bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural factors contributing to SARS-CoV-2 infection risk in the urban slum setting
Authors: Fofana Mariam O. , Nery Nivison , Aguilar Ticona Juan P. , Belitardo Emilia M.M.A. , Victoriano Renato , Anjos Rôsangela O. , Portilho Moyra M. , de Santana Mayara C. , dos Santos Laiara L. , de Oliveira Daiana , Cruz Jaqueline S. , Muencker M. Cate , Khouri Ricardo , Wunder Elsio A. , Hitchings Matthew D.T. , Johnson Olatunji , Reis Mitermayer G. , Ribeiro Guilherme S. , Cummings Derek A.T. , Costa Federico , Ko Albert I.
Published: February 2022

Background

The structural environment of urban slums, including physical, demographic and socioeconomic attributes, renders inhabitants more vulnerable to SARS-CoV-2 infection. Yet, little is known about the specific determinants that contribute to high transmission within these communities.

Methods and findings

We performed a serosurvey of an established cohort of 2,035 urban slum residents from the city of Salvador, Brazil between November 2020 and February 2021, following the first COVID-19 pandemic wave in the country. We identified high SARS-CoV-2 seroprevalence (46.4%, 95% confidence interval [CI] 44.3-48.6%), particularly among female residents (48.7% [95% CI 45.9-51.6%] vs. 43.2% [95% CI 39.8-46.6%] among male residents), and among children (56.5% [95% CI 52.3-60.5%] vs. 42.4% [95% CI 39.9-45.0%] among adults). In multivariable models that accounted for household-level clustering, the odds ratio for SARS-CoV-2 seropositivity among children was 1.96 (95% CI 1.42-2.72) compared to adults aged 30-44 years. Adults residing in households with children were more likely to be seropositive; this effect was particularly prominent among individuals with age 30-44 and 60 years or more. Women living below the poverty threshold (daily per capita household income <$1.25) and those who were unemployed were more likely to be seropositive.

Conclusions

During a single wave of the COVID-19 pandemic, cumulative incidence as assessed by serology approached 50% in a Brazilian urban slum population. In contrast to observations from industrialized countries, SARS-CoV-2 incidence was highest among children, as well as women living in extreme poverty. These findings emphasize the need for targeted interventions that provide safe environments for children and mitigate the structural risks posed by crowding and poverty for the most vulnerable residents of urban slum communities.
Combined oropharyngeal/nares and nasopharyngeal swab sampling remain effective for molecular detection of SARS-CoV-2 Omicron variant
Authors: Patriquin Glenn , LeBlanc Jason J. , Gillis Holly A. , McCracken Gregory R. , Pettipas Janice J. , Hatchette Todd F.
Published: February 2022

The world has experienced several waves of SARS-CoV-2 variants of concern (VoCs) throughout the COVID-19 pandemic since the first cases in December 2019. The Omicron VoC has increased transmission, compared to its predecessors, and can present with sore throat and other cold-like symptoms. Given the predominance of throat symptoms, and previous work demonstrating better sensitivity using antigen-based rapid detection tests when a throat swab is included in the standard nasal sampling, this quality improvement project sought to ensure ongoing suitability of both combined oropharyngeal/nares (OPN) and nasopharyngeal (NP) swab sampling used throughout the pandemic. Consenting participants meeting Public Health testing criteria (mostly symptomatic or a close contact of a known case) were enrolled, and paired NP and OPN swabs collections were subjected to nucleic acid amplification testing (NAAT). Comparing paired specimens from 392 participants sensitivity of NP swabs was 89.1% (95% CI, 78.8-94.9), and that of OPN was 98.4% (95% CI: 90.9->99.9) (p-value 0.052). This project demonstrated that both NP and combined OPN swabs detected the Omicron variant with similar sensitivity by NAAT, supporting the continued use of either swab collection for SARS-CoV-2 molecular detection.
Prognosis-related molecular subtypes and immune features associated with hepatocellular carcinoma
Authors: Ye Jiazhou , Lin Yan , Gao Xing , Lu Lu , Huang Xi , Huang Shilin , Bai Tao , Wu Guobin , Li Yongqiang , Luo Xiaoling , Liang Rong
Published: February 2022

Bioinformatics tools were used to identify prognosis-related molecular subtypes and biomarkers of hepatocellular carcinoma (HCC). Differential expression analysis of four datasets (TCGA, GSE76427, GSE25097, and GSE14520) identified 3,330 genes differentially expressed in the same direction in all four datasets; those genes were involved in the cell cycle, FOXO signaling pathway, as well as complement and coagulation cascades. Based on non-negative matrix decomposition, two molecular subtypes of HCC with different prognosis were identified, with subtype C2 showing better overall survival than subtype C1. Cox regression and Kaplan-Meier analysis showed that 217 of the overlapping DEGs were closely associated with HCC prognosis. The subset of those genes showing an area under the curve > 0.80 was used to construct random survival forest and least absolute shrinkage and selection operator models, which identified seven feature genes (SORBS2, DHRS1, SLC16A2, RCL1, IGFALS, GNA14, and FANCI) that may be involved in HCC occurrence and prognosis. Based on the feature genes, risk score and recurrence models were constructed, while a univariate Cox model identified FANCI as a key gene involved mainly in the cell cycle, DNA replication, and mismatch repair. Further analysis showed that FANCI had two mutation sites and that its gene may undergo methylation. Single-sample gene set enrichment analysis showed that Th2 and T helper cells are significantly upregulated in HCC patients compared to controls. Our results identify FANCI as a potential prognostic biomarker for HCC.
Uncertainties of cell number estimation in cyanobacterial colonies and the potential use of sphere packing
Authors: T-Krasznai Enikő , Lerf Verona , Tóth István , Kisantal Tibor , Várbíró Gábor , Vasas Gábor , B-Béres Viktória , Görgényi Judit , Lukács Áron , Kókai Zsuzsanna , Borics Gábor
Published: February 2022

