bluuebunny/crossref_metadata_2025 huggingface dataset:
Spd-2 Gene Duplication Suggests Cell-Type Specific Assembly Mechanisms of Pericentriolar Material
Authors: O’Neill Ryan S. , Sodeinde Afeez K. , Welsh Frances C. , Fagerstrom Carey J. , Galletta Brian J. , Rusan Nasser M.
Published: October 2021

Centrosomes are multi-protein complexes that function as the major microtubule organizing center (MTOC) for the cell. While centrosomes play tissue-specific MTOC functions, little is known about how particular centrosome proteins are regulated across cell types to achieve these different functions. To investigate this cell type-specific diversity, we searched for gene duplications of centrosome genes in the Drosophila lineage with the aim of identifying centrosome gene duplications where each copy evolved for specialized functions. Through in depth functional analysis of a Spd-2 gene duplication in the Willistoni group, we discovered differences in the regulation of PCM in somatic and male germline cells. The parental gene, Spd-2A, is expressed in somatic cells, where it can function to organize pericentriolar material (PCM) and the mitotic spindle in larval brain neuroblasts. Spd-2A is absent during male meiosis, and even when ectopically expressed in spermatocytes it fails to rescue PCM and spindle organization. In contrast, the new gene duplicate, Spd-2B, is expressed specifically in spermatocytes. During male meiosis, Spd-2B localizes to centrosomes, organizes PCM and spindles, and is sufficient for proper male fertility. Experiments using chimeric transgenes reveal that differences in the C-terminal tails of Spd-2A and Spd-2B are responsible for these functional changes. Thus, Spd-2A and Spd-2B have evolved complementary functions by specializing for distinct subsets of cells. Together, our results demonstrate that somatic cells and male germline cells have fundamentally different requirements for PCM, suggesting that PCM proteins such as Spd-2 is differentially regulated across cell types to satisfy distinct requirements.

Highlights

Spd-2 gene duplication in the Willistoni group is rapidly evolving

Parent gene Spd-2A is expressed in somatic cells, whereas the gene duplicate Spd-2B is expressed in spermatocytes

Spd-2A organizes pericentriolar material during somatic cell mitosis

Spd-2B is specialized for pericentriolar material organization during male meiosis
No robust coexistence in a canonical model of plant-soil feedbacks
Authors: Miller Zachary R. , Lechón-Alonso Pablo , Allesina Stefano
Published: October 2021

Plant-soil feedbacks (PSFs) are considered a key mechanism generating frequency-dependent dynamics in plant communities. Negative feedbacks, in particular, are often invoked to explain coexistence and the maintenance of diversity in species-rich communities. However, the primary modeling framework used to study PSFs considers only two plant species, and we lack clear theoretical expectations for how these complex interactions play out in communities with natural levels of diversity. Here, we demonstrate that this canonical model for PSFs is equivalent to a well-studied model from evolutionary game theory, and use this equivalence to characterize the dynamics with an arbitrary number of plant species. Surprisingly, we find that coexistence of more than two species is virtually impossible, suggesting that alternative theoretical frameworks are needed to describe feedbacks observed in diverse natural communities. Drawing on our analysis, we discuss future directions for PSF models and implications for experimental study of PSF-mediated coexistence in the field.
Altered Salience Network Connectivity in 6-Week-Old Infants at Risk for Autism
Authors: Tsang Tawny , Green Shulamite , Liu Janelle , Lawrence Katherine , Jeste Shafali , Bookheimer Susan Y. , Dapretto Mirella
Published: October 2021

Converging evidence implicates disrupted brain connectivity in autism spectrum disorder (ASD); however, the mechanisms linking altered connectivity early in development to the emergence of ASD symptomatology remain poorly understood. Here we examined whether atypicalities in the Salience Network (SN) – an early-emerging neural network involved in orienting attention to the most salient aspects of one’s internal and external environment – may predict the development of ASD markers such as reduced social attention and atypical sensory processing. Six-week-old infants at high-risk for ASD exhibited stronger SN connectivity with sensorimotor regions; low-risk infants demonstrated stronger SN connectivity with prefrontal regions involved in social attention. Infants with higher connectivity with sensorimotor regions had lower connectivity with prefrontal regions, suggesting a direct tradeoff between attention to basic sensory versus socially-relevant information. Early alterations in SN connectivity predicted subsequent ASD symptomatology, providing a plausible mechanistic account for the unfolding of atypical developmental trajectories associated with ASD risk.
Impact of the COVID-19 pandemic on routine immunization coverage in children under 2 years old in Ontario, Canada: A retrospective cohort study
Authors: Ji Catherine , Piché-Renaud Pierre-Philippe , Apajee Jemisha , Stephenson Ellen , Forte Milena , Friedman Jeremy N. , Science Michelle , Zlotkin Stanley , Morris Shaun K. , Tu Karen
Published: October 2021

Background

The COVID-19 pandemic has caused a disruption in childhood immunization coverage around the world. This study aimed to determine the change in immunization coverage for children under 2 years old in Ontario, Canada, comparing time periods pre-pandemic to during the pandemic.

