bluuebunny/crossref_metadata_2025 huggingface dataset:
Vaginal Community State Types (CSTs) Alter Environmental Cues and Production of theStaphylococcus aureusToxic Shock Syndrome Toxin-1 (TSST-1)
Authors: Maduta Carla S. , McCormick John K. , Dufresne Karine
Published: July 2023

Menstrual toxic shock syndrome (mTSS) is a rare but life-threatening disease associated with use of high-absorbency tampons. The production of theStaphylococcus aureustoxic shock syndrome toxin-1 (TSST-1) is involved in nearly all cases of mTSS and is tightly controlled by regulators responding to the environment. In the prototypic mTSS strainS. aureusMN8, the major repressor of TSST-1 is the carbon catabolite protein A (CcpA), which responds to glucose concentrations in the vaginal tract. Healthy vaginalLactobacillusspecies also depend on glucose for both growth and acidification of the vaginal environment through lactic acid production. We hypothesized that interactions between the vaginal microbiota (herein referred to as Community State Types, or CSTs) and MN8 depend on environmental cues, and that these interactions subsequently affect TSST-1 production. Using MN8 Δ1ccpAat various glucose levels, we demonstrate that the supernatants from different CSTs grown in vaginally defined media (VDM) significantly decreasetstexpression. When co-culturing CST species with MN8 ΔccpA, we show thatL. jenseniicompletely inhibits TSST-1 production in conditions mimicking healthy menstruation or mTSS. Finally, we show that growingS. aureusin “unhealthy” or “transitional” CST supernatants results in higher IL-2 production from T cells. These findings suggest that dysbiotic CSTs may encourage TSST-1 production in the vaginal tract, and further indicates that the CSTs are likely important for the development of mTSS.

IMPORTANCE

In this study, we investigate the impact of the vaginal microbiota againstS. aureusin conditions mimicking the vaginal environment at various stages of the menstrual cycle. We demonstrate thatL. jenseniican inhibit TSST-1 production, suggesting the potential for probiotic activity in treating mTSS. On the other side of the spectrum, “unhealthy” or “transient” bacteria such asG. vaginalisandL. inerssupport more TSST-1 production byS. aureus, suggesting that CSTs are important in the development of mTSS. This study sets forward a model for examining contact-independent interactions between pathogenic bacteria and the vaginal microbiota. It also demonstrates the necessity of replicating the environment when studying one as dynamic as the vagina.
Bacterial cGAS-like enzymes produce 2′,3′-cGAMP to activate an ion channel that restricts phage replication
Authors: Tak Uday , Walth Peace , Whiteley Aaron T.
Published: July 2023

The mammalian innate immune system uses cyclic GMP–AMP synthase (cGAS) to synthesize the cyclic dinucleotide 2′,3′-cGAMP during antiviral and antitumor immune responses. 2′,3′-cGAMP is a nucleotide second messenger that initiates inflammatory signaling by binding to and activating the stimulator of interferon genes (STING) receptor. Bacteria also encode cGAS/DncV-like nucleotidyltransferases (CD-NTases) that produce nucleotide second messengers to initiate antiviral (antiphage) signaling. Bacterial CD-NTases produce a wide range of cyclic oligonucleotides but have not been documented to produce 2′,3′-cGAMP. Here we discovered bacterial CD-NTases that produce 2′,3′-cGAMP to restrict phage replication. Bacterial 2′,3′-cGAMP binds to CD-NTase associated protein 14 (Cap14), a transmembrane protein of unknown function. Using electrophysiology, we show that Cap14 is a chloride-selective ion channel that is activated by 2′,3′-cGAMP binding. Cap14 adopts a modular architecture, with an N-terminal transmembrane domain and a C-terminal nucleotide-binding SAVED domain. Domain-swapping experiments demonstrated the Cap14 transmembrane region could be substituted with a nuclease, thereby generating a biosensor that is selective for 2′,3′-cGAMP. This study reveals that 2′,3′-cGAMP signaling extends beyond metazoa to bacteria. Further, our findings suggest that transmembrane proteins of unknown function in bacterial immune pathways may broadly function as nucleotide-gated ion channels.
TIAM-1 regulates polarized protrusions during dorsal intercalation in theC. elegansembryo through both its GEF and N-terminal domains
Authors: Zhu Yuyun , Hardin Jeff
Published: July 2023