Cyanobacteria are notorious bloom formers causing various water quality concerns, such as toxin production, extreme diurnal variation of oxygen, or pH, etc., therefore, their monitoring is essential to protect the ecological status of aquatic systems. Cyanobacterial cell counts and biovolumes are currently being used in water management and water quality alert systems. In this study, we investigated the accuracy of colonial biovolume and cell count estimation approaches used in the everyday practice. Using real like 3-dimensional images of cyanobacterial colonies, we demonstrated that their shape cannot be approximated by ellipsoids. We also showed that despite the significant relationship between overall colony volume and cell biovolumes because of the considerable scatter of cell count data the regressions give biased estimates for cyanobacterial cell counts. We proposed a novel approach to estimate cell counts in colonies that was based on the random close sphere packing method. This method provided good results only in those cases when overall colony volumes could be accurately measured. The visual investigation of colonies done by skilled experts has given precise but lower estimates for cell counts. Estimation results of several experts were surprisingly good which suggest that this capability can be improved, and estimation bias can be reduced to the level acceptable for water quality estimations.

Highlights

Cyanobacterial colony – cell biovolume relationships provide biased estimates for cellbiovolumes.

Sphere packing approach provides good cellcount estimates if colony volumes are accurately measured.

Considering cyanobacterial colonies as ellipsoids gives inaccurate volume estimates.

Skilled experts slightly underestimate the cellcounts but dispersion of their estimates is low.
Omicron Spike protein has a positive electrostatic surface that promotes ACE2 recognition and antibody escape
Authors: Gan Hin Hark , Zinno John , Piano Fabio , Gunsalus Kristin C.
Published: February 2022

High transmissibility is a hallmark of the Omicron variant of SARS-CoV-2. Understanding the molecular determinants of Omicron’s transmissibility will impact development of intervention strategies. Here we map the electrostatic potential surface of the Spike protein to show that major SARS-CoV-2 variants have accumulated positive charges in solvent-exposed regions of the Spike protein, especially its ACE2-binding interface. Significantly, the Omicron Spike-ACE2 complex has complementary electrostatic surfaces. In contrast, interfaces between Omicron and neutralizing antibodies tend to have similar positively charged surfaces. Structural modeling demonstrates that the electrostatic property of Omicron’s Spike receptor binding domain (S RBD) plays a role in enhancing ACE2 recognition and destabilizing Spike-antibody complexes. Collectively, our structural analysis implies that Omicron S RBD interaction interfaces have been optimized to simultaneously promote access to human ACE2 receptors and evade antibodies. These findings suggest that electrostatic interactions are a major contributing factor for increased Omicron transmissibility relative to other variants.
RABL2 Regulates Ciliation via Controlling IFT-B1 Basal Body Recruitment and ARL3-mediated BBSome Ciliary Retrieval
Authors: Zhang Rui-Kai , Liu Yan-Xia , Sun Wei-Yue , Bao Dong-Xue , Jia Rui-Qin , Zhang Chan , Fan Zhen-Chuan
Published: February 2022

Highly conserved intraflagellar transport (IFT) trains and certain small GTPases coordinate to direct ciliation and to maintain the ciliary dynamics of signaling molecules via the IFT cargo adaptor BBSome. Unlike murine Rab-like 2 (RABL2) GTPase that enters cilia to drive outward transition zone (TZ) passage of the BBSome, human orthologue fails to enter cilia but resides at the ciliary base, indispensable for ciliation. However, mechanisms underlying how RABL2 regulates ciliation and BBSome barrier passage remain elusive. Here, we show thatChlamydomonasRABL2 regulates basal body targeting of the IFT-B1 subcomplex component of IFT trains as a RABL2-specific effector, mediating ciliation via controlling IFT-B1 basal body amount available for assembling anterograde IFT trains. RABL2GTPbinds IFT-B1 to perform IFT; sheds from retrograde IFT trains at the proximal ciliary region right above the TZ; and converts to RABL2GDPrapidly. Next, RABL2GDPactivates the ciliary membrane anchored Arf-like 3 (ARL3) GTPase (ARL3GDP) as a ARL3-specific guanine nucleotide exchange factor. Upon detaching from the ciliary membrane, the active ARL3GTPrecruits its BBSome effector, autonomous of retrograde IFT train association, to move cross the TZ for ciliary retrieval. This ensures proper BBSome ciliary turnover for maintaining phototactic response ofChlamydomonascells. For finishing RABL2 ciliary cycle, RABL2GDPpasses the TZ for ciliary retrieval by loading onto the ARL3GTP/BBSome as a BBSome cargo. Our data thus propose that RABL2 mediates ciliation and BBSome ciliary retrieval simultaneously but via distinct molecular pathways.