Methods

We conducted an observational retrospective open cohort study, using primary care electronic medical record data from the University of Toronto Practice-Based Research Network (UTOPIAN) database, from January 2019 to December 2020. Children under 2 years old who had at least 2 visits recorded in UTOPIAN were included. We measured up-to-date (UTD) immunization coverage rates, overall and by type of vaccine (DTaP-IPV-Hib, Pneu-C-13, Rot, Men-C-C, MMR, Var), and on-time immunization coverage rates by age milestone (2, 4, 6, 12, 15 and 18 months). We compared average coverage rates over 3 periods of time: January 2019-March 2020 (T1); March-July 2020 (T2); and August-December 2020 (T3).

Results

12,313 children were included. Overall UTD coverage for all children was 71.0% in T1, dropped by 5.7% (95% CI: -6.2, -5.1) in T2, slightly increased in T3 but remained lower than in T1. MMR vaccine UTD coverage slightly decreased in T2 and T3 by approximately 2%. The largest decreases were seen at ages 15-month and 18-month old, with drops in on-time coverage of 14.7% (95% CI: -18.7, -10.6) and 16.4% (95% CI: -20.0, -12.8) respectively during T2. When stratified by sociodemographic characteristics, no specific subgroup of children was found to have been differentially impacted by the pandemic.

Conclusion

Childhood immunization coverage rates for children under 2 years in Ontario decreased significantly during the early period of the COVID-19 pandemic and only partially recovered during the rest of 2020. Public health and educational interventions for providers and parents are needed to ensure adequate catch-up of delayed/missed immunizations to prevent potential outbreaks of vaccine-preventable diseases.
Rapid health evaluation in migrant peoples in transit through Darien, Panama: Protocol for a multi-method qualitative and quantitative study
Authors: Gabster Amanda , Jhangimal Monica , Erausquin Jennifer Toller , Suárez José Antonio , Pinzón-Espinosa Justo , Baird Madeline , Katz Jennifer , Beltran-Henríquez Davis , Cabezas-Talavero Gonzalo , Henao-Martínez Andrés F. , Franco-Paredes Carlos , Agudelo-Higuita. Nelson I. , Pachar Mónica , González José Anel , Rodriguez Fátima , Pascale Juan Miguel ,   Migrant Peoples in Transit Study Group
Published: October 2021

Background

The world is currently unprepared to deal with a the drastic increase in global migration. There is an urgent need to develop programs to protect the well being and health of migrant peoples. Increased population movement is already evident throughout the Americas as exemplified by the rising number of migrant peoples that pass through the Darien neotropical moist broadleaf forest along the border region between Panama and Colombia. The transit of migrant peoples through this area has an increase in the last years. In 2021 an average of 9,400 people entered the region per month compared to 2,000-3,500 people monthly in 2019. Along this trail, there is no access to healthcare, food provision, potable water, or housing. To date, much of what is known about health needs and barriers to healthcare within this population is based on journalistic reports and anecdotes. There is a need for a comprehensive approach to assess the healthcare needs migrant peoples in transit. This study aims to describe demographic characteristics, mental and physical health status and needs, and experiences of host communities, and to identify opportunities to improve healthcare provision to migrant peoples in transit in Panama.

Study design and methods

This multi-method study will include qualitative (n=70) and quantitative (n=520) components. The qualitative component includes interviews with migrant peoples in transit, national and international non-governmental organizations and agencies based in Panama. The quantitative component is a rapid epidemiological study which includes a questionnaire and four clinical screenings: mental health, sexual and reproductive health, general and tropical medicine, and nutrition.

Conclusion

This study will contribute to a better understanding of the health status and needs of migrant peoples in transit through the region. Findings will be used to allocate resources and provide targeted healthcare interventions for migrant peoples in transit through Darien, Panama.
Evolutionarily divergent mTOR remodels the translatome to drive rapid wound closure and regeneration
Authors: Zhulyn Olena , Rosenblatt Hannah D. , Shokat Leila , Dai Shizhong , Kuzuoglu-Öztürk Duygu , Zhang Zijian , Ruggero Davide , Shokat Kevan M. , Barna Maria
Published: October 2021

An outstanding mystery in biology is why some species, such as the axolotl, can scarlessly heal and regenerate tissues while most mammals cannot. Here, we demonstrate that rapid activation of protein synthesis is a unique, and previously uncharacterized, feature of the injury response critical for limb regeneration in the axolotl (A. mexicanum). By applying polysome sequencing, we identify hundreds of transcripts, including antioxidants and ribosome components, which do not change in their overall mRNA abundance but are selectively activated at the level of translation from pre-existing mRNAs in response to injury. In contrast, we show that protein synthesis is not activated in response to digit amputation in the non-regenerative mouse. We further identify the mTORC1 pathway as a key upstream signal that mediates this regenerative translation response in the axolotl. Inhibition of this pathway is sufficient to suppress translation and axolotl regeneration. Surprisingly, although mTOR is highly evolutionarily conserved, we discover unappreciated expansions in mTOR protein sequence among urodele amphibians. By engineering an axolotl mTOR in human cells, we demonstrate that this change creates a hypersensitive kinase that may allow axolotls to maintain this pathway in a highly labile state primed for rapid activation. This may underlie metabolic differences and nutrient sensing between regenerative and non-regenerative species that are key to regeneration. Together, these findings highlight the unanticipated impact of the translatome on orchestrating the early steps of wound healing in highly regenerative species and provide a missing link in our understanding of vertebrate regenerative potential.
Sciara coprophila larvae upregulate DNA repair pathways and downregulate developmental regulators in response to ionizing radiation
Authors: Urban John M. , Bateman Jack R. , Garza Kodie R. , Borden Julia , Jain Jaison , Brown Alexia , Thach Bethany J. , Bliss Jacob E. , Gerbi Susan A.
Published: October 2021

