals have also been shown to represent simple hierarchies in spatial navigation, and human neuroimaging work has implicated the hippocampus in the encoding of items-in-contexts representations, which constitute 2-level hierarchical dependencies. These fields of research use distinct paradigms, leading to disjoint models and precluding adequate cross-species comparisons. In this study, we developed a paradigm to bring together these two areas of research and show that anterior hippocampus and medial prefrontal cortex encode hierarchical context, mimicking findings from animal spatial navigation. Additionally, we replicated classic neurolinguistic findings of 1) left IFG and posterior temporal cortex in the representation of hierarchies and 2) the association between IFG and processing automaticity. We propose that mammals share an evolutionary ancient system for the generation of simple hierarchies which is complemented in humans by additional capacities.

Highlights

HPC and mPFC activity is specifically modulated by hierarchical context

Syntax-related regions in the left hemisphere encode for hierarchy in general

IFGop activity is maintained in later trials for hierarchies but not sequences

These findings mimic those from animal spatial navigation and neurolinguistics
Quantifying oligomer populations in real time during protein aggregation using single-molecule mass photometry
Authors: Paul Simanta Sarani , Lyons Aaron , Kirchner Russell , Woodside Michael T.
Published: June 2022

Protein aggregation is a hallmark of many neurodegenerative diseases. The early stages of the aggregation cascade are crucial because small oligomers are thought to be key neurotoxic species, but they are difficult to study because they feature heterogeneous mixtures of transient states. We show how the populations of different oligomers can be tracked as they evolve over time during aggregation by using single-molecule mass photometry to measure individually the masses of the oligomers present in solution. Applying the approach to tau protein, whose aggregates are linked to diseases including Alzheimer’s and frontotemporal dementia, we found that tau existed in an equilibrium between monomers, dimers, and trimers before aggregation was triggered. Once aggregation commenced, the monomer population dropped continuously, paired first with a rise in the population of the smallest oligomers and then a steep drop as the protein was incorporated into larger oligomers and fibrils. Fitting these populations to kinetic models allowed different models of aggregation to be tested, identifying the most likely mechanism and quantifying the microscopic rates for each step in the mechanism. This work demonstrates a powerful new approach for characterizing previously inaccessible regimes in protein aggregation and building quantitative mechanistic models.
Multi-omics alleviates the limitations of panel-sequencing for cancer drug response prediction
Authors: Baranovskii Artem , Gunduz Irem B. , Franke Vedran , Uyar Bora , Akalin Altuna
Published: June 2022

Comprehensive genomic profiling using cancer gene panels has been shown to improve treatment options for a variety of cancer types. However, genomic aberrations detected via such gene panels don’t necessarily serve as strong predictors of drug sensitivity. In this study, using pharmacogenomics datasets of cell lines, patient-derived xenografts, and ex-vivo treated fresh tumor specimens, we demonstrate that utilizing the transcriptome on top of gene panel features substantially improves drug response prediction performance in cancer.
Integrated Proteomics Identifies Neuritin (NRN1) as a Mediator of Cognitive Resilience to Alzheimer’s Disease
Authors: Hurst Cheyenne , Pugh Derian A. , Abreha Measho H. , Duong Duc M. , Dammer Eric B. , Bennett David A. , Herskowitz Jeremy H. , Seyfried Nicholas T.
Published: June 2022

We present an integrative proteomic strategy for the nomination and validation of proteins associated with cognitive resilience to Alzheimer’s disease (AD). Correlation network analysis across distinct stages of AD was used to prioritize protein modules linked to resilience. Neuritin (NRN1), a hub protein in a module associated with synaptic biology, was identified as a top candidate of resilience and selected for functional validation in cultured neurons. NRN1 provided dendritic spine resilience against amyloid-β (Aβ), and NRN1 blocked Aβ-induced neuronal hyperexcitability. The impact of exogenous NRN1 on the proteome of cultured neurons was assessed and integrated with the AD brain network. This revealed over-lapping synapse-related biology that linked NRN1-induced changes in cultured neurons with human pathways associated with AD resilience. Collectively, this highlights the utility of integrating the proteome from human brain and model systems to prioritize therapeutic targets that mediate resilience to AD.
CITED2 is a Conserved Regulator of the Uterine-Placental Interface
Authors: Kuna Marija , Dhakal Pramod , Iqbal Khursheed , Dominguez Esteban M. , Kent Lindsey N. , Muto Masanaga , Moreno-Irusta Ayelen , Kozai Keisuke , Varberg Kaela M. , Okae Hiroaki , Arima Takahiro , Sucov Henry M. , Soares Michael J.
Published: June 2022

Establishment of the hemochorial uterine-placental interface requires exodus of trophoblast cells from the placenta and their transformative actions on the uterus, which represent processes critical for a successful pregnancy, but are poorly understood. We examined the involvement of CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) in rat and human trophoblast cell development. The rat and human exhibit deep hemochorial placentation. CITED2 was distinctively expressed in the junctional zone and invasive trophoblast cells of the rat. HomozygousCited2gene deletion resulted in placental and fetal growth restriction. SmallCited2null placentas were characterized by disruptions in the junctional zone, delays in intrauterine trophoblast cell invasion, and compromised plasticity. In the human placentation site, CITED2 was uniquely expressed in the extravillous trophoblast (EVT) cell column and importantly contributed to development of the EVT cell lineage. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation.