Mediolateral cell intercalation is a morphogenetic strategy used throughout animal development to reshape tissues. Dorsal intercalation in theC. elegansembryo involves the mediolateral intercalation of two rows of dorsal epidermal cells to create a single row that straddles the dorsal midline, and so is a simple model to study cell intercalation. Polarized protrusive activity during dorsal intercalation requires theC. elegansRac and RhoG orthologs CED-10 and MIG-2, but how these GTPases are regulated during intercalation has not been thoroughly investigated. In this study, we characterize the role of the Rac-specific guanine nucleotide exchange factor (GEF), TIAM-1, in regulating actin-based protrusive dynamics during dorsal intercalation. We find that TIAM-1 can promote protrusion formation through its canonical GEF function, while its N-terminal domains function to negatively regulate this activity, preventing the generation of ectopic protrusions in intercalating cells. We also show that the guidance receptor UNC-5 inhibits ectopic protrusive activity in dorsal epidermal cells, and that this effect is in part mediated via TIAM-1. These results expand the network of proteins that regulate basolateral protrusive activity during directed cell rearrangement.

Summary statement

TIAM-1 activates the Rac pathway to promote protrusion formation via its GEF domain, while its N-terminal domains suppress ectopic protrusions during dorsal intercalation in theC. elegansembryo.
The Role of the Tyrosine-Based Sorting Signals of the ORF3a Protein of SARS-CoV-2 on Intracellular Trafficking, Autophagy, and Apoptosis
Authors: Henke Wyatt , Kalamvoki Maria , Stephens Edward B
Published: July 2023

The open reading frame 3a (ORF3a) is an accessory transmembrane protein that is important to the pathogenicity of SARS-CoV-2. The cytoplasmic domain of ORF3a has three canonical tyrosine-based sorting signals (YxxΦ; where x is any amino acid and Φ is a hydrophobic amino acid with a bulky -R group). They have been implicated in the trafficking of membrane proteins to the cell plasma membrane and to intracellular organelles. Previous studies have indicated that mutation of the160YSNV163motif abrogated plasma membrane expression and inhibited ORF3a-induced apoptosis. However, two additional canonical tyrosine-based sorting motifs (211YYQL213,233YNKI236) exist in the cytoplasmic domain of ORF3a that have not been assessed. We removed all three potential tyrosine-based motifs and systematically restored them to assess the importance of each motif or combination of motifs that restored efficient trafficking to the cell surface and lysosomes. Our results indicate that the YxxΦ motif at position 160 was insufficient for the trafficking of ORF3a to the cell surface. Our studies also showed that ORF3a proteins with an intact YxxΦ at position 211 or at 160 and 211 were most important. We found that ORF3a cell surface expression correlated with the co-localization of ORF3a with LAMP-1 near the cell surface. These results suggest that YxxΦ motifs within the cytoplasmic domain may act cooperatively in ORF3a transport to the plasma membrane and endocytosis to lysosomes. Further, our results indicate that certain tyrosine mutants failed to activate caspase 3 and did not correlate with autophagy functions associated with this protein.

IMPORTANCE

Open reading frame 3a (ORF3a) encodes for the largest of the SARS-CoV-2 accessory proteins. While deletion of the ORF3a gene from SARS-CoV-2 results in a virus that replicates slightly less efficiently in cell culture, deletion also results in a virus that is less pathogenic in mouse models of SARS-CoV-2 infections. The ORF3a has been reported to be a viroporin, induces apoptosis and incomplete autophagy in cells. Thus, determining the domains involved in these functions will further our understanding of how this protein influences virus assembly and pathogenesis. Here, we investigated the role of the three potential tyrosine-based sorting signals in the cytoplasmic domain of the ORF3a on intracellular protein trafficking, apoptosis, and in the initiation of autophagy. Our results indicate that more than one YxxΦ motif is required for efficient transport of ORF3a, ORF3a expression resulted in minimal apoptosis, and cell surface expression was not required for autophagy.
Pre-existing heterogeneity facilitates development of heteroresistance upon gene acquisition
Authors: Jaggavarapu Siddharth , Hufnagel David A. , Weiss David S.
Published: July 2023