Robust DNA damage prevention and repair strategies are crucial to faithful reproduction and inheritance of the genetic material. Although many molecular pathways that respond to DNA damage are well conserved through evolution, the quality and effectiveness of these systems can vary between species. Studies dating back for nearly a century document that the dark-winged fungus gnat Sciara coprophila (Order: Diptera; sub-order: Nematocera) is relatively resistant to irradiation-induced mutations that cause visible phenotypes when compared to the fruit fly Drosophila melanogaster (Order: Diptera; sub-order: Brachycera). However, the molecular responses to irradiation for S. coprophila have yet to be analyzed. To address this gap, we first characterized the effects of ionizing radiation on S. coprophila throughout its life cycle. Our data show that developing S. coprophila embryos are highly sensitive to even low doses of gamma-irradiation, whereas larvae can tolerate up to 80 Gy and still retain their ability to develop to adulthood with a developmental delay of 5 to 8 extra days in the larval stage. To survey the genes involved in the early transcriptional response to irradiation, we compared RNA-seq profiles of larvae with and without radiation treatment. Our analysis showed that 327 genes are differentially expressed in irradiated larvae, with 232 genes upregulated and 95 genes downregulated relative to controls. The upregulated genes were enriched for DNA damage response genes, including those involved in DNA repair, cell cycle arrest, and apoptosis, whereas the down-regulated genes were enriched for developmental regulators, consistent with the developmental delay observed in irradiated larvae. Thus, our study has laid the groundwork to further dissect how Sciara copes with radiation-induced damage.
The autophagy activator Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer’s disease mouse model
Authors: Freitag Kiara , Sterczyk Nele , Obermayer Benedikt , Schulz Julia , Houtman Judith , Fleck Lara , Braeuning Caroline , Sansevrino Roberto , Hoffmann Christian , Milovanovic Dragomir , Sigrist Stephan J. , Conrad Thomas , Beule Dieter , Heppner Frank L. , Jendrach Marina
Published: October 2021

Deposition of amyloid beta (Aβ) along with glia cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer’s disease (AD). In recent years, impairment of autophagy has been found to be another important feature, contributing to AD progression and aging. Therefore, we assessed the effect of the autophagy activator Spermidine, a small body-endogenous polyamine often used as dietary supplement and known to promote longevity, on glia cell-mediated neuroinflammation. Spermidine reduced TLR3- and TLR4- mediated inflammatory processes in microglia and astrocytes by decreasing cytotoxicity, inflammasome activity and NF-κB signaling. In line with these anti-inflammatory effects, oral treatment of the amyloid prone AD-like APPPS1 mice with Spermidine reduced neuroinflammation and neurotoxic soluble Aβ. Mechanistically, single nuclei sequencing revealed microglia as one of the main targets of Spermidine treatment, with increased expression of genes implicated in cell motility and phagocytosis. Thus, Spermidine provides a promising therapeutic potential to target glia cells in AD progression.
Inhibition of Metastatic Uveal Melanoma Cell Proliferation by the Histone Deacetylase 6 Inhibitor, Ricolinostat, is Linked to Altered Microphthalmia-associated Transcription Factor and Phospho-ERK Expression
Authors: Sundaramurthi Husvinee , García-Mulero Sandra , Slater Kayleigh , Marcone Simone , Piulats Josep M. , Watson R. William , Tobin Desmond J. , Jensen Lasse D. , Kennedy Breandán N.
Published: October 2021

Metastatic uveal melanoma (MUM) is characterized by poor patient survival. Unfortunately, current treatment options demonstrate limited benefits. In this study, we evaluate the efficacy of ACY-1215, a histone deacetylase 6 inhibitor (HDAC6i), to attenuate MUM cell growth in vitro and in vivo, and elucidate the underlying molecular mechanisms. Treatment of OMM2.5 MUM cells with ACY-1215 resulted in a significant (p = 0.0001), dose-dependent reduction in cell survival and proliferation in vitro, and in vivo regression of primary OMM2.5 xenografts in zebrafish larvae. Furthermore, flow cytometry analysis revealed that ACY-1215 significantly arrested the OMM2.5 cell cycle in S phase (p = 0.0006) following 24 hours of treatment and significant apoptosis was triggered in a time- and dose-dependent manner (p = <0.0001). Additionally, ACY-1215 treatment resulted in a significant reduction in OMM2.5 p-ERK expression levels. Through proteome-profiling, attenuation of the microphthalmia-associated transcription factor (MITF) signaling pathway was linked to the observed anti-cancer effects of ACY-1215. In agreement, pharmacological inhibition of MITF signaling with ML329, significantly reduced OMM2.5 cell survival and viability in vitro (p = 0.0001) and in vivo (p = 0.0006). Our findings provide evidence that ACY-1215 and ML329 are efficacious against growth and survival of MUM cells and are potential therapeutic options for MUM.

