bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial variation in population genomic responses to over a century of anthropogenic change within a tidal marsh songbird
Authors: Benham Phred M. , Walsh Jennifer , Bowie Rauri C. K.
Published: June 2022

Combating the current biodiversity crisis requires the accurate documentation of population responses to human-induced ecological change. To this end, museum collections preserve a record of population responses to anthropogenic change that can provide critical baseline data on patterns of genetic diversity, connectivity, and population structure. We leveraged spatially-replicated time series of specimens to document population genomic responses to the destruction of nearly 90% of coastal habitats occupied by the Savannah sparrow (Passerculus sandwichensis) in California. Spatial-temporal analyses of genetic diversity from 219 sparrows collected between 1889-2017 showed that the amount of habitat lost was not predictive of genetic diversity loss. Despite experiencing the greatest levels of habitat loss, we found that genetic diversity in the San Francisco Bay Area remained relatively high. Over the past century, immigration into the Bay Area from interior populations has also increased. This may have minimized genetic diversity declines, but likely led to the erosion of divergence at loci associated with tidal marsh adaptation. Tracing the genomic trajectories of multiple populations over time provided unique insights into how shifting patterns of gene flow through time in response to human-induced habitat loss may contribute to negative fitness consequences.
Mapping Protein Dynamics at High Spatial Resolution with Temperature-Jump X-ray Crystallography
Authors: Wolff Alexander M. , Nango Eriko , Young Iris D. , Brewster Aaron S. , Kubo Minoru , Nomura Takashi , Sugahara Michihiro , Owada Shigeki , Barad Benjamin A. , Ito Kazutaka , Bhowmick Asmit , Carbajo Sergio , Hino Tomoya , Holton James M. , Im Dohyun , O’Riordan Lee J. , Tanaka Tomoyuki , Tanaka Rie , Sierra Raymond G. , Yumoto Fumiaki , Tono Kensuke , Iwata So , Sauter Nicholas K. , Fraser James S. , Thompson Michael C.
Published: June 2022

Understanding and controlling protein motion at atomic resolution is a hallmark challenge for structural biologists and protein engineers because conformational dynamics are essential for complex functions such as enzyme catalysis and allosteric regulation. Time-resolved crystallography offers a window into protein motions, yet without a universal perturbation to initiate conformational changes the method has been limited in scope. Here we couple a solvent-based temperature jump with time-resolved crystallography to visualize structural motions in lysozyme, a dynamic enzyme. We observed widespread atomic vibrations on the nanosecond timescale, which evolve on the sub-millisecond timescale into localized structural fluctuations that are coupled to the active site. An orthogonal perturbation to the enzyme, inhibitor binding, altered these dynamics by blocking key motions that allow energy to dissipate from vibrations into functional movements linked to the catalytic cycle. Because temperature-jump is a universal method for perturbing molecular motion, the method demonstrated here is broadly applicable for studying protein dynamics.
‘Formation and function of the meninges arachnoid barrier around the developing brain’
Authors: Derk Julia , Como Christina N. , Jones Hannah E. , Joyce Luke R. , Bonney Stephanie , O’Rourke Rebecca , Pawlikowski Brad , Doran Kelly S. , Siegenthaler Julie A.
Published: June 2022

Barriers at the level of the brain endothelium, choroid plexus, and meninges strictly regulate movement of molecules and cells into and out of the central nervous system (CNS). In contrast to the blood-brain barrier and choroid plexus epithelial barrier, developmental timing and function of the meningeal arachnoid barrier, a layer of epithelial-like cells connected by tight and adherens junctions, is largely unknown. To begin to address this, we mined our E14.5 mouse single cell transcriptomic (scRNA-seq) meningeal fibroblast data set and identified the repression of Wnt-β-catenin signaling as a key mechanism underlying the specification of epithelial-like arachnoid barrier cells from Collagen 1+ and Crabp2+ mesenchymal meningeal precursors. We show that elevating Wnt-β-catenin signaling in prenatal meningeal mesenchymal cells prevented the development of arachnoid barrier cells. In the absence of dorsal arachnoid barrier cells, the prenatal meninges and brain are penetrable to biocytin-TMR and Streptococcus agalactiae (Group B Streptococcus, GBS), the leading pathogen known to drive life-threatening neonatal meningitis. We show that a layer of Claudin 11 (tight junction) and E-cadherin (adherens junction) expressing arachnoid barrier cells appear around the mouse brain from E13-E15 and the emergence of a functional barrier by E17 coincides with junctional localization of Claudin 11. Postnatal growth of the arachnoid barrier is marked initially by proliferation and later re-organization of junctional domains. This work provides fundamental knowledge on development and prenatal function of a meningeal arachnoid barrier, and novel tools for future studies on regional functions of this CNS barrier in the meninges.
Nanoparticles targeted to fibroblast activation protein outperform PSMA for MRI delineation of primary prostate tumours
Authors: Dmochowska Nicole , Milanova Valentina , Mukkamala Ramesh , Chow Kwok Keung , Pham Nguyen T.H. , Srinivasarao Madduri , Ebert Lisa M. , Stait-Gardner Timothy , Le Hien , Shetty Anil , Nelson Melanie , Low Philip S. , Thierry Benjamin
Published: June 2022