Significance statement

Intraflagellar transport (IFT) and its cargo adaptor BBSome are indispensable for ciliation and ciliary singling. Rab-like 2 (RABL2) GTPase mediates ciliation and outward transition zone (TZ) passage of BBSomes with mechanisms yet to be determined. Here, we report that RABL2 decides ciliation by controlling the basal body amount of its effector IFT-B1 available for the assembly of anterograde IFT trains. RABL2GTPcycles through cilia as an IFT-B1 cargo; sheds from IFT at the ciliary base; and undergoes nucleotide exchange for activating ARL3 as an ARL3-specfic guanine nucleotide exchange factor. ARLGTPrecruits IFT-shed BBSomes to pass the TZ for ciliary retrieval. RABL2GDPexists cilia via ARL3GTP/BBSome as a BBSome cargo. Therefore, RABL2 functions both outside and inside cilia for initiating IFT and BBSome ciliary retrieval, respectively.
A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites
Authors: Hayward Jenni A. , Makota F. Victor , Cihalova Daniela , Rajendran Esther , Zwahlen Soraya M. , Shuttleworth Laura , Wiedemann Ursula , Spry Christina , Saliba Kevin J. , Maier Alexander G. , van Dooren Giel G.
Published: February 2022

With the advent of resistance to existing treatments, new drugs are needed to combat apicomplexan parasites such as the causative agents of malaria (Plasmodium species) and toxoplasmosis (Toxoplasma gondii). To identify new inhibitors of the mitochondrial electron transport chain (ETC) in these parasites, we developed a Seahorse XFe96 flux analyzer approach to screen compounds from the Medicines for Malaria Venture ‘Pathogen Box’ for ETC inhibition. We identified six chemically diverse, on-target inhibitors of the ETC of T. gondii, five of which also target the ETC of Plasmodium falciparum. Two of the identified compounds (MMV024937 and MMV688853) represent novel ETC inhibitor chemotypes. We pinpoint the molecular targets of these inhibitors, demonstrating that all target ETC Complex III, with MMV688853 additionally targeting a kinase with a key role in parasite invasion of host cells. Most of the compounds remain effective inhibitors of parasites that are resistant to the clinically used Complex III inhibitor atovaquone. In sum, we have developed a versatile screening approach to identify and characterize new inhibitors of the ETC in apicomplexan parasites.
Structure and mechanism of the tripartite ATP-independent periplasmic (TRAP) transporter
Authors: Davies James S. , Currie Michael J. , North Rachel A. , Wright Joshua D. , Scalise Mariafrancesca , Copping Jack M. , Remus Daniela M. , Gulati Ashutosh , Morado Dustin R. , Jamieson Sam A. , Abeysekera Gayan S. , Ramaswamy Subramanian , Friemann Rosmarie , Wakatsuki Soichi , Allison Jane R. , Indiveri Cesare , Drew David , Mace Peter D. , Dobson Renwick C.J.
Published: February 2022

In bacteria and archaea, tripartite ATP-independent periplasmic (TRAP) transporters uptake essential carboxylate- and sulfonate-containing nutrients into the cytoplasm. Unlike other secondary active transporters, TRAP transporters cannot receive their substrates directly, but do so indirectly via a secreted soluble substrate-binding protein. How a sodium-driven secondary active transporter is strictly coupled to a passenger-carrying substrate-binding domain is poorly understood. Here, we report the cryo-EM structure of the sialic acid TRAP transporter SiaQM from Photobacterium profundum at 2.97 Å resolution. SiaM has 12-TMs that come together to form a “transport” domain and a “scaffold” domain, with the transport domain consisting of helical hairpins as seen in the sodium-coupled elevator transporter VcINDY. Interestingly, the SiaQ protein forms intimate contacts with SiaM to extend the size of the scaffold domain, indicating TRAP transporters may operate as monomers, rather than the typically observed oligomers. We have identified the Na+ and sialic acid binding sites in SiaM and confirmed a strict dependence on the substrate-binding protein SiaP for uptake. We have determined the SiaP crystal structure that, together with co-evolution driven docking studies, provides a molecular basis for how sialic acid is delivered to the SiaQM transporter complex. We conclude that TRAP proteins are conceptually a marriage between an ABC importer and a secondary active transporter, which we describe herein as an ‘elevator-with-an-operator’ mechanism.
Syncollin secreted by activated human neutrophils targets bacteria
Authors: Waters Rosie A. , Robinson James , Edwardson J. Michael
Published: February 2022

Syncollin is a 16-kDa protein that was originally isolated from the pancreatic zymogen granule. Syncollin is also found in human neutrophils and is secreted from promyelocytic HL-60 cells upon stimulation. Recently, we reported that syncollin is able to bind to bacterial peptidoglycan, to damage the bacterial envelope and to restrict bacterial growth. Here, we show that syncollin is secreted from activated primary human neutrophils, and interacts with extracellular neutrophil traps (NETs) in a similar manner to the well-characterized granular protein myeloperoxidase. In addition, secreted syncollin is able to coat the surface of E. coli in co-cultures of neutrophils and bacteria. On the basis of our findings, we suggest that syncollin plays a role in host defence in the blood.
Architecture and self-assembly of the jumbo bacteriophage nuclear shell
Authors: Laughlin Thomas G. , Deep Amar , Prichard Amy M. , Seitz Christian , Gu Yajie , Enustun Eray , Suslov Sergey , Khanna Kanika , Birkholz Erica A. , Armbruster Emily , McCammon J. Andrew , Amaro Rommie E. , Pogliano Joe , Corbett Kevin D. , Villa Elizabeth
Published: February 2022