Simple Summary

Uveal melanoma (UM) is the most common adult eye cancer. UM originates in the iris, ciliary body, or choroid (collectively known as the uvea), in the middle layer of the eye. This first or primary UM is treated by targeting the cancer cells using ocular radiation implants or by surgical removal of the eye. However, when UM spreads to the liver and other parts of the body, patients have a poor survival prognosis. Unfortunately, there are no effective treatment options for UM that has spread. Our aim is to help identify effective treatments for UM cancer that has spread. In our study, we identified that the drug ACY-1215 prevents the growth of UM cells from the liver. Our study has found a promising treatment approach for advanced UM.
A novel approach in heart-rate-variability analysis
Authors: Búzás András , Horváth Tamás , Dér András
Published: October 2021

Heart-rate variability (HRV), measured by the fluctuation of beat-to-beat intervals, has been growingly considered the most important hallmark of heart rate (HR) time series. HRV can be characterized by various statistical measures both in the time and frequency domains, or by nonlinear methods. During the past decades, an overwhelming amount of HRV data has been piled up in the research community, but the individual results are difficult to reconcile due to the different measuring conditions and the usually HR-dependent statistical HRV-parameters applied. Moreover, the precise HR-dependence of HRV parameters is not known. Using data gathered by a wearable sensor of combined heart-rate and actigraphy modalities, here, we introduce a novel descriptor of HRV, based on a modified Poincaré plot of 24-h RR-recordings. We show that there exists a – regressive biexponential – HRV versus HR “master” curve (“M-curve”) that is highly conserved for a healthy individual on short and medium terms (on the hours to months scale, respectively). At the same time, we reveal how this curve is related to age in the case of healthy people, and establish alterations of the M-curves of heart-attack patients. A stochastic neuron model accounting for the observed phenomena is also elaborated, in order to facilitate physiological interpretation of HRV data. Our novel evaluation procedure applied on the time series of interbeat intervals allows the description of the HRV(HR) function with unprecedented precision. To utilize the full strength of the method, we suggest a 24-hour-long registration period under natural, daily-routine circumstances (i.e., no special measuring conditions are required). By establishing a patient’s M-curve, it is possible to monitor the development of his/her status over an extended period of time. On these grounds, the new method is suggested to be used as a competent tool in future HRV analyses for both clinical and training applications, as well as for everyday health promotion.
Activating natural product synthesis using CRISPR interference and activation systems inStreptomyces
Authors: Ameruoso Andrea , Villegas Kcam Maria Claudia , Cohen Katherine Piper , Chappell James
Published: October 2021

The rise of antibiotic-resistant bacteria represents a major threat to global health, creating an urgent need to discover new antibiotics. Natural products derived from the genusStreptomycesrepresent a rich and diverse repertoire of chemical molecules from which new antibiotics are likely to be found. However, a major challenge is that the biosynthetic gene clusters (BGCs) responsible for natural product synthesis are often poorly expressed under laboratory culturing conditions, thus preventing isolation and screening of novel chemicals. To address this, we describe a novel approach to activate silent BGCs through rewiring endogenous regulation using synthetic gene regulators based upon CRISPR-Cas. First, we create CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) systems that allow for highly programmable and effective gene repression and activation inStreptomyces. We then harness these tools to activate a silent BGC through perturbing its endogenous regulatory network. Together, this work advances the synthetic regulatory toolbox forStreptomycesand facilitates the programmable activation of silent BGCs for novel chemical discovery.
Modelling human zygotic genome activation in 8C-like cells in vitro
Authors: Taubenschmid-Stowers Jasmin , Rostovskaya Maria , Santos Fátima , Ljung Sebastian , Argelaguet Ricard , Krueger Felix , Nichols Jennifer , Reik Wolf
Published: October 2021

The remodelling of the epigenome and transcriptome of the fertilised oocyte to establish totipotency in the zygote and developing embryo is one of the most critical processes in mammalian embryogenesis. Zygotic or embryonic genome activation (ZGA, EGA) in the 2-cell embryo in mouse, and the 8-cell embryo in humans, constitutes the first major wave of transcription. Failure to initiate ZGA leads to developmental defects, and contributes to the high attrition rates of human pre-implantation embryos. Due to limitations in cell numbers and experimental tractability, the mechanisms that regulate human embryonic genome activation in the totipotent embryo remain poorly understood. Here we report the discovery of human 8-cell like cells (8CLCs) specifically among naïve embryonic stem cells, but not primed pluripotent cells. 8CLCs express ZGA marker genes such as ZSCAN4, LEUTX and DUXA and their transcriptome closely resembles that of the 8-cell human embryo. 8-cell like cells reactivate 8-cell stage specific transposable elements such as HERVL and MLT2A1 and are characterized by upregulation of the DNA methylation regulator DPPA3. 8CLCs show reduced SOX2 protein, and can be identified based on expression of the novel ZGA-associated protein markers TPRX1 and H3.Y in vitro. Overexpression of the transcription factor DUX4. as well as spliceosome inhibition increase ZGA-like transcription and enhance TPRX1+ 8CLCs formation. Excitingly, the in vitro identified 8CLC marker proteins TPRX1 and H3.Y are also expressed in 8-cell human embryos at the time of genome activation and may thus be relevant in vivo. The discovery of 8CLCs provides a unique opportunity to model and manipulate human ZGA-like transcriptional programs in vitro, and might provide critical functional insights into one of the earliest events in human embryogenesis in vivo.