Accurate and precise delineation of gross tumour volumes remains a barrier to radiotherapy dose escalation and boost dosing in the treatment of solid tumours, such as prostate cancer. Magnetic resonance imaging of tumour molecular targets has the power to enable focal dose boosting, particularly when combined with technological advances such as MRI-LINAC. Fibroblast activation protein (FAP) is a transmembrane protein overexpressed in stromal components of >90% of epithelial carcinomas. Herein we compare targeted MRI of gold standard PSMA with FAP in the delineation of orthotopic tumours in a mouse model of prostate cancer. Control (no ligand), FAP and PSMA-targeting iron oxide nanoparticles were prepared with modification of an MRI agent (FerroTrace). Mice with orthotopic LNCaP tumours underwent T2-weighted 3D MRI 24 hours after intravenous injection of contrast agents. FAP and PSMA nanoparticles produced contrast enhancement on MRI when compared to control nanoparticles, which was most pronounced on the tumour periphery. FAP-targeted MRI increased the proportion of tumour contrast enhancing black pixels by 13.37% when compared to PSMA. Furthermore, analysis of changes in R2 values between healthy prostates and LNCaP tumours indicated an increase in contrast enhancing pixels in the tumour border of 15%, when targeting FAP, in contrast to PSMA This study demonstrates preclinical feasibility of PSMA and FAP-targeted MRI which can enable targeted image-guided focal therapy of localized prostate cancer.
Lipid transport by Candida albicans Dnf2 is required for hyphal growth and virulence
Authors: Jain Bhawik K. , Wagner Andrew S. , Reynolds Todd B. , Graham Todd R.
Published: June 2022

Candida albicans is a common cause of human mucosal yeast infections, and invasive candidiasis can be fatal. Antifungal medications are limited, but those targeting the pathogen cell wall or plasma membrane have been effective. Therefore, virulence factors controlling membrane biogenesis are potential targets for drug development. P4-ATPases contribute to membrane biogenesis by selecting and transporting specific lipids from the extracellular leaflet to the cytoplasmic leaflet of the bilayer to generate lipid asymmetry. A subset of heterodimeric P4-ATPases, including Dnf1-Lem3 and Dnf2-Lem3 from Saccharomyces cerevisiae, transport phosphatidylcholine (PC), phosphatidylethanolamine (PE), and the sphingolipid glucosylceramide (GlcCer). GlcCer is a critical lipid for Candida albicans polarized growth and virulence, but the role of GlcCer transporters in virulence has not been explored. Here we show that the Candida albicans Dnf2 (CaDnf2) requires association with CaLem3 to form a functional transporter and flip fluorescent derivatives of GlcCer, PC and PE across the plasma membrane. Mutation of conserved substrate-selective residues in the membrane domain strongly abrogates GlcCer transport and partially disrupts PC transport by CaDnf2. Candida strains harboring dnf2 null alleles (dnf2ΔΔ) or point mutations that disrupt substrate recognition exhibit defects in the yeast to hyphal growth transition, filamentous growth and virulence in systemically infected mice. The influence of CaDNF1 deletion on the morphological phenotypes is negligible although the dnf1ΔΔ dnf2ΔΔ strain was less virulent than the dnf2ΔΔ strain. These results indicate that the transport of GlcCer and/or PC by plasma membrane P4-ATPases is important for pathogenicity of Candida albicans.
Mettl14-mediated m6A modification ensures the cell cycle progression of late-born retinal progenitor cells
Authors: Li Liang , Sun Yue , Davis Alexander E. , Wu Man-Ru , Lin Cheng-Hui , Ding Jun B. , Wang Sui
Published: June 2022

Neural progenitor cells lengthen their cell cycle to prime themselves for differentiation as development proceeds. It is currently not clear how they counter this lengthening and avoid being halted in the cell cycle. Here, we show that m6A (N6-methyladenosine) methylation of cell cycle-related mRNAs ensures the proper cell cycle progression of late-born retinal progenitor cells (RPCs), which are born towards the end of retinogenesis and have long cell cycle durations. Conditional deletion ofMettl14, which is required for depositing m6A on mRNAs, significantly reduced the level of m6A modification in the developing mouse retina. This led to delayed cell cycle exit of late-born RPCs and neuronal cell death in mature retina, but appeared to have no effect on retinal development prior to birth. M6A-seq, which maps m6A modified mRNAs, and single cell transcriptomic analyses revealed that mRNAs involved in slowing down cell cycle progression were highly enriched for m6A modification, which could target them for degradation and guarantee proper cell cycle progression of late-born RPCs. In addition, we identifiedZfp292as a novel target of m6A and potent inhibitor of RPC cell cycle progression. Overall, our work establishes m6A modification as an important mechanism countering cell cycle lengthening in late-born retinal progenitor cells.
Benzidine Induces Proliferation of UMUC3 Bladder Cancer Cells Through Activation of ERK5 Pathway
Authors: Sun Xin , Zhang Tao , Tang Liang , Min Jie , Wang Yi , Yu De-Xin
Published: June 2022