Bacteria encode myriad defenses that target the genomes of infecting bacteriophage, including restriction-modification and CRISPR/Cas systems. In response, one family of large bacteriophage employs a nucleus-like compartment to protect their replicating genomes by excluding host defense factors. However, the principle composition and structure of this compartment remain unknown. Here, we find that the bacteriophage nuclear shell assembles primarily from one protein, termed chimallin. Combining cryo-electron tomography of nuclear shells in bacteriophage-infected cells and cryo-electron microscopy of a minimal chimallin compartment in vitro, we show that chimallin cooperatively self-assembles as a flexible sheet into closed micron-scale compartments. The architecture and assembly dynamics of the chimallin shell suggest mechanisms for its nucleation and growth, and its role as a scaffold for phage-encoded factors mediating macromolecular transport, cytoskeletal interactions, and viral maturation.
Daam1 negatively regulates USP10 activity
Authors: Phillips Andrew T. , Boumil Edward F. , Venkatesan Arunkumar , Castro Nileyma , Bernstein Audrey M.
Published: February 2022

The differentiation of fibroblasts into pathological myofibroblasts during wound healing is in part characterized by increased cell surface expression of αv-integrins. Our previous studies found that the deubiquitinase (DUB) USP10 removes ubiquitin from αv-integrins, leading to cell surface integrin accumulation, subsequent TGFβ1 activation, and myofibroblast differentiation. In this study, a yeast-two hybrid screen elucidated a novel binding partner for USP10, the formin, Daam1. The USP10/Daam1 interaction was also supported by proximity ligation assay (PLA) activity. Treatment with TGFβ1 significantly increased USP10 and Daam1 protein expression, PLA signal, and co-localization to actin stress fibers. Furthermore, Daam1 siRNA knockdown significantly reduced a) co-precipitation of USP10 and Daam1 on purified actin stress fibers, and b) β1- and β5-integrin ubiquitination resulting in increased αv-, β1-, and β5-integrin total protein levels, αv integrin recycling to the cell surface, and extracellular fibronectin (FN) organization. Together, our data suggest that Daam1 negatively regulates USP10’s DUB activity and subsequently maintains integrin protein homeostasis.
Single extracellular vesicle analysis in human amniotic fluid shows evidence of phenotype alterations in preeclampsia
Authors: Gebara Natalia , Scheel Julia , Skovronova Renata , Grange Cristina , Marozio Luca , Gupta Shailendra , Giorgione Veronica , Caicci Federico , Benedetto Chiara , Khalil Asma , Bussolati Benedetta
Published: February 2022

Amniotic fluid surrounding the developing fetus is a complex biological fluid rich in metabolically active bio-factors. The presence of extracellular vesicles (EVs) in amniotic fluid has been mainly related to fetal urine. We here characterized EVs from term amniotic fluid in terms of surface marker expression using different orthogonal techniques. EVs appeared to be a heterogeneous population expressing markers of renal, placental, epithelial and stem cells. Moreover, we compared amniotic fluid EVs from normal pregnancies with those of preeclampsia, a hypertensive disorder affecting up to 8% of pregnancies worldwide. An increase of CD105 (endoglin) expressing EVs was observed in preeclamptic amniotic fluid by bead-based cytofluorimetric analysis, and further confirmed using a chip-based analysis. HLA-G, a typical placental marker, was not co-expressed by the majority of CD105+EVs, suggesting their origin from amniotic fluid cells. At a functional level, preeclampsia-derived EVs, but not normal pregnancy EVs, showed an antiangiogenic effect, possibly due to the decoy effect of endoglin. In addition, several miRNAs were differentially expressed in preeclampsia-derived EVs and directly related to the modulation of angiogenesis and trophoblast function. Our results provide a characterization of term amniotic fluid-EVs, supporting their origin from fetal and placental cells. In preeclampsia, the observed antiangiogenic characteristics of amniotic fluid-EVs may reflect the hypoxic and antiangiogenic microenvironment and could possibly impact on the developing fetus or on the surrounding fetal membranes.
Biosynthesis of aurodox, a Type III secretion system inhibitor from Streptomyces goldiniensis
Authors: McHugh Rebecca E , Munnoch John T , Braes Robyn E , McKean Iain J. W. , Giard Josephine M , Taladriz-Sender Andrea , Peschke Frederik , Burley Glenn A , Roe Andrew J , Hoskisson Paul A
Published: February 2022

The global increase in antimicrobial-resistant infections means that there is a need to develop new antimicrobial molecules and strategies to combat the issue. Aurodox is a linear polyketide natural product that is produced by Streptomyces goldiniensis, yet little is known about aurodox biosynthesis or the nature of the biosynthetic gene cluster (BGC) that encodes its production. To gain a deeper understanding of aurodox biosynthesis by S. goldiniensis, the whole genome of the organism was sequenced, revealing the presence of an 87 kb hybrid Polyketide Synthase/Non-Ribosomal Peptide Synthetase (PKS/NRPS) BGC. The aurodox BGC shares significant homology with the kirromycin BGC from S. collinus Tϋ 365; however, the genetic organisation of the BGC differs significantly. The candidate aurodox gene cluster was cloned and expressed in a heterologous host to demonstrate that it was responsible for aurodox biosynthesis and disruption of the primary PKS gene (aurAI) abolished aurodox production. These data support a model whereby the initial core biosynthetic reactions involved in aurodox biosynthesis follow that of kirromycin. Cloning aurM* from S. goldiniensis and expressing this in the kirromycin producer S. collinus Tϋ 365 enabled methylation of the pyridone group, suggesting this is the last step in biosynthesis. This methylation step is also sufficient to confer the unique Type III Secretion System inhibitory properties to aurodox.