Significance Statement

The process of establishing the uterine-placental interface is a poorly understood tissue re-engineering event that involves genetically foreign trophoblast cells breaching the immunologically secure uterus. When optimal, mother and fetus thrive, whereas failures represent the root cause of life-threatening diseases of pregnancy. CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) is a transcriptional co-regulator with a conspicuous presence in trophoblast cell lineages infiltrating the uterine parenchyma. CITED2 helps coordinate the differentiation of rat and human trophoblast cells into invasive/extravillous trophoblast cells capable of transforming the uterus. These actions ensure requisite placental development and adaptations to physiological stressors. CITED2 exemplifies a conserved regulator of transcriptional events essential for establishing the uterine-placental interface.
cAMP−EPAC−PKCε−RIM1α signaling regulates presynaptic long-term potentiation and motor learning
Authors: Wang Xin-Tai , Zhou Lin , Xu Fang-Xiao , Wang De-Juan , Cai Xin-Yu , Wang Yin , Ji Sheng-Jian , Schonewille Martijn , Zhu J. Julius , De Zeeuw Chris I. , Shen Ying
Published: June 2022

The cerebellum is involved in learning of fine motor skills, yet whether presynaptic plasticity contributes to such learning remains elusive. Here we report that the EPAC-PKCε module has a critical role in a presynaptic form of long-term potentiation in the cerebellum and motor behavior. Presynaptic cAMP−EPAC−PKCε signaling cascade induces a previously unidentified threonine phosphorylation of RIM1α, and thereby initiates the assembly of the Rab3A−RIM1α−Munc13-1 tripartite complex that facilitates docking and release of synaptic vesicles. Granule cell-specific blocking of EPAC−PKCε signaling abolishes presynaptic long-term potentiation at the parallel fiber to Purkinje cell synapses and impairs basic performance and learning of cerebellar motor behavior. These results unveil a functional relevance of presynaptic plasticity that is regulated through a novel signaling cascade, thereby enriching the spectrum of cerebellar learning mechanisms.
Glutamatergic neuron types in the amygdala of the urodele amphibian Pleurodeles waltl
Authors: Deryckere Astrid , Woych Jamie , Jaeger Eliza C. B. , Tosches Maria Antonietta
Published: June 2022

The amygdala is a complex brain structure in the vertebrate telencephalon, essential for regulating social behaviors, emotions and (social) cognition. In contrast to the vast majority of neuron types described in the many nuclei of the mammalian amygdala, little is known about the neuronal diversity in non-mammals, making reconstruction of its evolution particularly difficult. Here, we characterize glutamatergic neuron types in the amygdala of the salamander Pleurodeles waltl. Our single-cell RNA sequencing data indicate the existence of at least ten distinct types and subtypes of glutamatergic neurons in the salamander amygdala. In situ hybridization for marker genes indicates that these neuron types are located in three major subdivisions: the lateral amygdala, the medial amygdala, and a newly-defined area demarcated by high expression of the transcription factor Sim1. The gene expression profiles of these neuron types suggest similarities with specific neuron types in the sauropsid and mammalian amygdala, and in particular the evolutionary conservation of Sim1-expressing amygdalar neurons in tetrapods. Taken together, our results reveal a surprising diversity of glutamatergic neuron types in the amygdala of salamanders, despite the anatomical simplicity of their brain.
Source to sink partitioning is altered by the expression of the transcription factor AtHB5
Authors: Raminger L , Miguel VN , Zapata C. , Chan RL , Cabello JV
Published: June 2022

Carbohydrates are transported from source to sink tissues. The efficiency of such transport determines plant growth and development. The process is finely regulated, and transcription factors are crucial in such modulation. AtHB5 is a homeodomain-leucine zipper I transcription factor, repressed during stem secondary growth. However, its function in this developmental event was unknown. Here, we investigated the expression pattern and role of AtHB5. AtHB5 localized in conductive tissues: roots, hypocotyls, stems, pedicels, and central leaf veins. Mutant plants exhibited wider and more lignified stems than controls, whereas overexpressors showed the opposite phenotype. Cross-sections of athb5 mutant stems showed enlarged vascular bundle, xylem, phloem, and petiole areas, whereas AtHB5 overexpressors exhibited callose deposits. Several genes involved in starch biosynthesis and degradation had altered transcript levels in athb5 mutants and AtHB5 overexpressors. Rosette and stem biomasses were enhanced in athb5 mutants, positively impacting seed yield and lipid content. Moreover, these effects were more evident in debranched plants. Finally, the transport to roots significantly slowed down in AtHB5 overexpressors.