Mounting evidences have revealed that benzidine, a known human carcinogen, is a pivotal risk factor for bladder cancer (BC). Dysregulated cell proliferation serves as a pivotal pathophysiological step in BC development. The potential mechanisms of MAPK pathways, particularly extracellular regulated protein kinases 5 (ERK5), regarding the modulation of benzidine-elicited cell proliferation are still elusive. Herein, human BC cells UMUC-3 were exposed to indicated levels of benzidine for 5 days. Cell growth, cell cycle progression, cell cycle-related, MAPK genetic expression, and related protein contents were investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test, flow cytometry, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and western blotting (WB), respectively. XMD8-92 (a specific suppressor of ERK5) and small interfering RNA (siRNA) were utilized to identify the roles of ERK5. Our results illustrated that benzidine elevated the proliferative ability of UMUC3 cells and accelerated the cell cycle transition from G1 to S phase, and it increased the expressions of cyclin D1 and proliferating cell nuclear antigen (PCNA) and reduced the expression of p21. Meanwhile, benzidine treatment resulted in the activation of ERK5 pathway and activator protein 1 (AP-1) proteins. In addition, benzidine-elicited cell proliferation and ERK5 stimulation were fully inhibited by XMD8-92 and siRNAs specific to ERK5. Taken together, these results demonstrated that ERK5-mediated cell proliferation was tightly related to benzidine-assoicated BC development, which established the foundation for targeting the ERK5 pathway in BC treatment.
Denaturation resistant P2 tetramer is required to import fatty acids into intraerythrocytic Plasmodium falciparum
Authors: Das Sudipta , Majumder Kaustav , Bhattacharjya Anwesha , Roy Bhaskar
Published: June 2022

The initiation of asymmetric karyokinesis of intraerythrocytic Plasmodium falciparum (Pf) begins without dismantling the nuclear envelope showing the hallmark feature of closed mitosis (1-10). In Pf, karyokinesis precedes cytokinesis and cell body formation (6, 8-10). Regulation at the beginning of nuclear division either through checkpoints or by importing serum components was largely unknown. At the trophozoite stage, PfP2 tetramer trafficked to the infected erythrocyte (IE) surface and the inaccessibility of IE surface PfP2 to its bonafide ligand led to the arrest of nuclear division (11-13). Here we show that PfP2 tetramer localization on the IE surface and the beginning of nuclear division are concomitant in nature. Synthetically induced denaturation resistant PfP2 tetramer interacts with human serum fatty acids and phospholipids for its import into IEs at the beginning of karyokinesis. In the natively folded denaturation resistant PfP2 tetramer cage, the Cys-Cys redox switch regulates the binding and subsequent release of fatty acids on the IE surface. This mechanistic insight of fatty acids import inside IEs using synthetically induced denaturation resistant PfP2 tetramer provides an unique drug screening platform for novel small molecule screening against malaria.
The application of mixed linear models for the estimation of functional effects on bovine stature based on SNP summary statistics from a whole-genome association study
Authors: Kotlarz Krzysztof , Kosinska-Selbi Barbara , Cai Zexi , Sahana Goutam , Szyda Joanna
Published: June 2022

Genome-Wide Association Studies (GWAS) help identify polymorphic sites or genes linked to phenotypic variance, but a few identified genes / Single Nucleotide Polymorphisms are unlikely to explain a large part of the phenotypic variability of complex traits. In this study, the focus was moved from single loci to functional units, expressed by the metabolic pathways: Kyoto Encyclopaedia of Genes and Genomes (KEGG). Consequently, this study aimed to estimate KEGG effects on stature in three Nordic dairy cattle breeds using SNPs effects from GWAS as the dependent variable. The SNPs were annotated to genes, then the genes to KEGG pathways. The effects of KEGG were estimated separately for each breed using a mixed linear model incorporating the similarity between pathways expressed by common genes. The KEGG pathway D-amino acid metabolism (map00473) was estimated as significant on stature in two of the analysed breeds and revealed a borderline significance in the third breed. Interestingly, biological evidence exists that described the importance of D-amino acids for growth in experimental organisms as well as in cattle.
Low diversity and microdiversity of comammox bacteria in wastewater systems suggests wastewater-specific adaptation within the Ca. Nitrospira nitrosa cluster
Authors: Cotto Irmarie , Vilardi Katherine J. , Huo Linxuan , Fogarty Emily C. , Khunjar Wendell , Wilson Christopher , De Clippeleir Haydee , Gilmore Kevin , Bailey Erika , Lücker Sebastian , Pinto Ameet J.
Published: June 2022

Studies have found Ca. Nitrospira nitrosa-like bacteria to be the principal or sole comammox bacteria in nitrogen removal systems for wastewater treatment. In contrast, multiple populations of strict ammonia and nitrite oxidizers co-exist in similar systems. This apparent lack of diversity is surprising and could impact the feasibility of leveraging comammox bacteria for nitrogen removal. We used full-length 16S rRNA gene sequencing and genome-resolved metagenomics to compare population-level (i.e., species) diversity of comammox bacteria with that of strict nitrifiers in full-scale wastewater treatment systems and assess whether these observations were consistent or diverged at the strain-level. Full-length 16S rRNA gene sequencing indicated that while Nitrosomonas-like bacteria exhibited higher population-level diversity, the effective microdiversity of most Nitrospira-like bacteria were comparatively higher except for one Nitrospira Lineage II population. Comammox bacterial metagenome assembled genomes (MAGs) were associated with Ca. Nitrospira nitrosa. The average amino acid identity between comammox bacterial MAGs (93% ± 3) across systems was significantly higher than that of the Nitrosomonas-like ammonia oxidizers (73%±8) and the Nitrospira-like nitrite oxidizer MAGs (75%±13), suggesting that the same comammox population was detected in all systems. Comammox bacteria and some ammonia oxidizers MAGs were significantly less microdiverse than most ammonia and nitrite oxidizers. Interestingly, strain-resolved analysis also indicates that different nitrogen removal systems harbor different comammox bacterial strains within the Ca. Nitrospira nitrosa cluster. These results suggest that comammox bacteria associated with Ca. Nitrospira nitrosa have low species- and strain-level diversity in nitrogen removal systems and may thus harbor specific adaptations to the wastewater ecosystem.
Noisy circumnutations facilitate self-organized shade avoidance in sunflowers
Authors: Nguyen Chantal , Dromi Imri , Kempinski Aharon , Gall Gabriella E. C. , Peleg Orit , Meroz Yasmine
Published: June 2022