Highlights

ZGA markers and transposable elements are expressed in 8CLCs among naïve human stem cells

The transcription factor DUX4 and spliceosome inhibition induce ZGA-like transcription

8CLC marker proteins TPRX1 and H3.Y are expressed in nuclei of 8-cell human embryos

8CLCs serve as a novel in vitro model for human ZGA
CHD4 is recruited by GATA4 and NKX2-5 silencers to repress non-cardiac gene programs in the developing heart
Authors: Robbe Zachary L. , Shi Wei , Wasson Lauren K. , Wilczewski Caralynn M. , Sheng Xinlei , Hepperla Austin J. , Akerberg Brynn N. , Pu William T. , Cristea Ileana M. , Davis Ian J. , Conlon Frank L.
Published: October 2021

The Nucleosome Remodeling and Deacetylase (NuRD) complex is one of the central chromatin remolding complexes that mediate gene repression. NuRD is essential for numerous developmental events, including heart development. Clinical and genetic studies have provided direct evidence for the role of chromodomain helicase DNA-binding protein 4 (CHD4), the catalytic component of NuRD, in congenital heart disease (CHD), including atrial and ventricular septal defects. Further, it has been demonstrated that CHD4 is essential for mammalian cardiomyocyte formation and function. A key unresolved question is how CHD4/NuRD is localized to specific cardiac targets genes, as neither CHD4 nor NuRD can directly bind DNA. Here, we coupled a bioinformatics-based approach with mass spectrometry analyses to demonstrate that CHD4 interacts with the core cardiac transcription factors GATA4, NKX2-5 and TBX5 during embryonic heart development. Using transcriptomics and genome-wide occupancy data, we have characterized the genomic landscape of GATA4, NKX2-5 and TBX5 repression and defined the direct cardiac gene targets of GATA4-CHD4, NKX2-5-CHD4 and TBX5-CHD4 complexes. These data were used to identify putative cis-regulatory elements regulated controlled by these complexes. We genetically interrogated two of these silencers in vivo,Acta1andMyh11. We show that deletion of these silencers leads to inappropriate skeletal and smooth muscle gene mis-expression, respectively, in the embryonic heart. These results delineate how CHD4/NuRD is localized to specific cardiac loci and explicates how mutations in the broadly expressed CHD4 protein lead to cardiac specific disease states.
Vagus nerve stimulation accelerates motor learning through cholinergic modulation
Authors: Bowles Spencer , Hickman Jordan , Peng Xiaoyu , Williamson W. Ryan , Huang Rongchen , Washington Kayden , Donegan Dane , Welle Cristin G
Published: October 2021

Vagus nerve stimulation (VNS) is a neuromodulation therapy for a broad and rapidly expanding set of neurologic conditions. Classically used to treat epilepsy and depression, VNS has recently received FDA approval for stroke rehabilitation and is under preclinical and clinical investigation for other neurologic indications. Despite benefits across a diverse range of neurological disorders, the mechanism through which VNS influences central nervous system circuitry is not well described, limiting therapeutic optimization. A deeper understanding of the influence of VNS on neural circuits and activity is needed to maximize the use of VNS therapy across a broad range of neurologic conditions.

To investigate how VNS can influence the neurons and circuits that underlie behavior, we paired VNS with upper limb movement in mice learning a skilled motor task. We leveraged genetic tools to perform optogenetic circuit dissection, as well as longitudinal in vivo imaging of calcium activity in cortical neurons to understand the effect of VNS on neural function. We found that VNS robustly enhanced motor learning when temporally paired with successful movement outcome, while randomly applied VNS impaired learning. This suggests that temporally-precise VNS may act through augmenting outcome cues, such as reinforcement signals. Within motor cortex, VNS paired with movement outcome selectively modulates the neural population that represents outcome, but not other movement-related neurons, across both acute and behaviorally-relevant timescales. Phasic cholinergic signaling from basal forebrain is required both for VNS-driven improvements in motor learning and the effects on neural activity in M1. These results indicate that VNS enhances motor learning through precisely-timed phasic cholinergic signaling to reinforce outcome, resulting in the recruitment of specific, behaviorally-relevant cortical circuits. A deeper understanding of the mechanisms of VNS on neurons, circuits and behavior provides new opportunities to optimize VNS to treat neurologic conditions.
Coloring inside the lines: genomic architecture and evolution of a widespread color pattern in frogs
Authors: Goutte Sandra , Hariyani Imtiyaz , Utzinger Kole Deroy , Bourgeois Yann , Boissinot Stéphane
Published: October 2021