Altogether, the results indicated that AtHB5 is a negative modulator of sucrose transport from source to sink tissues, and its overexpression diminished plant biomass and seed yield.

Highlight

The homeodomain-leucine zipper transcription factor AtHB5 is expressed in different tissues along the life cycle, repressing carbohydrate transport from source to sink and promoting callose and lignin deposition. AtHB5 mutants exhibit physiological differences with the wild-type, impacting seed yield and lipid content.
Sex-specific age-related changes in excitatory and inhibitory intra-cortical circuits in mouse primary auditory cortex
Authors: Xue Binghan , Kao Joseph P-Y , Kanold Patrick O.
Published: June 2022

A common impairment in aging is age-related hearing loss (presbycusis), which manifests as impaired spectrotemporal processing. Aging is accompanied by alteration in normal inhibitory (GABA) neurotransmission and changes in excitatory (NMDA and AMPA) synapses in the auditory cortex (ACtx). However, the circuit mechanisms responsible for age-related auditory dysfunction remain unknown. Here we investigated how auditory cortical microcircuits change with age. We performed laser-scanning photostimulation (LSPS) combined with whole-cell patch clamp recordings from Layer (L) 2/3 cells in primary auditory cortex (A1) in young adult (postnatal day (P) 47-P72) and aged (P543 to P626) male and female CBA/CaJ mice. We found that L2/3 cells in aged male animals display functional hypoconnectivity of both excitatory and inhibitory circuits originating from L4. Compared to cells from young adult mice, cells from aged male mice have fewer inhibitory connections from L4 while female mice show weaker connection strength. These results suggest a sex-specific reduction in excitatory and inhibitory intralaminar cortical circuits in aged mice compared with young adult animals. We speculate that these unbalanced changes in cortical circuits contribute to the functional manifestations of age-related hearing loss in both males and females.
Inferring CTCF binding patterns and anchored loops across human tissues and cell types
Authors: Xu Hang , Yi Xianfu , Wang Wei , Chu Xinlei , Zhang Shijie , Dong Xiaobao , Wang Zhao , Wang Jianhua , Zhou Yao , Zhao Ke , Yao Hongcheng , Nan Zheng , Wang Junwen , Plewczynski Dariusz , Sham Pak Chung , Chen Kexin , Huang Dandan , Li Mulin Jun
Published: June 2022

CCCTC-binding factor (CTCF) is a transcription regulator which is involved in many cellular processes. How CTCF recognizes DNA sequence to exert chromosome barrier or enhancer blocking effects remains to be fully interrogated. Despite many computational tools were developed to predict CTCF-mediated loops qualitatively or quantitatively, few could specially evaluate the regulatory potential of DNA sequence at CTCF binding sites (CBSs) and how it affects chromatin loop formation. Here, we developed a deep learning model, DeepAnchor, to precisely characterize the binding patterns for different types of CBSs. By incorporating base-wise genomic/epigenomic features, we revealed distinct chromatin and sequence features for CTCF-mediated insulation and looping at a high resolution, such as two sequence motifs flanking the core CTCF motif at loop-associated CBSs. Besides, we leveraged the predicted anchor score to optimize the loop extrusion model and achieved the best performance in predicting CTCF-anchored loops. We established a compendium of context-specific CTCF-anchored loops across 52 human tissue/cell types and found that genomic disruption of CTCF-anchored loops may represent a general causal mechanism of disease pathogenesis. These computational models, together with the established resource, could facilitate the mechanistic research on how the CTCF-mediatedcis-regulatory elements (CREs) shapes context-specific gene regulation in cell development and disease progression.
A library of promoter-gfpfusion reporters for studying systemic expression pattern of cyclic-di-GMP metabolism-related genes inPseudomonas aeruginosa
Authors: Liu Dejian , Wang Di , Wei Qing , Zhang Yu , Ma Luyan Z
Published: June 2022