Circumnutations are widespread in plants and typically associated with exploratory movements, however a quantitative understanding of their role remains elusive. In this study we report, for the first time, the role of noisy circumnutations in facilitating an optimal growth pattern within a crowded group of mutually shading plants. We revisit the problem of self-organization observed for sunflowers, mediated by shade response interactions. Our analysis reveals that circumnutation movements conform to a bounded random walk characterized by a remarkably broad distribution of velocities, covering three orders of magnitude. In motile animal systems such wide distributions of movement velocities are frequently identified with enhancement of behavioral processes, suggesting that circumnutations may serve as a source of functional noise. To test our hypothesis, we developed a Langevin-type parsimonious model of interacting growing disks, informed by experiments, successfully capturing the characteristic dynamics of individual and multiple interacting plants. Employing our simulation framework we examine the role of circumnutations in the system, and find that the observed breadth of the velocity distribution represents a sharp transition in the force-noise ratio, conferring advantageous effects by facilitating exploration of potential configurations, leading to an optimized arrangement with minimal shading. These findings represent the first report of functional noise in plant movements, and establishes a theoretical foundation for investigating how plants navigate their environment by employing computational processes such as task-oriented processes, optimization, and active sensing. Since plants move by growing, space and time are coupled, and dynamics of self-organization lead to emergent 3D patterns. As such this system provides conceptual insight for other interacting growth-driven systems such fungal hyphae, neurons and self-growing robots, as well as active matter systems where agents interact with past trajectories of their counterparts, such as stigmergy in social insects. This foundational insight has implications in statistical physics, ecological dynamics, agriculture, and even swarm robotics.

One sentence summary of paper

The study highlights noisy circumnutations as a strategy plants use for optimizing growth in crowded conditions.
Cooperation between Imp2p and Cdc15p imparts stiffness to the constricting contractile ring in fission yeast
Authors: Bellingham-Johnstun Kimberly , Commer Blake , Levesque Brié , Tyree Zoe L. , Laplante Caroline
Published: June 2022

The contractile ring must anchor to the plasma membrane and cell wall to transmit its tension to the plasma membrane. F-BAR domain containing proteins including Cdc15p and Imp2p in fission yeast are likely candidate anchoring proteins based on their mutant phenotypes. Cdc15p is a node component, links the actin bundle to the plasma membrane, recruits Bgs1p to the division plane, prevents contractile ring sliding, and contributes to the stiffness of the contractile ring. Less is known about Imp2p. We found that similarly to Cdc15p, Imp2p contributes to the stiffness of the contractile ring and assembles into protein clusters. Imp2p clusters contain ∼8 Imp2p dimers and depend on the actin network for their stability at the division plane. Importantly, Imp2p and Cdc15p reciprocally affect the amount of the other in the contractile ring indicating that the two proteins influence each other during cytokinesis and may explain their similar phenotypes.
Increased volatile thiol release during beer fermentation using constructed interspecies yeast hybrids
Authors: Krogerus Kristoffer , Rettberg Nils , Gibson Brian
Published: June 2022

Interspecies hybridization has been shown to be a powerful tool for developing and improving brewing yeast in a number of industry-relevant respects. Thanks to the popularity of heavily hopped ‘India Pale Ale’-style beers, there is an increased demand from brewers for strains that can boost hop aroma. Here, we explored whether hybridization could be used to construct strains with an enhanced ability to release hop-derived flavours through β-lyase activity, which releases desirable volatile thiols. Wild Saccharomyces strains were shown to possess high β-lyase activity compared to brewing strains, however, they also produced phenolic off-flavours (POF) and showed poor attenuation. To overcome these limitations, interspecies hybrids were constructed by crossing pairs of one of three brewing and one of three wild Saccharomyces strains (S. uvarum and S. eubayanus). Hybrids were screened for fermentation ability and β-lyase activity, and selected hybrids showed improved fermentation and formation of both volatile thiols (4MMP, 3MH and 3MH acetate) and aroma-active esters compared to the parent strains. Undesirable traits (e.g. POF) could be removed from the hybrid by sporulation. To conclude, it was possible to boost the release of desirable hop-derived thiols in brewing yeast by hybridization with wild yeast. This allows production of beer with boosted hop aroma with less hops (thus improving sustainability issues).
Single-Cell RNA-seq Uncovers Dynamic Processes Orchestrated by RNA-Binding Protein DDX43 in Chromatin Remodeling during Spermiogenesis
Authors: Tan Huanhuan , Wang Weixu , Zhou Chongjin , Wang Yanfeng , Zhang Shu , Yang Pinglan , Guo Rui , Chen Wei , Ye Lan , Cui Yiqiang , Ni Ting , Zheng Ke
Published: June 2022