Traits shared among distantly related lineages are indicators of common evolutionary constraints, at the ecological, physiological or molecular level. The vertebral stripe is a color pattern that is widespread across the anuran phylogeny. Despite its prevalence in the order, surprisingly little is known about the genetic basis and evolutionary dynamic of this color pattern. Here we combine histology, genome- and transcriptome-wide analyses with order-scale phylogenetic comparative analyses to investigate this common phenotype. We show that the vertebral stripe has evolved hundreds of times in the evolutionary history of anurans and is selected for in terrestrial habitats. Using the Ethiopian Ptychadena radiation as a model system, we demonstrate that variation at the ASIP gene is responsible for the different vertebral stripe phenotypes. Alleles associated to these phenotypes are younger than the split between closely related Ptychadena species, thus indicating that the vertebral stripe results from parallel evolution within the group. Our findings demonstrate that this widespread color pattern evolves rapidly and recurrently in terrestrial anurans, and therefore constitute an ideal system to study repeated evolution.
Allele frequency dynamics under sex-biased demography and sex-specific inheritance in a pedigreed jay population
Authors: Driscoll Rose M.H. , Beaudry Felix E.G. , Cosgrove Elissa J. , Fitzpatrick John W. , Schoech Stephan J. , Chen Nancy
Published: October 2021

Sex-biased demography, including sex-biased survival or migration, can alter allele frequency changes across the genome. In particular, we can expect different patterns of genetic variation on autosomes and sex chromosomes due to sex-specific differences in life histories, as well as differences in effective population size, transmission modes, and the strength and mode of selection. Here, we demonstrate the role that sex differences in life history played in shaping short-term evolutionary dynamics across the genome. We used a 25-year pedigree and genomic dataset from a long-studied population of Florida Scrub-Jays (Aphelocoma coerulescens) to directly characterize the relative roles of sex-biased demography and inheritance in shaping genome-wide allele frequency trajectories. We used gene dropping simulations to estimate individual genetic contributions to future generations and to model drift and immigration on the known pedigree. We quantified differential expected genetic contributions of males and females over time, showing the impact of sex-biased dispersal in a monogamous system. Due to female-biased dispersal, more autosomal variation is introduced by female immigrants. However, due to male-biased transmission, more Z variation is introduced by male immigrants. Finally, we partitioned the proportion of variance in allele frequency change through time due to male and female contributions. Overall, most allele frequency change is due to variance in survival and births. Males and females make similar contributions to autosomal allele frequency change, but males make higher contributions to allele frequency change on the Z chromosome. Our work shows the importance of understanding sex-specific demographic processes in characterizing genome-wide allele frequency change in wild populations.
Deciphering the species-level structure of topologically associating domains
Authors: Singh Rohit , Berger Bonnie
Published: October 2021

Chromosome conformation capture technologies such as Hi-C have revealed a rich hierarchical structure of chromatin, with topologically associating domains (TADs) as a key organizational unit, but experimentally reported TAD architectures, currently determined separately for each cell type, are lacking for many cell/tissue types. A solution to address this issue is to integrate existing epigenetic data across cells and tissue types to develop a species-level consensus map relating genes to TADs. Here, we introduce the TAD Map, a bag-of-genes representation that we use to infer, or “impute,” TAD architectures for those cells/tissues with limited Hi-C experimental data. The TAD Map enables a systematic analysis of gene coexpression induced by chromatin structure. By overlaying transcriptional data from hundreds of bulk and single-cell assays onto the TAD Map, we assess gene coexpression in TADs and find that expressed genes cluster into fewer TADs than would be expected by chance, and show that time-course and RNA velocity studies further reveal this clustering to be strongest in the early stages of cell differentiation; it is also strong in tumor cells. We provide a probabilistic model to summarize any scRNA-seq transcriptome in terms of its TAD activation profile, which we term a TAD signature, and demonstrate its value for cell type inference, cell fate prediction, and multimodal synthesis. More broadly, our work indicates that the TAD Map’s comprehensive, quantitative integration of chromatin structure and scRNA-seq data should play a key role in epigenetic and transcriptomic analyses.

Software availability: https://tadmap.csail.mit.edu

Graphical Abstract
Genetic evidence for signal transduction within the Bacillus subtilis GerA germinant receptor
Authors: Amon Jeremy D. , Artzi Lior , Rudner David Z.
Published: October 2021

Bacterial spores can rapidly exit dormancy through the process of germination. This process begins with the activation of nutrient receptors embedded in the spore membrane. The prototypical germinant receptor in Bacillus subtilis responds to L-alanine and is thought to be a complex of proteins encoded by the genes in the gerA operon: gerAA, gerAB, and gerAC. The GerAB subunit has recently been shown to function as the nutrient sensor, but beyond contributing to complex stability, no additional functions have been attributed to the other two subunits. Here, we investigate the role of GerAA. We resurrect a previously characterized allele of gerA (termed gerA*) that carries a mutation in gerAA and show it constitutively activates germination even in the presence of a wild-type copy of gerA. Using an enrichment strategy to screen for suppressors of gerA*, we identified mutations in all three gerA genes that restore a functional receptor. Characterization of two distinct gerAB suppressors revealed that one (gerAB-E105K) reduces the GerA complex’s ability to respond to L-alanine, while another (gerAB-F259S) disrupts the germinant signal downstream of L-alanine recognition. These data argue against models in which GerAA is directly or indirectly involved in germinant sensing. Rather, our data suggest that GerAA is responsible for transducing the nutrient signal sensed by GerAB. While the steps downstream of gerAA have yet to be uncovered, these results validate the use of a dominant-negative genetic approach in elucidating the gerA signal transduction pathway.