The opportunistic pathogenPseudomonas aeruginosais an environmental microorganism, which is notorious for its resistance or tolerance to antibiotics due to the formation of biofilms. Cyclic diguanosine monophosphate (c-di-GMP) is a bacterial second messenger that plays critical roles in biofilm formation.P. aeruginosacontains 41 genes that encode enzymes to participate in the metabolism of c-di-GMP (biosynthesis or degradation), yet it lacks tools to investigate the systemic expression pattern of those genes. Here, we constructed a promoter-gfptranscriptional fusion reporters’ library that consists of 41 reporter plasmids. Each plasmid contains a promoter of correspondingc-di-GMPmetabolism-related (CMR) genes fromP. aeruginosaPAO1 strain, thus each promoter-Gfp fusion reporter can be used to detect the promotor’ activity as well as the transcription of corresponding gene. The promoters’ activity was tested inP. aeruginosaandEscherichia colirespectively. Among the 41 genes, the promoter of 26 genes showed activity in bothP. aeruginosaandE. coli. The library was applied to determine the influence of different temperatures, growth media, and sub-inhibitory concentrations of antibiotics on transcriptional profile of the 41 CMR genes inP. aeruginosa. The results showed different growth conditions did impact different genes’ transcription, while the promoter’ activity of a few genes kept at the same level under several different growth conditions. In summary, we provided a promoter-gfpfusion reporters’ library for systemic monitoring or study of the regulation of CMR genes inP. aeruginosaand the functional promoters can also be used as a bio-brick for synthetic biology studies.

Importance

The opportunistic pathogenP. aeruginosacan cause acute and chronic infections in humans and it is one of main pathogens in nosocomial infections. Biofilm formation is one of most important causes forP. aeruginosato persist in hosts and evade immune and antibiotic attacks. c-di-GMP is an important second messenger to control biofilm formation. InP. aeruginosa, there are 41 genes that are predicted to participate in the making and breaking this dinucleotide. A major missing information in this field is the systemic expression profile of those genes in response to changing environment. Toward this goal, we constructed a promoter-gfptranscriptional fusion reporters’ library that consists of 41 reporter plasmids, each of which contains a promoter of corresponding c-di-GMP metabolism-related genes inP. aeruginosa. This library provides a helpful tool to understand the complex regulation network related to c-di-GMP and to discover potential therapeutic targets.
Potent clinical predictive and systemic adjuvant therapeutic value of plasma fractalkine in PD-L1/PD-1 blockade immunotherapy for lung cancer
Authors: Bocanegra Ana , Fernández Gonzalo , Ajona Daniel , Arasanz Hugo , Blanco Ester , Zuazo Miren , Chocarro Luisa , Piñeiro-Hermida Sergio , Morente Pilar , Fernández Leticia , Garnica Maider , Remirez Ana , Martinez-Aguillo Maite , Morilla Idoia , Tavira Beatriz , Ramos Pablo , Echaide Miriam , Lasarte Juan José , Montuenga Luis , Vera Ruth , Pio Ruben , Escors David , Kochan Grazyna
Published: June 2022

Recent studies highlight the importance of baseline functional immunity for efficacious immune checkpoint blockade therapies. High-dimensional systemic immune profiling was performed in a discovery cohort of 112 non-small cell lung cancer patients undergoing PD-L1/PD-1 blockade immunotherapy. Responders showed high baseline phenotypic diversity of myeloid cell types in peripheral blood, in which elevated activated monocytic cells and decreased granulocytic phenotypes were potent predictive biomarkers. High-throughput profiling of soluble factors in plasma identified fractalkine (FKN), a chemokine involved in immune chemotaxis and adhesion, as a biomarker of myeloid cell diversity in human patients and in murine models, which was found significantly increased in objective responders. Secreted FKN inhibited adenocarcinoma and squamous cell carcinoma growth in vivo through a prominent contribution of systemic effector NK cells, enhanced tumor infiltration with immunostimulatory immune cells and inhibition of MDSCs within tumors. A synergy between FKN and PD-L1/PD-1 blockade immunotherapy was found in murine lung cancer models refractory to anti-PD-L1/anti-PD-1 treatment. Transcriptional data from 515 human lung adenocarcinoma samples independently confirmed the results from the discovery cohort. Importantly, recombinant FKN and tumor expressed-FKN were efficacious in delaying tumor growth in vivo with significant abscopal effects, indicating a potential therapeutic use of FKN in combination with immunotherapies.

One Sentence Summary

Serum fractalkine as a biomarker of response to immune checkpoint blockade.
Inter- and intra-chromosomal modulators of the APOE ε2 and ε4 effects on the Alzheimer’s disease risk
Authors: Nazarian Alireza , Philipp Ian , Culminskaya Irina , He Liang , Kulminski Alexander M.
Published: June 2022