Antibiotic resistance causes 1.27 million global deaths annually and is predicted to worsen. Heteroresistance is a form of resistance in which only a minor and unstable subpopulation of cells of a bacterial isolate are resistant to a given antibiotic, and are therefore often undetected by clinical diagnostics. These infrequent and undetected resistant cells can be selected during antibiotic therapy, expand in number, and cause unexplained treatment failures. A major question is how heteroresistance evolves. Here, studying the antibiotic fosfomycin, we report that heteroresistance can develop from a pre-existing state of phenotypic heterogeneity in which an isolate harbors a subpopulation with increased minimum inhibitory concentration (MIC), but below the clinical resistance breakpoint. We call this phenomenon heterosusceptibility and demonstrate that acquisition of a resistance gene,fosA, increases the MIC of the subpopulation beyond the breakpoint, making the isolate heteroresistant. Conversely, deletion offosAfrom a heteroresistant isolate led to reduction of the MIC of the resistant subpopulation without a loss of heterogeneity, thus generating heterosusceptibility. A survey of 103 carbapenem-resistant Enterobacterales (CRE) revealed that theEscherichia sp. isolates lacked thefosAgene and uniformly exhibited fosfomycin heterosusceptibility, whereas theKlebsiellaandEnterobacterencoded thefosAgene and were almost exclusively heteroresistant. Furthermore, some isolates exhibited heterosusceptibility to other antibiotics, demonstrating that this is a widespread phenomenon. These results highlight a mechanism for the evolution of heteroresistance and suggest that surveillance for heterosusceptibility may facilitate the prediction of impending heteroresistance before it evolves.
Functional analysis of cyclic diguanylate-modulating proteins inVibrio fischeri
Authors: Isenberg Ruth Y. , Holschbach Chandler S. , Gao Jing , Mandel Mark J.
Published: July 2023

As bacterial symbionts transition from a motile free-living state to a sessile biofilm state, they must coordinate behavior changes suitable to each lifestyle. Cyclic diguanylate (c-di-GMP) is an intracellular signaling molecule that can regulate this transition, and it is synthesized by diguanylate cyclase (DGC) enzymes and degraded by phosphodiesterase (PDE) enzymes. Generally, c-di-GMP inhibits motility and promotes biofilm formation. While c-di-GMP and the enzymes that contribute to its metabolism have been well-studied in pathogens, considerably less focus has been placed on c-di-GMP regulation in beneficial symbionts.Vibrio fischeriis the sole beneficial symbiont of the Hawaiian bobtail squid (Euprymna scolopes) light organ, and the bacterium requires both motility and biofilm formation to efficiently colonize. C-di-GMP regulates swimming motility and cellulose exopolysaccharide production inV. fischeri. The genome encodes 50 DGCs and PDEs, and while a few of these proteins have been characterized, the majority have not undergone comprehensive characterization. In this study, we use protein overexpression to systematically characterize the functional potential of all 50V. fischeriproteins. All 28 predicted DGCs and 14 predicted PDEs displayed at least one phenotype consistent with their predicted function, and a majority of each displayed multiple phenotypes. Finally, active site mutant analysis of proteins with the potential for both DGC and PDE activities revealed potential activities for these proteins. This work presents a systems-level functional analysis of a family of signaling proteins in a tractable animal symbiont and will inform future efforts to characterize the roles of individual proteins during lifestyle transitions.

IMPORTANCE

C-di-GMP is a critical second messenger that mediates bacterial behaviors, andV. fischericolonization of its Hawaiian bobtail squid host presents a tractable model in which to interrogate the role of c-di-GMP during animal colonization. This work provides systems-level characterization of the 50 proteins predicted to modulate c-di-GMP levels. By combining multiple assays, we generated a rich understanding of which proteins have the capacity to influence c-di-GMP levels and behaviors. Our functional approach yielded insights into how proteins with domains to both synthesize and degrade c-di-GMP may impact bacterial behaviors. Finally, we integrated published data to provide a broader picture of each of the 50 proteins analyzed. This study will inform future work to define specific pathways by which c-di-GMP regulates symbiotic behaviors and transitions.
Dynamic regulatory phosphorylation of mouse CDK2 occurs during meiotic prophase I
Authors: Bradley Rachel A. , Wolff Ian D. , Cohen Paula E. , Gray Stephen
Published: July 2023