Importance

Endospore formers are a broad group of bacteria that can enter dormancy upon starvation and exit dormancy upon sensing the return of nutrients. How dormant spores sense and respond to these nutrients is poorly understood. Here, we identify a key step in the signal transduction pathway that is activated after spores detect the amino acid L-alanine. We present a model that provides a more complete picture of this process that is critical for allowing dormant spores to germinate and resume growth.
Classification of the canonical splice alterationMUTYHc.934-2A > G is likely benign based on RNA and clinical data
Authors: Hernandez Felicia , Conner Blair R. , Richardson Marcy E. , LaDuca Holly , Chao Elizabeth , Pesaran Tina , Karam Rachid
Published: October 2021

MUTYH-associated polyposis (MAP) is an autosomal recessive disorder characterized by the development of multiple adenomatous colonic polyps and an increased lifetime risk of colorectal cancer. Germline biallelic pathogenic variants inMUTYHare responsible for MAP. TheMUTYHc.934-2A > G (NM_001128425.1) variant, which is also known as c.850-2A > G for NM_001048174.2, has been identified in our laboratory in more than 800 patients, including homozygous and compound heterozygote carriers. The variant was initially classified as a variant of uncertain significance (VUS) because of lack of a MAP phenotype in biallelic carriers. In two unrelated female patients who were heterozygous carriers of this variant, further testing by RNA sequencing identified an aberrant transcript with a deletion of 9 nt at the start of exon 11 (MUTYHr.934_942del9). This event is predicted to lead to an in-frame loss of three amino acids in a noncritical domain of the protein. This was the only splice defect identified in these patients that was not present in the controls, and the aberrant transcript is derived exclusively from the variant allele, strongly supporting the cause of this splice defect as being the intronic variant,MUTYHc.934-2A > G. The splicing analysis demonstrating a small in-frame skipping of three amino acids in a noncritical domain, along with the absence of a MAP phenotype in our internal cohort of biallelic carriers, provides evidence that the variant is likely benign and not of clinical significance.
Crystal structure of trans-diaqua(1,4,8,11-tetraazaundecane)nickel(II) bis(pyridine-2,6-dicarboxylato)nickel(II)
Authors: Andriichuk Irina L. , Tsymbal Liudmyla V. , Arion Vladimir B. , Lampeka Yaroslaw D.
Published: October 2021

The asymmetric unit of the title compound, trans-diaqua(1,4,8,11-tetraazaundecane-κ4
N
1,N
4,N
8,N
11)nickel(II) bis(pyridine-2,6-dicarboxylato-κ3
O
2,N,O
6)nickel(II) {[Ni(L)(H2O)2][Ni(pdc)2] where L = 1,4,8,11-tetraazaundecane (C7H20N4) and pdc = the dianion of pyridine-2,6-dicarboxylic acid (C7H3NO4
2−)} consists of an [Ni(L)(H2O)2]2+ complex cation and a [Ni(pdc)2]2– anion. The metal ion in the cation is coordinated by the four N atoms of the tetraamine ligand and the mutually trans O atoms of the water molecules in a tetragonally elongated octahedral geometry with the average equatorial Ni—N bond length slightly shorter than the average axial Ni—O bond [2.087 (4) versus 2.128 (4) Å]. The ligand L adopts its energetically favored conformation with five-membered and six-membered chelate rings in gauche and chair conformations, respectively. In the complex anion, the NiII ion is coordinated by the two tridentate pdc2– ligands via their carboxylate and nitrogen atom donors in a distorted octahedral trans-NiO4N2 geometry with nearly orthogonal orientation of the planes defining the carboxylate rings and the average Ni—N bond length [1.965 (4) Å] shorter than the average Ni—O bond distance [2.113 (7) Å]. In the crystal, the NH donor groups of the tetraamine, the carboxylic groups of the pdc2– anion and the coordinated water molecules are involved in numerous N—H...O and O—H...O hydrogen bonds, leading to electroneutral sheets oriented parallel to the (001) plane.
The structure of natively iodinated bovine thyroglobulin
Authors: Kim Kookjoo , Kopylov Mykhailo , Bobe Daija , Kelley Kotaro , Eng Edward T. , Arvan Peter , Clarke Oliver B.
Published: October 2021

Thyroglobulin is a homodimeric glycoprotein that is essential for the generation of thyroid hormones in vertebrates. Upon secretion into the lumen of follicles in the thyroid gland, tyrosine residues within the protein become iodinated to produce monoiodotyrosine (MIT) and diiodotyrosine (DIT). A subset of evolutionarily conserved pairs of DIT (and MIT) residues can then engage in oxidative coupling reactions that yield either thyroxine (T4; produced from coupling of a DIT `acceptor' with a DIT `donor') or triiodothyronine (T3; produced from coupling of a DIT acceptor with an MIT donor). Although multiple iodotyrosine residues have been identified as potential donors and acceptors, the specificity and structural context of the pairings (i.e. which donor is paired with which acceptor) have remained unclear. Here, single-particle cryogenic electron microscopy (cryoEM) was used to generate a high-resolution reconstruction of bovine thyroglobulin (2.3 Å resolution in the core region and 2.6 Å overall), allowing the structural characterization of two post-reaction acceptor–donor pairs as well as tyrosine residues modified as MIT and DIT. A substantial spatial separation between donor Tyr149 and acceptor Tyr24 was observed, suggesting that for thyroxine synthesis significant peptide motion is required for coupling at the evolutionarily conserved thyroglobulin amino-terminus.
UGC's responses to the pandemic: roles of Institutional Quality Assurance Cells in Bangladesh
Authors: Genilo Jude William Ramiro
Published: October 2021

Purpose

The paper documents the roles played by the institutional quality assurance cells (IQACs) to implement the University Grants Commission (UGC) directive to shift to online education during the COVID-19 pandemic period in Bangladesh. It highlights the government's efforts to ensure quality education, particularly in utilizing IQACs in the various public and private universities. The paper starts with the pandemic situation in the country, followed by the overall responses of the government, including its directives regarding the conduct of higher education.