Importance

Enterohaemorrhagic Escherichia coli (EHEC) is a significant global pathogen for which traditional antibiotic treatment is not recommended. Aurodox inhibits the ability of EHEC to establish infection in the host gut through the specific targeting of the Type III Secretion System, whilst circumventing the induction of toxin production associated with traditional antibiotics. These properties suggest aurodox could be a promising anti-virulence compound for EHEC, which merits further investigation. Here, we have characterised the aurodox biosynthetic gene cluster from Streptomyces goldiniensis and have established the key enzymatic steps of aurodox biosynthesis that give rise to the unique anti-virulence activity. These data provide the basis for future chemical and genetic approaches to produce aurodox derivatives with increased efficacy and the potential to engineer novel elfamycins.
The Transcription Factor Bach2 Negatively Regulates Natural Killer Cell Maturation and Function
Authors: Li Shasha , Bern Michael D. , Miao Benpeng , Inoue Takeshi , Piersma Sytse J. , Colonna Marco , Kurosaki Tomohiro , Yokoyama Wayne M.
Published: February 2022

BTB domain And CNC Homolog 2 (Bach2) is a transcription repressor that actively participates in T and B lymphocyte development, but it is unknown if Bach2 is also involved in the development of innate immune cells, such as natural killer (NK) cells. Here, we followed the expression of Bach2 during NK cell development, finding that it peaked in CD27+CD11b+cells and decreased upon further maturation. Bach2 expression positively correlated with that of the transcription factor TCF1 and negatively correlated with genes encoding NK effector molecules as well as genes involved in the cell cycle. Bach2-deficient mice showed increased numbers of terminally differentiated NK cells with increased production of granzymes and cytokines. NK cell-mediated control of tumor metastasis was also augmented in the absence of Bach2. Therefore, Bach2 is a key checkpoint protein regulating NK terminal maturation.
Single-cell transcriptomic and proteomic analysis of Parkinson’s disease Brains
Authors: Zhu Biqing , Park Jae-Min , Coffey Sarah , Hsu I-Uen , Lam TuKiet T. , Gopal Pallavi P. , Ginsberg Stephen D. , Wang Jiawei , Su Chang , Zhao Hongyu , Hafler David A. , Chandra Sreeganga S. , Zhang Le
Published: February 2022

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder where recent evidence suggests pathogenesis may be mediated by inflammatory processes. The molecular architecture of the disease remains to be fully elucidated. We performed single-nucleus transcriptomics and unbiased proteomics using postmortem tissue obtained from the prefrontal cortex of 12 individuals with late-stage PD and age-matched controls. We analyzed ∼80,000 nuclei and identified eight major cell types, including brain-resident T cells, each with distinct transcriptional changes in line with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem tissue, we found that α-synuclein pathology is inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in prefrontal cortex that were preferentially downregulated in PD. Strikingly, comparing this dataset to a regionally similar published analysis for Alzheimer’s disease (AD), we found no common differentially expressed genes in neurons, but identified many shared differentially expressed genes in glial cells, suggesting that disease etiology in PD and AD are likely distinct. These data are presented as a resource for interrogating the molecular and cellular basis of PD and other neurodegenerative diseases.

One Sentence Summary

We provide an extensive single cell analysis profiling nearly 80,000 brain nuclei from prefrontal cortex of late-stage Parkinson’s disease brains, demonstrate that α-synuclein pathology is inversely correlated with chaperone expression in excitatory neurons, found a selective abatement of neuron-astrocyte interactions with enhanced neuroinflammation, and augmented the study with proteomic analysis and cross-comparisons with Alzheimer’s disease datasets, providing valuable insights into the pathways of neurodegeneration and a deep definition of the underlying molecular pathology for Parkinson’s disease.
Constitutively active STAT5b feminizes mouse liver gene expression
Authors: Lau-Corona Dana , Ma Hong , Vergato Cameron , Sarmento-Cabral Andre , del Rio-Moreno Mercedes , Kineman Rhonda D , Waxman David J
Published: February 2022

STAT5 is an essential transcriptional regulator of the sex-biased actions of growth hormone (GH) in the liver. Delivery of constitutively active STAT5 (STAT5CA) to male mouse liver using an engineered adeno-associated virus with high tropism for the liver is shown to induce widespread feminization of the liver, with extensive induction of female-biased genes and repression of male-biased genes, largely mimicking results obtained when male mice are given GH as a continuous infusion. Many of the gene expression changes observed were associated with STAT5 binding to liver chromatin, supporting the proposed direct role of persistently active STAT5 in continuous GH-induced liver feminization. The feminizing effects of STAT5CA were dose-dependent; moreover, at higher levels, overexpression of STAT5CA resulted in some histopathology not seen in continuous GH-infused male liver, including hepatocyte hyperplasia and distorted liver architecture. These findings establish that the persistent activation of STAT5 by GH that characterizes female liver is by itself sufficient to account for the female-biased expression of a majority of female-biased genes. Moreover, histological changes seen when STAT5CA is overexpressed highlight the importance of carefully evaluating such effects before considering such STAT5 derivatives for therapeutic use in treating liver disease.
Insulin/IGF Signaling Regulates Presynaptic Glutamate Release in Aversive Olfactory Learning
Authors: Cheng Du , Lee James , Brown Maximillian , Ebert Margaret S. , Tomioka Masahiro , Iino Yuichi , Bargmann Cornelia I
Published: February 2022