During prophase I of meiosis, DNA double-strand breaks form throughout the genome, with a subset repairing as crossover events, enabling the accurate segregation of homologous chromosomes during the first meiotic division. The mechanism by which DSBs become selected to repair as crossovers is unknown, although the crossover positioning and levels in each cell indicate it is a highly regulated process. One of the proteins that localises to crossover sites is the serine/threonine cyclin-dependent kinase CDK2. Regulation of CDK2 occurs via phosphorylation at tyrosine 15 (Y15) and threonine 160 (T160) inhibiting and activating the kinase, respectively. In this study we use a combination of immunofluorescence staining on spread spermatocytes and fixed testis sections, and STA-PUT gravitational sedimentation to isolate cells at different developmental stages to further investigate the temporal phospho regulation of CDK2 during prophase I. Western blotting reveals differential levels of the two CDK2 isoforms (CDK233kDaand CDK239kDa) throughout prophase I, with inhibitory phosphorylation of CDK2 at Y15 occurring early in prophase I, localising to telomeres and diminishing as cells enter pachynema. Conversely, the activatory phosphorylation on T160 occurs later, specifically the CDK233kDaisoform, and T160 signal is detected in spermatogonia and pachytene spermatocytes, where it co-localises with the Class I crossover protein MLH3. Taken together, our data reveals intricate control of CDK2 both with regards to levels of the two CDK2 isoforms, and differential regulation via inhibitory and activatory phosphorylation.
Early-life stress triggers long-lasting organismal resilience and longevity via tetraspanin
Authors: Jiang Wei I. , Belly Henry De , Wang Bingying , Wong Andrew , Kim Minseo , Oh Fiona , DeGeorge Jason , Huang Xinya , Guang Shouhong , Weiner Orion D. , Ma Dengke K.
Published: July 2023

Early-life stress experiences can produce lasting impacts on organismal adaptation and fitness. How transient stress elicits memory-like physiological effects is largely unknown. Here we show that early-life thermal stress strongly up-regulatestsp-1, a gene encoding the conserved transmembrane tetraspanin inC. elegans. TSP-1 forms prominent multimers and stable web- like structures critical for membrane barrier functions in adults and during aging. The up- regulation of TSP-1 persists even after transient early-life stress. Such regulation requires CBP- 1, a histone acetyl-transferase that facilitates initialtsp-1transcription. Tetraspanin webs form regular membrane structures and mediate resilience-promoting effects of early-life thermal stress. Gain-of-function TSP-1 confers markedC. eleganslongevity extension and thermal resilience in human cells. Together, our results reveal a cellular mechanism by which early-life thermal stress produces long-lasting memory-like impact on organismal resilience and longevity.

Teaser

Studies reveal mechanisms of how early-life heat exposure produces long-lasting benefits on longevity in the nematodeC. elegans.
Extensive and diverse lanthanide-dependent metabolism in the ocean
Authors: Voutsinos Marcos Y. , Banfield Jillian F. , McClelland Harry-Luke O.
Published: July 2023

Lanthanide (Ln)-dependent enzymes have evolved roles in organic carbon metabolism despite low Ln availability in natural environments1–8. The oceans are the major reservoir of dissolved organic carbon (DOC) on the planet, yet the prevalence and diversity of Ln-dependent enzymes in the ocean, and their biogeochemical importance in the ocean carbon cycle is unknown. Here, we analyzed a global ocean metagenomic/metatranscriptomic dataset and found Ln-dependent methanol-, ethanol- and putative sorbose- and glucose-dehydrogenases in all metagenomes and 20% of all resolved microbial genomes, with several individual organisms hosting dozens of unique Ln-dependent genes. We find that biological methanol oxidation in the ocean is overwhelmingly Ln-dependent, and that methanol dehydrogenases are the most highly expressed Ln-dependent genes in most ocean regions, particularly in surface oceans. As Ln availability is a function of phosphate concentration and pH, Ln-dependent metabolism likely underpins complex biogeochemical feedbacks determining the efficiency of organic matter remineralization, thus impacting the oceanic DOC pool and Earth’s climate system. The widespread biological utility of Ln also explains their nutrient-like vertical concentration profiles observed in ocean waters, and shows that the preferential utilization of light lanthanides by biology must be considered when interpreting patterns of relative Ln concentrations in seawater.
A preliminary study exploring the nature of aggression supportive beliefs in a forensic psychiatric sample
Authors: Sebalo Ivan , Steene Lisa Maria Beethoven , Gaylor Lisa Lee Elaine , Ireland Jane Louise
Published: July 2023

Purpose

This preliminary study aims to investigate and describe aggression-supportive normative beliefs among patients of a high-secure hospital.

Design/methodology/approach

Therapy data from a sample of high-secure forensic hospital patients (N = 11) who had participated in Life Minus Violence-Enhanced, a long-term violence therapy, was examined using interpretative phenomenological analysis (IPA). During therapy, cognitions linked to past incidences of aggression were explored using aggression choice chains.

Findings

IPA was applied to data generated through this process to examine the presence and nature of normative beliefs reported, identifying seven themes: rules for aggressive behaviour; use of violence to obtain revenge; processing emotions with violence; surviving in a threatening world; do not become a victim; using violence to maintain status; and prosocial beliefs.