Design/methodology/approach

The paper utilizes as framework the Sloan Consortium's Five Pillars of Quality Online Learning – learning effectiveness, student satisfaction, teacher satisfaction, scale and access. The paper then analyzes the oral reports of 26 IQACs, which were presented to government officials in two meetings.

Findings

From the analysis, it is apparent that IQACs have contributed toward the shift to full online education during the pandemic period. Universities responded to the crisis mainly in the areas of governance, teaching and learning and student support services. To guide policy formulation, the IQACs (with the help of other university units) conducted surveys among their faculty and students regarding their access to Internet, financial difficulties and mental health situation. From here, they drafted academic policies (attendance, student assessment and online teaching), conducted capacity building activities, monitored faculty performance, formulated guidelines on student online behavior and encouraged stakeholders to trust the online system.

Originality/value

The study is original since (like many countries) the pandemic has forced education activities to go online. It looks at both the macro level (the concerns of the University Grants Commission or UGC concerning quality education in an online setting) and the micro level (what universities have undertaken to address the concerns of the UGC).
Multi-objective design optimisation of steel framed structures using three different methods
Authors: Alkhadashi Abdalhakem , Mohammad Fouad , Zubayr Rasheedah Olamide , Aoun Klalib Hynda , Balik Piotr
Published: October 2021

Purpose

The optimality objectives are the structure weight and embodied energy as well as calculating the cost and embodied carbon of the resulting optimum options. Three optimality algorithms developed in MATLAB, namely, genetic algorithms (GA), particle swarm optimisation (PSO) and harmony search algorithm (HSA), were used for structural optimisation to compare the effectiveness of the algorithms. Two life-cycle stages were considered, production and construction stages, which include three boundaries: materials, transportation and erection. In the formulation of the optimum design problem, 107 universal steel beams (UKB) and 64 columns (UKC) sections were considered for the discrete design variables. The imposed behavioural constraints in the optimum design process were set according to the provision of Eurocode 3 (EC3). The study aims to find the optimum solution of 2D steel frames whilst considering weight and embodied energy, investigate the performance of the analysis integrated with MATLAB and provide three examples to which all these are applied to.

Design/methodology/approach

Undoubtedly, in structural engineering, the best design of any structure aims at the most economical and environmental option, without impairing the functional and its structural integrity. In the paper, multi-objective stochastic search methods are proposed for optimum design of three two-dimensional multi-story frames.

Findings

Results showed that the optimised designs obtained by HSA are better than those found by the GA and PSO with an average difference of 16% from GA and PSO, where this difference increases at larger frame structures. It was, therefore, concluded that the integration of the analysis, design and optimisation methods employed in MATLAB can be effective in obtaining prompt optimum results during the decision-making stage.

Research limitations/implications

There may be some possible limitations in the study. Due to the time constraints, only three meta-heuristic approaches were investigated, where more methods should be investigated to fully understand their effectiveness in multi-objective problems.

Originality/value

Investigating the performance of three optimisation methods in multi-objective problems developed in MATLAB. More importantly, developing optimisation models for evaluation of embodied energy, embodied carbon and cost for steel structures to assist designers, during the initial stages, to evaluate design decisions against their energy consumption and carbon impacts.
How to select good leaders in Asian countries: the case of China and Singapore
Authors: Choi Franky K.H.
Published: October 2021

Purpose

The purpose of this paper is to bring out the possibility of selecting good leaders in Asian countries, i.e., China and Singapore.

Design/methodology/approach

Since comparative historical analysis enhances the objectivity for academic discussion, Deng Xiaoping’s and Lee Kuan Yew’s leadership successions have been chosen as the cases for studies by virtue of “method of agreement”. Incorporating “argument based on the contrary” into the context for macro-historical analysis, this paper characterises the duo’s successful (at least quite successful) leadership successions, thus offering an alternative paradigm beyond Western-style democracy.

Findings

Both cases of post-Mao China and the independent Singapore indicate that in quite a number of Asian countries, good leaders could still be selected beyond universal suffrage as practised among Western Electoral Democracies, mainly because of the elites-driven context. As to the duo’s succession results, Deng Xiaoping’s selection of leaders was somewhat successful, while Lee Kuan Yew’s was phenomenal.

Originality

This paper offers readers a glance over the possibility of selecting good leaders in Asian countries not fully based on Western-style democracy. Learning from the duo’s leadership successions, the West may treat elite politics as the supplement under Western Electoral Democracies in order to avoid their countries falling into the trap of populism. The West could meanwhile consider the exceptional criteria prized by the duo for leadership successions. Considering such interactions among elites in the real-life context, it could serve as an alternative model to Western-style democracy.