Advances in single-cell RNA sequencing (scRNA-seq) have allowed for elucidating biological mechanisms at cell state level. Mammalian spermatogenic process showcases dynamic switches of gene expression pattern with delicate morphological and functional alterations of germ cells, but it is unclear how such dynamics is genetically controlled. Here we demonstrate that mouse testis-enriched RNA helicase DDX43, as well as its ATP hydrolysis site, is required for spermiogenesis. Genetic mutation of Ddx43 renders spermatids heterogeneously defective in multiple steps of chromatin remodeling, resulting in incomplete substitution of transition protein by protamine and less condensed sperm nucleus. Through scRNA-seq analyses of testicular cells derived from adult wild-type and Ddx43 mutant testes in mice, we reveal that the DDX43 deficiency-elicited perturbation in the dynamic RNA regulatory processes underlies the differentiation deficiency of spermatids. Further, focused analyses on early-stage spermatids combined with enhanced CLIP sequencing (eCLIP-seq) identify Elfn2 as DDX43-targeted hub gene, whose in vivo knockdown shows similar phenotypic defects as Ddx43 mutant. Our study illustrates an essential role for DDX43 in post-meiotic chromatin remodeling and highlights the single cell-based strategy for a refined dissection of stage-specific regulation of germline differentiation.
CRISPR/Cas9 and FLP-FRT mediated multi-modular engineering of the cis-regulatory landscape of the bithorax complex of Drosophila melanogaster
Authors: Hajirnis Nikhil , Pandey Shubhanshu , Mishra Rakesh K
Published: June 2022

The Homeotic genes or Hox define the anterior-posterior (AP) body axis formation in bilaterians and are often present on the chromosome in an order which is collinear to their function across the AP axis. The expression pattern of Hox genes is attributed to the cis-regulatory modules (CRMs) that regulate the genes in a segment-specific manner. In the bithorax complex (BX-C), one of the two Hox complexes in Drosophila melanogaster, even the CRMs consisting of enhancers, initiators, insulators, and Polycomb/trithorax response elements are organized in order that is collinear to their function in the thoracic and abdominal region. Much of these findings are based on the analysis of hundreds of mutations in the BX-C. However, targeted genomic rearrangements comprising of duplications, inversions, etc., that can reveal the basis of collinearity and the number of regulatory modules with respect to body segments have not been reported. In the present study, we generated a series of transgenic lines with the insertion of FRT near the regulatory domain boundaries, to shuffle the CRMs associated with the posterior Hox, Abd-B, of the BX-C. Using these FRT lines, we created several alterations such as deletion, duplication, or inversion of multiple CRMs to comprehend their peculiar genomic arrangement and numbers in the BX-C.
Intrabacterial regulation of a cytotoxic effector by its cognate metaeffector promotes Legionella pneumophila virulence
Authors: Chauhan Deepika , Joseph Ashley M. , Shames Stephanie R.
Published: June 2022

Legionella pneumophila is a natural pathogen of unicellular protozoa that can opportunistically infect macrophages and cause Legionnaires’ Disease. Intracellular replication is driven by hundreds of bacterial effector proteins that are translocated into infected host cells by a Dot/Icm type IV secretion system. L. pneumophila effectors are temporally regulated in part by a unique family of translocated regulatory effectors, termed metaeffectors, which bind and modulate the function of a cognate effector in host cells. We discovered that regulation of the cytotoxic effector SidI by its metaeffector, MesI, is critical for L. pneumophila virulence in natural and opportunistic hosts. MesI binds and negatively regulates SidI activity in vitro but how dysregulation of SidI impairs L. pneumophila intracellular replication is unclear. Using a chromosomally-encoded inducible expression system, we discovered that dysregulation of SidI, via loss of MesI, was toxic to L. pneumophila. SidI enzymatic activity was required for toxicity since L. pneumophila growth was unaffected by induced expression of a catalytically inactive sidI allele. We found MesI translocation into host cells was dispensable for intracellular replication and that MesI-deficient bacteria were rapidly degraded within host cells. Together, our data suggest a unique role for intrabacterial effector regulation by a translocated metaeffector in L. pneumophila virulence.

Importance

Legionella pneumophila replicates within phagocytic host cells using hundreds of effector protein virulence factors, which canonically subvert the function of host proteins and pathways. L. pneumophila encodes a unique family of translocated effectors called metaeffectors, which bind and regulate the function of a cognate effector in host cells. The metaeffector MesI promotes L. pneumophila virulence by regulating the cytotoxic effector SidI; however, the MesI regulatory mechanism is poorly understood. We discovered a unique intrabacterial role for MesI in L. pneumophila virulence. When uncoupled from MesI, SidI was toxic to L. pneumophila in vitro and triggered robust bacterial degradation in host cells. Importantly, translocation of MesI was dispensable for intracellular replication, demonstrating that intrabacterial regulation of SidI contributes to L. pneumophila virulence. These data show a unique and important role for MesI regulation of SidI within the bacterium, which challenges the dogma that effectors function exclusively within host cells.
Intelligibility and cellularity in the villas of Palladio and Le Corbusier: examining Rowe's observations
Authors: Dawes Michael J. , Lee Ju Hyun , Ostwald Michael J.
Published: June 2022

Purpose

In the 1947 article, The Mathematics of the Ideal Villa, Colin Rowe famously compared the spatial and geometric properties of buildings by two architects: Palladio and Le Corbusier. Many of Rowe's observations in this article have since been extensively debated but not rigorously tested. This paper examines Rowe's proposition that Palladio's villa plans possess greater intelligibility and cellularity than Le Corbusier's villa plans.

Design/methodology/approach

Two established computational techniques, axial line analysis and isovist analysis, are adopted in this paper to quantify and compare the properties of intelligibility and cellularity in the four villas that Rowe used to construct his argument: Malcontenta, Rotunda, Stein, and Savoye.