Information flow through neural circuits is continuously modified by context-dependent learning. In the nematode Caenorhabditis elegans, pairing specific odors with food deprivation results in aversion to the odor. Here we identify cell-specific mechanisms of insulin/IGF receptor signaling that integrate sensory information with food context during aversive olfactory learning. Using a conditional allele of the insulin/IGF receptor DAF-2, we show that aversive learning to butanone, an odor sensed only by the AWCON olfactory neuron, requires DAF-2 in AWCON. Learning requires an axonally-localized DAF-2c isoform and the insulin receptor substrate (IRS) protein IST-1, but is partly independent of the FoxO transcription factor DAF-16. Upon food deprivation, the unconditioned stimulus for learning, DAF-2 expression increases post-transcriptionally through an insulin- and ist-1-dependent process. Aversive learning suppresses odor-regulated glutamate release from AWCON in wild-type animals but not in ist-1 mutants, suggesting that localized insulin signaling drives presynaptic depression to generate an aversive memory.
The calcium channel Orai1 is required for osteoblast development: studies in a chimeric mouse with variable in vivo Runx-cre deletion of Orai-1
Authors: Robinson Lisa J , Soboloff Jonathan , Tourkova Irina L , Larrouture Quitterie C , Papachristou Dionysios J , Gross Scott , Hooper Robert , Samakai Elsie , Worley Paul F , Tuckermann Jan , Witt Michelle R , Blair Harry C
Published: February 2022

The calcium-selective ion channel Orai1 has a complex role in bone homeostasis, with defects in both bone production and resorption detected in Orai1 germline knock-out mice. To determine whether Orai1 has a direct, cell-intrinsic role in osteoblast differentiation and function, we bred Orai1 flox/flox (Orai1f/f) mice with Runx2-cre mice to eliminate its expression in osteoprogenitor cells. Interestingly, Orai1 was expressed in a mosaic pattern in Orai1f/f-Runx2-cre bone. Specifically, antibody labeling for Orai1 in vertebral sections was uniform in wild type animals, but patchy regions in Orai1f/f-Runx2-cre bone revealed Orai1 loss while in other areas expression persisted. Nevertheless, by micro-CT, bones from Orai1f/f-Runx2-cre mice showed reduced bone mass overall, with impaired bone formation identified by dynamic histomorphometry. Cortical surfaces of Orai1f/f-Runx2-cre vertebrae however exhibited patchy defects. In cell culture, Orai1-negative osteoblasts showed profound reductions in store-operated Ca2+ entry, exhibited decreased alkaline phosphatase activity, and had markedly impaired substrate mineralization. We conclude that defective bone formation observed in the absence of Orai1 reflects an intrinsic role for Orai1 in differentiating osteoblasts.
Mineralized coleoid cranial cartilage from the Late Triassic Polzberg Konservat-Lagerstätte (Austria)
Authors: Lukeneder Petra , Lukeneder Alexander
Published: February 2022

Although hyaline cartilage is widely distributed in various invertebrate groups such as sabellid polychaetes, molluscs (cephalopods, gastropods) and a chelicerate arthropod group (horseshoe crabs), the enigmatic relationship and distribution of cartilage in taxonomic groups remains to be explained. It can be interpreted as a convergent trait in animal evolution and thus does not seem to be a vertebrate invention. Due to the poor fossil record of cartilaginous structures, occurrences of mineralized fossil cartilages are important for evolutionary biology and paleontology. Although the biochemical composition of recent cephalopod cartilage differs from vertebrate cartilage, histologically the cartilages of these animal groups resemble one another remarkably. In this study we present fossil material from the late Triassic Polzberg Konservat-Lagerstätte near Lunz am See (Lower Austria, Northern Calcareous Alps). A rich Carnian fauna is preserved here, whereby a morphogroup (often associated with coleoid remains) of black, amorphous appearing fossils still remained undetermined. These multi-elemental, mirroring fossils show remarkable similarities to recent cephalopod cartilage. We examined the conspicuous micro- and ultrastructure of these enigmatic fossils by thin-sectioning and Scanning Electron Microscopy (SEM). The geochemical composition analyzed by Microprobe and Energy Dispersive X-ray Spectroscopy (SEM-EDX) revealed carbonisation as the taphonomic pathway for this fossil group. 3D preservation of this otherwise degradable soft tissue can be explained by the mineralization processes that may take place in particular environments. Fifty-nine specimens from the Polzberg locality and five specimens from Cave del Predil (formerly Raibl, Julian Alps, Italy) underwent extensive studies. The detected grooves are interpreted to be muscular attachment areas, and the preserved branched system of canaliculi is comparable to a channel system that is also present in recent coleoid cartilage. The new findings on these long-known enigmatic structures strongly point to the preservation of cranial cartilage belonging to the belemnoid Phragmoteuthis bisinuata.
Omicron-specific mRNA vaccination alone and as a heterologous booster against SARS-CoV-2
Authors: Fang Zhenhao , Peng Lei , Filler Renata , Suzuki Kazushi , McNamara Andrew , Lin Qianqian , Renauer Paul A. , Yang Luojia , Menasche Bridget , Sanchez Angie , Ren Ping , Xiong Qiancheng , Strine Madison , Clark Paul , Lin Chenxiang , Ko Albert I. , Grubaugh Nathan D. , Wilen Craig B. , Chen Sidi
Published: February 2022