The mechanisms of incomplete penetrance of risk modifying impacts of apolipoprotein E (APOE) ε2 and ε4 alleles on Alzheimer’s disease (AD) have not been fully understood. We performed genome-wide analysis of differences in linkage disequilibrium (LD) patterns between 6136 AD-affected and 10555 AD-unaffected subjects from five independent studies to explore whether the association of the APOE ε2 allele (encoded by rs7412 polymorphism) and ε4 allele (encoded by rs429358 polymorphism) with AD was modulated by autosomal polymorphisms. The LD analysis identified 24 (mostly inter-chromosomal) and 57 (primarily intra-chromosomal) autosomal polymorphisms with significant differences in LD with either rs7412 or rs429358, respectively, between AD-affected and AD-unaffected subjects, indicating their potential modulatory roles. Our Cox regression analysis showed that minor alleles of four inter-chromosomal and ten intra-chromosomal polymorphisms exerted significant modulating effects on the ε2- and ε4-associated AD risks, respectively, and identified ε2-independent (rs2884183 polymorphism, 11q22.3) and ε4-independent (rs483082 polymorphism, 19q13.32) associations with AD. Our functional analysis highlighted ε2- and/or ε4-linked processes affecting the lipid and lipoprotein metabolism, and cell junction organization which may contribute to AD pathogenesis. These findings provide insights into the ε2- and ε4-associated mechanisms of AD pathogenesis, underlying their incomplete penetrance.
Data-driven dissection of the fever effect in autism spectrum disorder
Authors: Muller Efrat , Shalev Ido , Bachmat Eitan , Eran Alal
Published: June 2022

Some individuals with autism spectrum disorder (ASD) demonstrate marked behavioral improvements during febrile episodes, in what is perhaps the only present-day means of modulating the core ASD phenotype. Understanding the nature of this so-calledfever effectis therefore essential for leveraging this natural temporary relief of symptoms to a sustained efficacious intervention. Towards this goal, we used machine learning to analyze the rich clinical data of the Simons Simplex Collection, in which 1 out of every 6 children with ASD was reported to improve during febrile episodes, across multiple ASD domains. Reported behavioral improvements during febrile episodes were associated with maternal infection in pregnancy (OR = 1.7, 95% CI = [1.42, 2.03], P = 4.24×10−4) and gastrointestinal (GI) dysfunction (OR=1.46, 95% CI = [1.15, 1.81], P = 1.94×10−3). Family members of children reported to improve when febrile have an increased prevalence of autoimmune disorders (OR=1.43, 95% CI = [1.23, 1.67], P = 3.0×10−6), language disorders (OR=1.63, 95% CI = [1.29, 2.04], P = 2.5×10−5), and neuropsychiatric disorders (OR=1.59, 95% CI = [1.34, 1.89], P < 1×10−6). Since both GI abnormalities and maternal immune activation have been linked to ASD via proinflammatory cytokines, these results might suggest a possible involvement of immune dysregulation in the fever effect, consistent with findings in mouse models. This work advances our understanding of the fever-responsive ASD subtype and motivates future studies to directly test the link between proinflammatory cytokines and behavioral modifications in individuals with ASD.

Lay summary

Some individuals with ASD demonstrate marked behavioral improvements when they have a fever. However, the magnitude, scope, nature, and underlying neurobiological basis of the so-called fever effect remain unknown. This large-scale biomedical data analysis found that children with ASD reported to improve when febrile tend to be those with worse gastrointestinal symptoms and whose mothers reported an infection during pregnancy. These and other findings point to the involvement of proinflammatory cytokines in this phenomenon.
An S1 subunit vaccine and combination adjuvant (COVAC-1) elicits robust protection against SARS-CoV-2 challenge in African green monkeys
Authors: Garnett Lauren , Tran Kaylie N , Chan Mable , Tierney Kevin , Schiffman Zachary , Audet Jonathan , Lew Jocelyne M. , Meilleur Courtney , Chan Michael , Manguiat Kathy , Tailor Nikesh , Vendramelli Robert , Deschambault Yvon , Beaudoin-Bussières Guillaume , Bourassa Catherine , Richard Jonathan , Finzi Andrés , Higgins Rick , Littlel-van den Hurk Sylvia van Drunen , Gerdts Volker , Strong James E , Falzarano Darryl
Published: June 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent responsible for the ongoing global pandemic. With over 500 million cases and more than 6 million deaths reported globally, the need for access to effective vaccines is clear. An ideal SARS-CoV-2 vaccine will prevent pathology in the lungs and prevent virus replication in the upper respiratory tract, thus reducing transmission. Here, we assessed the efficacy of an adjuvanted SARS-CoV-2 S1 subunit vaccine, called COVAC-1, in an African green monkey (AGM) model. AGMs immunized and boosted with COVAC-1 were protected from SARS-CoV-2 challenge compared to unvaccinated controls based on reduced pathology and reduced viral RNA levels and infectious virus in the respiratory tract. Both neutralizing antibodies and antibodies capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) were observed in vaccinated animals prior to the challenge. COVAC-1 induced effective protection, including in the upper respiratory tract, thus supporting further development and utility for determining the mechanism that confers this protection.