Findings

While acknowledging methodological limitations, the results of this paper do not support Rowe's claims, but they do lead to a unique quantitative examination of spatial configurations and properties of four famous villa plans.

Originality/value

This is the first paper to quantitatively examine Rowe's claims that Palladian villas possess greater intelligibility and cellularity than Le Corbusier's villas.
Forming an academic program review learning community: description of a conceptual model
Authors: Hoare Alana , Dishke Hondzel Catharine , Wagner Shannon
Published: June 2022

Purpose

Higher education institutions are required to evaluate program quality through cyclical program review processes. Despite often being considered the “gold standard” of academic review, there persists dissatisfaction with the lack of integration of program review findings into other planning processes, such as budgeting, assessment and strategic planning. As a result, the notion of program review action plans “collecting dust on the shelf” is so ubiquitous that the concept is normalized as an expected outcome. The purpose of this paper is to describe a conceptual model whereby teams of faculty members receive education and training from quality assurance practitioners and educational developers, access to institutional resources, opportunities for cross-departmental collaborations and collective advocacy to increase the capacity of faculty members to implement improvement goals resulting from program reviews.

Design/methodology/approach

The authors theorize that a professional learning community is a meaningful approach to program review and present a conceptual model – the Academic Program Review Learning Community (PRLC) – as an antidote to hierarchical, fragmented, compliance-oriented processes. The authors suggest that the PRLC offers a reliable institutional framework for learning through formalized structures and nested support services, including peer learning and external coaching, which can enhance the catalytic capacity of reviews.

Findings

The authors argue that postsecondary institutions should create formal structures for incorporating learning communities because, without a reliable infrastructure for collective learning, decision-making may be fragmented oridiosyncratic because of shifting demands, priorities or disconnected faculty.

Originality/value

A learning community model for program review fits well with a new way to think about program review because faculty are most engaged when they feel ownership over the process. Furthermore, few models exist for conducting program review; as a result, chairs and academics often struggle to conduct reviews without a coherent framework to draw upon.
Deep learning framework for true amplitude imaging: Effect of conditioners and initial models
Authors: Kaur Harpreet , Sun Junzhe , Aharchaou Mehdi , Baumstein Anatoly , Fomel Sergey
Published: June 2022

We propose a workflow to correct migration amplitudes by estimating the inverse Hessian operator weights using a neural network–based framework. We train the network such that it learns the transformation between the migration output and true amplitude reflectivity constrained by different conditioners. We analyse the network output with a velocity model and with source illumination as a conditioner. Compared to the velocity model, source illumination as a conditioner performs better because source illumination encodes the geometrical spreading information and accounts for non‐stationarity. We further use the output of the deep neural network as a starting model for accelerating the convergence of iterative least‐squares reverse time migration. Using a deep learning framework, the proposed method combines the model domain and data domain least‐squares migration approaches to recover images with interpretable amplitudes, attenuated migration artefacts, better signal‐to‐noise ratio and improved resolution. We compare the output of the proposed algorithm with conventional least‐squares output and show that the proposed workflow is more robust, especially in the areas with weak illumination.
Pharmacological characterization of linzagolix, a novel, orally active, non‐peptide antagonist of gonadotropin‐releasing hormone receptors
Authors: Tezuka Motohiro , Tamai Yasuaki , Kuramochi Yu , Kobayashi Kaoru , Fushimi Nobuhiko , Kiguchi Sumiyoshi
Published: June 2022

Control of gonadotropin‐releasing hormone (GnRH) signalling is an effective strategy for the treatment of sex hormone‐dependent diseases. GnRH analogues have been widely used for treating these diseases; however, initial stimulation or complete suppression of GnRH signalling by GnRH analogues results in the occurrence of several distinct adverse effects. Accordingly, we aimed to discover small molecule GnRH antagonists with superior pharmacokinetic and pharmacodynamic profiles. Linzagolix is a potent, orally available, and selective GnRH antagonist. Here, we reported the pharmacological characterization of linzagolix in vitro and in vivo. Linzagolix selectively binds to the GnRH receptor and inhibits GnRH‐stimulated signalling, in a manner comparable to cetrorelix, a peptide GnRH antagonist. Because the inhibitory effect of the gonad axis is useful for the treatment of gynaecological conditions such as endometriosis and uterine fibroids, we investigated the effect of orally administrated linzagolix on the gonadal axis in ovariectomized and intact cynomolgus monkeys. In ovariectomized monkeys, linzagolix immediately suppressed the serum luteinizing hormone concentration at doses over 1 mg/kg, indicating dose‐dependent inhibition that correlated with serum linzagolix concentrations. In intact female monkeys, repeated linzagolix administration suppressed hormone surges and ceased or prolonged menstrual cycles. Furthermore, all animals presenting arrested menstrual cycles following linzagolix treatment showed recovery of hormone secretion and regular menstrual cycles after administration periods ended. Our results demonstrated that linzagolix has potential as a novel agent for reproductive‐age women suffering from sex hormone‐dependent diseases.
Risk governance during the COVID‐19 pandemic: A quantitative content analysis of governors' narratives on twitter
Authors: Zahry Nagwan R. , McCluskey Michael , Ling Jiying
Published: June 2022

The current study addresses the communication aspect of risk governance during the COVID‐19 pandemic by examining whether governors' tweets differ by political party, gender and crisis phase. Drawing on the Centers for Disease Control and Prevention's Crisis Emergency Risk Communication (CERC) model and framing literature, we examined the salience of five CERC's communication objectives, namely acknowledge crisis with empathy, promote protective actions, describe preparedness/response efforts, address rumours and misunderstanding and segment audience. Using a deductive and inductive approach, we analysed 7000 Twitter messages sent by the 50 US state governors during the period of 13 March 2020 to 17 August 2020. Our findings suggest that governors' tweets aligned with CERC's communication objectives to a varying degree. We found main and interaction effects of political party, gender and crisis phase on governors' communication objectives. New emergent communication objectives included attention to mental health, call for social influencers and promoting hope. Implications are discussed.
Predictors of mortality in COVID‐19 induced acute kidney injury
Authors: Yüksel Enver , Arac Songül , Deniz Altintaş Derya
Published: June 2022

Background

We aimed to investigate the predictors of mortality in patients with COVID‐19‐induced acute kidney injury (COV‐AKI).