Originality/value

Findings demonstrate that forensic patients have specific aggression-supportive normative beliefs, which may be malleable. Limitations and implications are discussed.
Learning and knowledge transfer by humans and digital platforms: which tools best support the decision-making process?
Authors: Russo Giuseppe , Manzari Alberto , Cuozzo Benedetta , Lardo Alessandra , Vicentini Francesca
Published: July 2023

Purpose

This study aims to investigate the impact of technologies on the knowledge transfer process. In particular, the authors aim to analyze the topic of knowledge brokers and the relationship between broker and digital tools in the knowledge transfer process in the sport context. The study developed, therefore, aims to investigate the creating of this environment for knowledge transfer and knowledge sharing between man and machine, looking to improve the planning of technical sports projects of the clubs.

Design/methodology/approach

This paper presents a qualitative approach aimed at analyzing how platforms and the players’ agents can be useful tools in the knowledge transfer process. The research was conducted through a survey with a structured questionnaire via e-mail to 64 managers at the head of clubs playing in the Italian Series B basketball in the 2021–2022 championship. The total number of questions administered is 21.

Findings

The results demonstrate how sports directors, for the construction of a technical sports project, in addition to learning off the pitch by interactions with media, fans, pressure management, leadership skills, positive attitude, tolerance, understanding of other opinions, background and cultures, see the athletes’ agents as the main stakeholder of the managers. The research resulted, by the clubs’ managers, in both formal learning and informal-type learning. Informal learning, by far the most frequently used and most important in the general learning process of executives, is identified in the use that executives make of information available on digital platforms and of the fiduciary relationships that management has with players’ agents.

Originality/value

The results demonstrate the valuable opportunities for executives, coaches, managers and clubs to strategically manage learning and knowledge sharing. Improving and managing knowledge-sharing strategies would help increase knowledge, not only of the sports directors but also of the entire club, thus improving the absolute quality of the game within the Italian basketball divisions. The authors have developed an innovative framework regarding the construction of a “typed sports technical project”, and the authors have identified a series of crucial phases capable of determining the creation of a new roster of athletes.
Leveraging open data for reference services delivery in academic libraries
Authors: Oladokun Bolaji David , Gaitanou Panorea
Published: July 2023

Purpose

Librarians play a critical role in curating, organizing and facilitating access to open data (OD) resources, supporting research, learning and information dissemination. This study aims to explore the use of OD for reference services delivery in academic libraries. It is believed that the concept of OD in librarianship refers to the practice of making publicly available data freely accessible, usable and shareable by anyone.

Design/methodology/approach

This research examined how the utilization of OD may affect library services and operations. This paper used the systematic review of literature to answer the research questions; hence, it was a desk study.

Findings

Given that there has been recently a research shift in linking OD to library metadata, this study revealed some interesting findings. More specifically, it discovered that incorporating OD into reference services can provide several benefits and enhance the quality and relevance of the information provided to library users. In addition, this paper reported that OD enriches reference services by providing comprehensive, current and interdisciplinary information, supporting evidence-based research, enabling data visualization and analysis, fostering community engagement and promoting innovation.

Originality/value

This paper proposes that libraries that possess extensive collections are in a favorable position to embrace the shift toward becoming OD and open big data libraries. It is also believed that academic libraries, through reference services, meet the challenge of providing access to their institutional repositories by holding many sets of data in various formats and providing various interfaces, developing metadata systems for various data streams, supporting all ecosystems of software and data products for reformatting and reusing large and complex data, and support for data sets identifiers. By actively engaging with OD, librarians can play a vital role in facilitating access to information and promoting the use of open knowledge for academic pursuits.
Militarization, globalization and liberal democracy: a nexus?
Authors: Kollias Christos , Tzeremes Panayiotis
Published: July 2023

Purpose

Using composite indices, the paper examines the nexus between militarization, globalization and liberal democracy. The democratic peace theory, the conflict inhibiting effects of international trade – a key and dominant facet of globalization – and the democracy promoting globalization hypothesis form the theoretical underpinnings of the empirical investigation.

Design/methodology/approach

To probe into the issue at hand, the paper adopts a dynamic panel VAR estimation procedure. Given the usual data constraints, the sample consists of 113 countries, and the estimations span the period 1995–2019.

Findings

The findings from the dynamic panel VAR estimations suggest the presence of a negative and statistically significant nexus between the level of globalization and the level of militarization. No statistically traceable nexus between globalization and liberal democracy was found.