AUTHOR SUMMARY

Vaccines that can prevent the onward transmission of SARS-CoV-2 and prevent disease are highly desirable. Whether this can be accomplished without mucosal immunization by a parenterally administered subunit vaccine is not well established. Here we demonstrate that following two vaccinations, a protein subunit vaccine containing the S1 portion of the SARS-CoV-2 spike glycoprotein and the novel adjuvant TriAdj significantly reduces the amount of virus in the lungs and also mediates rapid clearance of the virus from the upper respiratory tract. Further support of the effectiveness of COVAC-1 was the observation of reduced pathology in the lungs and viral RNA being largely absent from tissues, blood, and rectal swabs. Thus COVAC-1 appears promising at mediating protection in both the upper and lower respiratory tract and may be capable of reducing subsequent transmission of SARS-CoV-2. Further investigation into the mechanism of protection in the upper respiratory tract and the initial immune response that supports this would be warranted.
PhaseTypeR: phase-type distributions in R with reward transformations and a view towards population genetics
Authors: Rivas-González Iker , Nørvang Andersen Lars , Hobolth Asger
Published: June 2022

Phase-type distributions are a general class of models that are traditionally used in actuarial sciences and queuing theory, and more recently in population genetics. A phase-type distributed random variable is the time to absorption in a discrete or continuous time Markov chain on a finite state space with an absorbing state. The R package PhaseTypeR contains all the key functions—mean, (co)variance, probability density function, cumulative distribution function, quantile function, random sampling and reward transformations—for both continuous (PH) and discrete (DPH) phase-type distributions. Additionally, we have also implemented the multivariate continuous case (MPH) and the multivariate discrete case (MDPH). We illustrate the usage of PhaseTypeR in simple examples from population genetics (e.g. the time until the most recent common ancestor or the total number of mutations in an alignment of homologous DNA sequences), and we demonstrate the power of PhaseTypeR in more involved applications from population genetics, such as the coalescent with recombination and the structured coalescent. The multivariate distributions and ability to reward-transform are particularly important in population genetics, and a unique feature of PhaseTypeR.
The MeshCODE to scale – Visualising synaptic binary information
Authors: Barnett Samuel F H , Goult Benjamin T
Published: June 2022

The Mercator projection map of the world provides a useful, but distorted, view of the relative scale of countries. Current cellular models suffer from a similar distortion. Here, we undertook an in-depth structural analysis of the molecular dimensions in the cell’s computational machinery, the MeshCODE, that is assembled from a meshwork of binary switches in the scaffolding proteins talin and vinculin. Talin contains a series of force-dependent binary switches and each domain switching state introduces quantised step-changes in talin length on a micrometre scale. The average dendritic spine is 1 µm in diameter so this analysis identifies a plausible Gearbox-like mechanism for dynamic regulation of synaptic function, whereby the positioning of enzymes and substrates relative to each other, mechanically-encoded by the MeshCODE switch patterns, might control synaptic transmission. Based on biophysical rules and experimentally derived distances, this analysis yields a novel perspective on biological digital information.
Hybrid Autoencoder with Orthogonal Latent Space for Robust Population Structure Inference
Authors: Yuan Meng , Hoskens Hanne , Goovaerts Seppe , Herrick Noah , Shriver Mark D. , Walsh Susan , Claes Peter
Published: June 2022

Background

Analysis of population structure and genomic ancestry remains an important topic in human genetics and bioinformatics. Commonly used methods require high-quality genotype data to ensure accurate inference. However, in practice, laboratory artifacts and outliers are often present in the data. Moreover, existing methods are typically affected by the presence of related individuals in the dataset.

Results

In this work, we propose a novel hybrid method, called SAE-IBS, which combines the strengths of traditional matrix decomposition-based (e.g., principal component analysis) and more recent neural network-based (e.g., autoencoders) solutions. I.e., it yields an orthogonal latent space enhancing dimensionality selection while learning non-linear transformations. The proposed approach achieves higher accuracy than existing methods for projecting poor quality target samples (genotyping errors and missing data) onto a reference ancestry space and generates a robust ancestry space in the presence of relatedness.

Conclusion

We introduce a new approach and an accompanying open-source program for robust ancestry inference in the presence of missing data, genotyping errors, and relatedness. The obtained ancestry space allows for non-linear projections and exhibits orthogonality with clearly separable population groups.
De novodesign of site-specific protein interactions with learned surface fingerprints
Authors: Gainza Pablo , Wehrle Sarah , Van Hall-Beauvais Alexandra , Marchand Anthony , Scheck Andreas , Harteveld Zander , Buckley Stephen , Ni Dongchun , Tan Shuguang , Sverrisson Freyr , Goverde Casper , Turelli Priscilla , Raclot Charlène , Teslenko Alexandra , Pacesa Martin , Rosset Stéphane , Georgeon Sandrine , Marsden Jane , Petruzzella Aaron , Liu Kefang , Xu Zepeng , Chai Yan , Han Pu , Gao George F. , Oricchio Elisa , Fierz Beat , Trono Didier , Stahlberg Henning , Bronstein Michael , Correia Bruno E.
Published: June 2022