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has high transmissibility and recently swept the globe. Due to the extensive number of mutations, this variant has high level of immune evasion, which drastically reduced the efficacy of existing antibodies and vaccines. Thus, it is important to test an Omicron-specific vaccine, evaluate its immune response against Omicron and other variants, and compare its immunogenicity as boosters with existing vaccine designed against the reference wildtype virus (WT). Here, we generated an Omicron-specific lipid nanoparticle (LNP) mRNA vaccine candidate, and tested its activity in animals, both alone and as a heterologous booster to existing WT mRNA vaccine. Our Omicron-specific LNP-mRNA vaccine elicited strong and specific antibody response in vaccination-naïve mice. Mice that received two-dose WT LNP-mRNA, the one mimicking the commonly used Pfizer/Moderna mRNA vaccine, showed a >40-fold reduction in neutralization potency against Omicron variant than that against WT two weeks post second dose, which further reduced to background level >3 months post second dose. As a booster shot for two-dose WT mRNA vaccinated mice, a single dose of either a homologous booster with WT LNP-mRNA or a heterologous booster with Omicron LNP-mRNA restored the waning antibody response against Omicron, with over 40-fold increase at two weeks post injection as compared to right before booster. Interestingly, the heterologous Omicron LNP-mRNA booster elicited neutralizing titers 10-20 fold higher than the homologous WT booster against the Omicron variant, with comparable titers against the Delta variant. All three types of vaccination, including Omicron mRNA alone, WT mRNA homologous booster, and Omicron heterologous booster, elicited broad binding antibody responses against SARS-CoV-2 WA-1, Beta, and Delta variants, as well as other Betacoronavirus species such as SARS-CoV, but not Middle East respiratory syndrome coronavirus (MERS-CoV). These data provided direct proof-of-concept assessments of an Omicron-specific mRNA vaccination in vivo, both alone and as a heterologous booster to the existing widely-used WT mRNA vaccine form.
Crystal structure and Hirshfeld surface analysis of 2-oxo-2-phenylethyl 3-nitroso-2-phenylimidazo[1,2-a]pyridine-8-carboxylate
Authors: El Kalai Fouad , Baydere Cemile , Dege Necmi , Abudunia Abdulmalik , Benchat Noureddine , Karrouchi Khalid
Published: February 2022

The title compound, C22H15N3O4, is built up from a central imidazo[1,2-a]pyridine ring system connected to a nitroso group, a phenyl ring and a 2-oxo-2-phenylethyl acetate group. The imidazo[1,2-a] pyridine ring system is almost planar (r.m.s. deviation = 0.017 Å) and forms dihedral angles of 22.74 (5) and 45.37 (5)°, respectively, with the phenyl ring and the 2-oxo-2-phenylethyl acetate group. In the crystal, the molecules are linked into chains parallel to the b axis by C—H...O hydrogen bonds, generating R
2
1 (5) and R
4
4 (28) graph-set motifs. The chains are further linked into a three-dimensional network by C—H...π and π-stacking interactions. The intermolecular interactions were investigated using Hirshfeld surface analysis and two-dimensional fingerprint plots, revealing that the most important contributions for the crystal packing are from H...H (36.2%), H...C/C...H (20.5%), H...O/O...H (20.0%), C...O/O...C (6.5%), C...N/N...C (6.2%), H...N/N...H (4.5%) and C...C (4.3%) interactions.
Factors influencing organic food purchase decision: fuzzy DEMATEL approach
Authors: Yeo Sook Fern , Tan Cheng Ling , Tseng Ming-Lang , Tam Steven , San Weng Kuan
Published: February 2022

Purpose

In recent years, consumers today recognise organic foods as high-quality products which can benefit them in various aspects. The tendency to switch consumption behaviours from conventional to ecological food products or organic food has largely been due to the claims that organic crops are grown in eco-friendly and sustainable environments. Thus, the study highlighted unique results on young consumers' purchasing intentions from a new perspective. The paper aims to investigate the factors influencing consumers' purchase decision towards organic food, particularly amongst Generation Y consumers.

Design/methodology/approach

The underlying fuzzy set theory is employed to handle the fuzziness of consumers' perceptions since the attributes are usually expressed in linguistic preferences. Overall, the study focussed on five important aspects – health consciousness, environmental concern, social influencing and ethical concern – that also include twenty criteria that had been identified and introduced after a thorough review of related literature.

Findings

The results reveal that the most important criteria in the selected firm are environment protection, chemical instrument, buying attitude and animal testing. In comparison, the cause group includes criteria such as environment protection, natural food and support for training programmes, whilst the effect group includes production practices, monitoring protections and ethically produced food.

Research limitations/implications

The sample collection from the study focussed on Generation Y consumers who consume organic food in Malaysia. This could lead to the limitation towards external generalisability. The study will provide numerous advantages to the communities. The policy maker should develop a proper marketing strategy to promote organic food as food that is healthier, better in nutrition and safer for society.