Methods

We enrolled 803 patients who developed COV‐AKI. The patients were divided into two groups: survivors and nonsurvivors.

Results

A multivariate logistic regression analysis showed that age (p < 0.001), increased admission C‐reactive protein (p = 0.016), procalcitonin (p = 0.019), creatine kinase (p = 0.04), KDIGO stage 1 versus 2 AKI (p < 0.001), KDIGO stage 1 versus 3 (p < 0.001), the need for renal replacement therapy (p = 0.002) and highest creatinine (p = 0.004) were significantly associated with increased inhospital mortality. However, the mortality of patients with AKI on admission (p = 0.002) was found to be lower than those who developed AKI after hospitalization.

Conclusions

Among patients with COV‐AKI, high‐inflammatory response and severe AKI were associated with significantly higher mortality.
Impact of chemotherapy cycles on oncological outcomes in elders with locally advanced cervical cancer treated with concurrent chemoradiotherapy
Authors: Tangkananan Aimwarin , Thongkhao Pitchaya , Janmunee Narumon , Hanprasertpong Jitti
Published: June 2022

Introduction

To investigate the association between chemotherapy (CMT) cycles and oncological outcomes in elders with locally advanced cervical cancer (LACC) who treated with concurrent chemoradiotherapy (CCRT).

Methods

We retrospective studied 498 elders with LACC who treated with radiotherapy (RT) or CCRT between 2002 and 2018. Patients were divided into three groups: RT, CCRT with 1–4 and CCRT with 5–6 cycles of CMT. We compared progression‐free survival (PFS) and overall survival (OS) among the three groups and explored survival prognostic factors via multivariate analysis and time‐varying analysis effect.

Results

There were 453 eligible patients; 222, 119 and 112 patients who received RT, CCRT with 1–4 and CCRT with 5–6 cycles of CMT, respectively. Patients in the RT group had older age, poorer performance status, more treatment with conventional RT technique and earlier treatment year comparing with both CCRT groups. Patients who received 5–6 cycles of CMT were less to have underweight, comorbidities and anaemia compared with the RT group. There were patients with lower FIGO stage in 5–6 cycles than in 1–4 cycles of CMT and RT groups. The 5‐year PFS and OS between RT, CCRT with 1–4 and CCRT with 5–6 cycles of the CMT group were significantly different. Performance status, comorbidity, histology, FIGO stage and total received 5–6 CMT cycles were significant prognostic factors of PFS and OS. However, the benefits of receiving 5–6 CMT cycles were evidenced only within the first 2.5 years.

Conclusion

Elders with LACC who received 5–6 cycles of CMT concurrently with RT can improve PFS and OS, but the benefit persisted only within the first 2.5 years.
Cognitive subgroups and their longitudinal trajectories in bipolar disorder
Authors: Ehrlich Tobin J. , Ryan Kelly A. , Burdick Katherine E. , Langenecker Scott A. , McInnis Melvin G. , Marshall David F.
Published: June 2022

Introduction

Cognitive functioning in bipolar disorder is heterogeneous with evidence for multiple subgroups. However, cognitive subgroup change patterns over time remains unknown. While prior work suggests minimal differences in cognitive functioning patterns over time between those with bipolar disorder and controls, group‐based analyses may obscure unique subgroup‐based changes.

Material and Methods

Participants diagnosed with bipolar disorder (I, II, NOS; n = 568) and unaffected controls (n = 234) completed baseline, one‐ and five‐year neuropsychological assessments. Data reduction techniques were used to limit the number of neuropsychological variables. Bipolar disorder participant baseline neuropsychological data were entered into hierarchical cluster analyses and resultant clusters were entered in multilevel models, which tested for differences in baseline and longitudinal cognitive changes in cognition among the cluster groups and with controls.

Results

Results were consistent with bipolar disorder participants forming three subgroups with high (n = 209), mid (n = 259), and low (n = 100) cognition. These groups were associated with unique clinical characteristics. Multilevel models demonstrated that over a five‐year period, the low group improved, relative to the high and mid groups, and with controls, in auditory memory. Over the five‐year period, the mid group, in comparison with the high group, improved in visual memory; additionally, the high group remained stable, in comparison with a slight decline in the control group, in inhibitory control.