Physical interactions between proteins are essential for most biological processes governing life. However, the molecular determinants of such interactions have been challenging to understand, even as genomic, proteomic, and structural data grows. This knowledge gap has been a major obstacle for the comprehensive understanding of cellular protein-protein interaction (PPI) networks and for thede novodesign of protein binders that are crucial for synthetic biology and translational applications. We exploit a geometric deep learning framework operating on protein surfaces that generates fingerprints to describe geometric and chemical features critical to drive PPIs. We hypothesized these fingerprints capture the key aspects of molecular recognition that represent a new paradigm in the computational design of novel protein interactions. As a proof-of-principle, we computationally designed severalde novoprotein binders to engage four protein targets: SARS-CoV-2 spike, PD-1, PD-L1, and CTLA-4. Several designs were experimentally optimized while others were purely generatedin silico, reaching nanomolar affinity with structural and mutational characterization showing highly accurate predictions. Overall, our surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling a novel approach for thede novodesign of protein interactions and, more broadly, of artificial proteins with function.
The complex roles of genomic DNA modifications of bacteriophage T4 in resistance to nuclease-based defense systems of E. coli
Authors: Wang Shuangshuang , Sun Erchao , Liu Yuepeng , Yin Baoqi , Zhang Xueqi , Li Mengling , Huang Qi , Tan Chen , Qian Ping , Rao Venigalla B. , Tao Pan
Published: June 2022

The interplay between defense and counter-defense systems of bacteria and phages is a major driver of evolution of both organisms, leading to their greatest genetic diversity. Bacterial restriction-modification (R-M) and CRISPR-Cas are two well-known defense systems that target phage DNAs through their nuclease activities, whereas phages have developed counter-defense systems through covalent modifications of their genomes. Recent studies have revealed many novel nuclease-containing antiphage systems, which leads to the question of what’s the role of phage genome modifications in countering these systems. Here, we scanned Escherichia coli genome sequences available in the NCBI databases and found abundant nuclease-containing defense systems, indicating that phage genomic DNA could be a major target for E. coli to restrict infection. From a collection of 816 E. coli strains, we cloned and validated 14 systems. Particularly, Gabija and type III Druantia systems have broad antiphage activities. Using wild-type phage T4 and its mutants, T4 (hmC) and T4 (C), which contain glucosyl-5-hydroxymethylcytosines, 5-hydroxymethylcytosines, and unmodified cytosines in the genomic DNA respectively, we revealed the complex roles of genomic modification of phage T4 in countering the nuclease-containing defense systems other than simply blocking the degradation of genomic DNA by nuclease.
Optimizing Cryo-FIB Lamellas for sub-5Å in situ Structural Biology
Authors: Khavnekar Sagar , Vrbovská Veronika , Zaoralová Magda , Kelley Ron , Beck Florian , Klumpe Sven , Kotecha Abhay , Plitzko Jürgen , Erdmann Philipp S.
Published: June 2022

We here present a method based on metallic platinum sputtering that can substantially enhance the quality of subtomogram averages from lamellas and thereby reduce the number of particles needed for high-resolution subtomogram averaging. We provide evidence for the physical background of this improvement and demonstrate its usefulness by producing sub-5Å ribosome averages from yeast.
Using Watershed Characteristics for Improving Fecal Source Identification
Authors: Hart John J. , Jamison Megan N. , McNair James N. , Woznicki Sean A. , Jordan Ben , Rediske Richard
Published: June 2022

Fecal pollution is one of the most prevalent forms of pollution affecting waterbodies worldwide, threatening public health, and negatively impacting aquatic environments. Microbial source tracking (MST) applies polymerase chain reaction (PCR) technology to help identify the source of fecal pollution. In this study, we combine spatial data for two watersheds with general and host-specific MST markers to target human, bovine, and general ruminant sources. Two different PCR technologies were applied for quantifying the targets: quantitative PCR (qPCR) and droplet digital PCR (ddPCR). We found that ddPCR had a higher detection rate (75%) of quantifiable samples compared to qPCR (27%), indicating that ddPCR is more sensitive than qPCR. The three host-specific markers were detected at all sites (n=25), suggesting that humans, cows, and ruminants are contributing to fecal contamination in these watersheds. MST results, combined with watershed characteristics, suggest that streams draining areas with low-infiltration soil groups, high septic system prevalence, and high agricultural land use are at an increased risk for fecal contamination. Microbial source tracking has been applied in numerous studies to aid in identifying the sources of fecal contamination, however these studies usually lack information on the involvement of watershed characteristics. Our study combined watershed characteristics with MST results, applying more sensitive PCR techniques, in addition to watershed characteristics to provide more comprehensive insight into the factors that influence fecal contamination in order to implement the most effective best management practices.