Originality/value

Utilising fuzzy decision-making trial and evaluation laboratory (DEMATEL) in analysing the fuzziness of consumers' perceptions towards consumers' purchase decision can be expected to expand the breadth of knowledge to both academic and practical.
Dried orange juice waste as a source of bioactive compounds
Authors: Galindo Rosa Gabriela , Chiș Maria Simona , Martínez-Navarrete Nuria , Camacho María del Mar
Published: February 2022

Purpose

The waste generated in the process of obtaining orange juice (J) may be used as a natural source of bioactive compounds, thus contributing to the profitability and sustainability of the process. To offer orange J as a dried matter would contribute to the integral valorisation of the J waste and also may expand the field of application.

Design/methodology/approach

To find out whether the JW matrix protects the bioactive compounds, the study compares the behaviour of the extracts of the compounds against drying with that resulting from drying the JW for further extraction. Dehydration was carried out at 25 or 50 C and gum Arabic (GA) and bamboo fibre (BF) were used as stabilising biopolymers (Bp). Vitamin C (VC) (L-ascorbic and L-dehydroascorbic acids [AA and DHAA, respectively]) and hesperidin (HES) were analysed before and after the drying.

Findings

The results suggest that to dry the JW gives a higher yield of bioactive compounds, which are also more stable, than when the extract is dried. Furthermore, both the higher temperature and the presence of the Bp favour the extraction of both VC and HES. In this way, all the waste from the orange J-processing industries is converted into a high-value product to be used for cosmeceutical or nutraceutical purposes and also as an ingredient for human food.

Social implications

The utilisation of organic waste for use in human food, but also in other sectors, is part of the new economic model that aims to do away with the concept of waste as people know it, focussing on a new paradigm in which each resource is a nutrient for nature, industry or society.

Originality/value

The results suggest that to dry the waste gives a higher yield of bioactive compounds, which are also more stable, than when the extract is dried. Furthermore, both the higher temperature and the presence of the Bp favour the extraction of both VC and HES. In that way, all the waste from the orange J-processing industries are converted into a high-value product to be used for cosmeceutical or nutraceutical purposes and also as an ingredient for human food.
Clashes of cultures during crises: coordinating firefighter, police and paramedic interactions
Authors: Van Scotter James R. , Leonard Karen Moustafa
Published: February 2022

Purpose

The purpose is to expand our understanding of different organizational group interactions in crises and extend the Competing Values Framework of organizational culture into three first responder groups – firefighters, police and emergency medical technicians. Because unique organizational culture is a critical element in the success or failure of any organization, when organizations combine during crisis, failure often results. The authors examined the cultures of first responders in a crisis to determine whether differences in cultural type might explain some failures.

Design/methodology/approach

Using the Competing Values Framework for organizational culture, the authors examined literature on the three first responder cultures. The literature is available on the failure of these organizations to work together in crisis, but little on the deep organizational reasons for these failures.

Findings

In view of the different challenges each profession faces and ways they organize to address those challenges, self-directed coordination of these three distinct groups may be optimal, rather than an overall system of command and control. This can be visualized when the authors examine the three cultures using the Competing Values Framework. The authors discuss specific reasons for problems in crisis coordination and give suggestions on coping with three or more different cultures.

Research limitations/implications

This is a literature review and conceptual paper. A meta-analysis of incidences would be helpful.

Practical implications

When disparate organizations work together, culture may interfere with cooperation and coordination. Taking organizational culture into account will enable operations with less friction. In this paper, the authors explain why.

Social implications

Lack of cooperation and coordination among firefighters, police and EMTs could create loss of life or property. Understanding potential cultural differences will help the disparate groups work together better.

Originality/value

The authors examine organizational culture differences in detail as a reason for the failures of coordination of first responders in crisis. In addition, the authors extend the Competing Values Framework to these essential groups of first responders. The authors are the first to propose a taxonomy of culture for these three groups, based on the Competing Values Framework.
Gender, diversity and the 2020 US presidential election: towards an androgynous presidential profile?
Authors: Powell Gary N. , Butterfield D. Anthony , Jiang Xueting
Published: February 2022

Purpose

The purpose of this study was to explore issues of gender and diversity raised by the 2020 US presidential election.

Design/methodology/approach

Samples from two populations (n= 667) described either an ideal president or one of the major-party candidates for president (Donald Trump and Joe Biden) or vice president (Mike Pence and Kamala Harris) on an instrument that assessed self-ascribed masculinity and femininity. Androgyny was calculated as the difference between masculinity and femininity; the closer the score to zero, the more androgynous the candidate.

Findings

The ideal president was viewed as androgynous (i.e. balanced in masculine and feminine traits) rather than masculine as in previous studies of presidential leadership. Compared to the White male candidates, Harris, a woman of color, displayed the most androgynous profile. The Democratic ticket represented a “balanced” team, with one candidate (Biden) higher on femininity and the other (Harris) higher on masculinity; in essence, an androgynous ticket. In contrast, the Republican ticket (Trump and Pence) represented a decidedly masculine ticket. Ideal president profiles differed according to respondents’ gender and preferred president.

Practical implications

The Democrats winning the election with an androgynous ticket suggests that a more level playing field for femalevis-à-vismale candidates for political leader roles may be arriving.

Originality/value

The finding of an ideal president as androgynous rather than masculine is an original contribution to the literature on presidential leadership.