Conclusion

These results demonstrate that cognition‐based subgroups of bipolar disorder participants have minimal differences in their longitudinal course in relation to each other and with unaffected controls.
Evaluation of endodontically treated teeth and related apical periodontitis using periapical and endodontic status scale: Retrospective cone‐beam computed tomography study
Authors: Şanal Çikman Ahter , Köse Taha Emre , Günaçar Dilara Nil , Çene Erhan , Arıcıoğlu Banu
Published: June 2022

The purpose of this study was to evaluate the technical treatment quality and the status of apical pathology of endodontically treated teeth, as well as apical periodontitis (AP) prevalence, in a Turkish population using cone‐beam computed tomography (CBCT). The CBCT images obtained between January 2018 and April 2020 were retrospectively examined. The quality of the endodontic treatments and the related periapical inflammatory lesions were classified according to the periapical and endodontic status scale (PESS). The data were statistically analysed using logistic regression, crosstabs and chi‐square tests. AP was detected in 41% of 429 endodontically treated teeth. The prevalence of AP was significantly higher in teeth with inadequate root canal treatment compared with those with adequate treatment, 70.8% and 29.3%, respectively. Inadequate canal length and homogeneity, and complications were significantly associated with the prognostic periapical status scores of higher risk.
Effects of 28 days of cannabis abstinence on cognition in major depressive disorder: A pilot study
Authors: Sorkhou Maryam , Rabin Rachel A. , Rabin Jennifer S. , Kloiber Stefan , McIntyre Roger S. , George Tony P.
Published: June 2022

Background and Objectives

Cannabis is a widely used substance that may impair select cognitive domains, including attention and memory. Problematic cannabis use is a common clinical problem among patients with major depressive disorder (MDD). Few studies have investigated the effects of cannabis abstinence on cognition in MDD. Thus, our study aimed to determine whether a 28‐day period of cannabis abstinence is associated with improvements in cognition in patients with MDD and comorbid cannabis use disorder (CUD).

Methods

We evaluated the effects of 28 days of cannabis abstinence on cognition in MDD patients with comorbid CUD facilitated by contingency management, motivational interviewing, psychoeducation, and coping‐skills training (N = 11). Primary outcomes included Baseline to Day 28 changes in verbal memory and learning, while secondary outcomes included Baseline to Day 28 changes in working memory, visuospatial working memory (VSWM), visual search speed, mental flexibility, response inhibition, attention, manual dexterity, and fine motor movement.

Results

Eight participants (72.7%) met the pre‐specified criteria for cannabis abstinence and three participants significantly reduced their cannabis use (≥90%). Visual search speed, selective attention, and VSWM improved over the study period. These improvements were not associated with changes in cannabis metabolite levels from baseline to endpoint.

Discussion and Conclusions

Our findings suggest that 28 days of cannabis abstinence may improve select cognitive domains in patients with MDD and comorbid CUD.

Scientific Significance

This is the first study to longitudinally examine the effects of cannabis on cognition in MDD. Clinical trial: Effects of Cannabis Abstinence on Symptoms and Cognition in Depression (NCT03624933; https://www.clinicaltrials.gov).
Combined assessment of S‐ and N‐specific IL‐2 and IL‐13 secretion and CD69 neo‐expression for discrimination of post–infection and post‐vaccination cellular SARS‐CoV‐2‐specific immune response
Authors: Kratzer Bernhard , Schlax Larissa C. , Gattinger Pia , Waidhofer‐Söllner Petra , Trapin Doris , Tauber Peter A. , Sehgal Al Nasar Ahmed , Körmöczi Ulrike , Rottal Arno , Feichter Melanie , Oberhofer Teresa , Grabmeier‐Pfistershammer Katharina , Borochova Kristina , Dorofeeva Yulia , Tulaeva Inna , Weber Milena , Mühl Bernhard , Kropfmüller Anna , Negrin Bettina , Kundi Michael , Valenta Rudolf , Pickl Winfried F.
Published: June 2022

Background

Antibody‐based tests are available for measuring SARS‐CoV‐2‐specific immune responses but fast T‐cell assays remain scarce. Robust T cell‐based tests are needed to differentiate specific cellular immune responses after infection from those after vaccination.

Methods

One hundred seventeen individuals (COVID‐19 convalescent patients: n = 40; SARS‐CoV‐2 vaccinees: n = 41; healthy controls: n = 36) were evaluated for SARS‐CoV‐2‐specific cellular immune responses (proliferation, Th1, Th2, Th17, and inflammatory cytokines, activation‐induced marker [AIM] expression) by incubating purified peripheral blood mononuclear cells (PBMC) or whole blood (WB) with SARS‐CoV‐2 peptides (S, N, or M), vaccine antigens (tetanus toxoid, tick borne encephalitis virus) or polyclonal stimuli (Staphylococcal enterotoxin, phytohemagglutinin).

Results

N‐peptide mix stimulation of WB identified the combination of IL‐2 and IL‐13 secretion as superior to IFN‐γ secretion to discriminate between COVID‐19‐convalescent patients and healthy controls (p < .0001). Comparable results were obtained with M‐ or S‐peptides, the latter almost comparably recalled IL‐2, IFN‐γ, and IL‐13 responses in WB of vaccinees. Analysis 10 months as opposed to 10 weeks after COVID‐19, but not allergic disease status, positively correlated with IL‐13 recall responses. WB cytokine responses correlated with cytokine and proliferation responses of PBMC. Antigen‐induced neo‐expression of the C‐type lectin CD69 on CD4+ (p < .0001) and CD8+ (p = .0002) T cells informed best about the SARS‐CoV‐2 exposure status with additional benefit coming from CD25 upregulation.

Conclusion

Along with N‐ and S‐peptide‐induced IL‐2 and CD69 neo‐expression, we suggest to include the type 2 cytokine IL‐13 as T‐cellular recall marker for SARS‐CoV‐2 specific T‐cellular immune responses after infection and vaccination.