Abstract Figure

Highlights

ddPCR provided higher sensitivity over qPCR when analyzing environmental samples

Human markers had an association with the number of septic systems in a watershed

Every site had positive detections for all FIB markers

Both ruminant markers were associated with low infiltration hydrologic soil groups

Combining watershed characteristics with MST testing improved source identification
Engineered protein nanocages for concurrent RNA and protein packagingin vivo
Authors: Kwon Seokmu , Giessen Tobias W.
Published: June 2022

Protein nanocages have emerged as an important engineering platform for biotechnological and biomedical applications. Among naturally occurring protein cages, encapsulin nanocompartments have recently gained prominence due to their favorable physico-chemical properties, ease of shell modification, and highly efficient and selective intrinsic protein packaging capabilities. Here, we expand encapsulin function by designing and characterizing encapsulins for concurrent RNA and protein encapsulationin vivo. Our strategy is based on modifying encapsulin shells with nucleic acid binding peptides without disrupting the native protein packaging mechanism. We show that our engineered encapsulins reliably self-assembleinvivo, are capable of efficient size-selectivein vivoRNA packaging, can simultaneously load multiple functional RNAs, and can be used for concurrentin vivopackaging of RNA and protein. Our engineered encapsulation platform has potential for co-delivery of therapeutic RNAs and proteins to elicit synergistic effects, and as a modular tool for other biotechnological applications.
Towards A More Informative Representation of the Fetal-Neonatal Brain Connectome using Variational Autoencoder
Authors: Kim Jung-Hoon , De Asis-Cruz Josepheen , Krishnamurthy Dhineshvikram , Limperopoulos Catherine
Published: June 2022

Recent advances in functional magnetic resonance imaging (fMRI) have helped elucidate previously inaccessible trajectories of early-life prenatal and neonatal brain development. To date, the interpretation of fetal-neonatal fMRI data has relied on linear analytic models, akin to adult neuroimaging data. However, unlike the adult brain, the fetal and newborn brain develops extraordinarily rapidly, far outpacing any other brain development period across the lifespan. Consequently, conventional linear computational models may not adequately capture these accelerated and complex neurodevelopmental trajectories during this critical period of brain development along the prenatal-neonatal continuum. To obtain a nuanced understanding of fetal-neonatal brain development, including non-linear growth, for the first time, we developed quantitative, systems-wide representations of neuronal circuitry in a large sample (>700) of fetuses, preterm, and full-term neonates using an unsupervised deep generative model called Variational Autoencoder (VAE), a model previously shown to be superior to linear models in representing complex resting state data in healthy adults. Here, we demonstrated that non-linear brain features, i.e., latent variables, derived with the VAE, carried important individual neural signatures, leading to improved representation of prenatal-neonatal brain maturational patterns and more accurate and stable age prediction compared to linear models. Using the VAE decoder, we also revealed distinct functional brain networks spanning the sensory and default mode networks. Using the VAE, we are able to reliably capture and quantify complex, non-linear fetal-neonatal functional neural connectivity. This will lay the critical foundation for detailed mapping of healthy and aberrant functional brain signatures that have their origins in fetal life.
Combined transcriptome and metabolome analysis of a new species of microalgae from Tibetan plateau and its response to sewage treatment
Authors: Jinhu Wang , Qiangying Zhang , Junyu Chen , Jinna Zhou , Jing Li , Yanli Wei , Duo Bu
Published: June 2022

Microalgae are pivotal in maintaining water quality in the lakes and rivers of Qinghai-Tibet plateau. The optimum sewage treatment conditions for Desmodesmus sp. are, temperature: 20–25°C, light intensity: 3000–8000 lx, and pH: 7.0–7.5, identified based on orthogonal experiments. The maximum removal rate of total nitrogen, total phosphorus, and chemical oxygen demand was more than 95% in the actual sewage treatment. The sewage treatment capacity of Desmodesmus sp. from plateau is higher than that from plains under the same treatment conditions. To identify the differentially expressed genes and metabolites in Desmodesmus sp. in response to sewage treatment, a combination of metabolomics and transcriptomics was employed to the microalgae with and without sewage treatment. The results showed that the oxidative phosphorylation, photosynthesis, and propanoate metabolism pathways were the most significantly enriched pathways in sewage treatment. Further, the metabolism of adenosine diphosphate, 2-oxobutanoate, and succinate were significantly upregulated, downregulated, and both upregulated and downregulated, respectively, as shown by the combined transcriptome and metabolome analysis. Additionally, we found that sewage treatment could also induce numerous changes in the primary metabolism, such as carbohydrate, fatty acid biosynthesis, and amino acid metabolism when compared with control. Overall, our results should improve fundamental knowledge of molecular responses to Desmodesmus sp. in sewage treatment and contribute to the design of strategies in microalgae response to sewage treatment.