Research limitations/implications

The findings offer empirical support to the hypothesis that the strong links of interdependence shaped by globalization reduce the need for military preparedness. The results lead to a tentative inference in favor of the doux commerce thesis. Nonetheless, given that the estimations span a historically specific period – the entire post-bipolar era – the inferences that stem from the findings should be treated with caution.

Originality/value

To the best of the authors’ knowledge, the composite indices Bonn International Centre for Conflict Studies (BICC) militarization index, the globalization index of the Swiss Economic Institute (Konjunkturforschungsstelle) (KOF), LibDem, polyarchy have not hitherto been jointly used in previous studies to examine the nexus between militarization, globalization and liberal democracy.
How Tesla’s management innovations operationalize its “Deep Purpose” to save the planet
Authors: Denning Stephen
Published: July 2023

Purpose

Instead of merely adding a socially popular mission to its existing business goals, Tesla’s CEO Elon Musk has innovated its operations by working backwards from its mission of saving the planet by making and selling a vast number of electric cars in order to help remove a principal cause of an approaching global environmental disaster.

Design/methodology/approach

When Elon Musk became CEO in 2008, Tesla’s mission of saving the planet by replacing gasoline-driven cars with electric cars seemed a preposterous overreach.

Findings

Tesla is not only making extraordinary progress towards the accomplishment of its mission, but the mission serves as an accelerator of its business generally and its innovations in particular.

Practical implications

The example of CEO Musk showing up on the factory floor, and working shoulder to shoulder with the staff in teams and mobs to solve urgent bottleneck issues sets the tone of Tesla’s workplace. The overriding preoccupation with accelerating innovation is enabled by modularity in design.

Originality/value

A unique study of Tesla’s post-Agile management innovations by an expert on Agile teams and practices.
Litter quality controls tradeoffs in soil carbon decomposition and replenishment in a subtropical forest
Authors: Lyu Maokui , Homyak Peter M. , Xie Jinsheng , Peñuelas Josep , Ryan Michael G. , Xiong Xiaoling , Sardans Jordi , Lin Weisheng , Wang Minhuang , Chen Guangshui , Yang Yusheng
Published: July 2023

Species‐rich forests can produce litter of varying carbon (C) and nitrogen (N) composition (i.e. quality), which can affect decomposition and play a central role in long‐term soil organic carbon (SOC) accumulation. However, how differences in litter quality affect SOC decomposition and formation remains unclear over the full litter decomposition trajectory.

We followed the in situ complete decomposition of added 13C‐labelled high‐ (low C:N) and low‐quality (high C:N) leaf‐litter and its effect on particulate organic matter (POM) and mineral‐associated organic matter (MAOM) fractions over 2 years in a natural subtropical forest.

We found that during early stages of decomposition, low‐quality litter inputs decreased SOC via a positive priming effect (i.e. new C inputs favoured decomposition of native SOC), but these SOC losses were offset by SOC gains observed via a negative priming effect during decomposition of high‐quality litter. In contrast, this pattern reversed during late stages of decomposition—SOC losses via a positive priming effect induced by high‐quality litter were offset by SOC gains via a negative priming effect induced by low‐quality litter. Over the full decomposition of litter, both high‐ and low‐quality litter stimulated microbial breakdown of SOC tied to POM, but also replenished more persistent SOC that associated with soil minerals (MAOM). Altogether, we observed that low‐quality litter formed twice as much new SOC as high‐quality litter (24% vs. 12% of added litter‐C). We extend the notion of the priming effect from primarily a negative role promoting losses of native SOC, to a functional role that can replenish persistent SOC.

Synthesis. Our measurements raise the possibility that, in species‐rich forests, high‐ and low‐quality litter decomposition play opposite but dynamically complementary roles in renewing POM—both by inducing its decomposition and formation—while exclusively favouring MAOM formation, which can help explain how differences in litter quality favour SOC accumulation and persistence. Global change factors that shift plant community composition may ultimately affect the fate of soil C, as changes in litter quality may force soil transitions from sinks to sources or sources to sinks of atmospheric CO2.
Alternative relay regulates the adenosine triphosphatase activity of Locusta migratoria striated muscle myosin
Authors: Hao Jie , Liu Chang , Zhang Ning , Li Jing , Ni Tong , Qu Mingbo , Li Xiang‐dong
Published: July 2023

Locust (Locusta migratoria) has a single striated muscle myosin heavy chain (Mhc) gene, which contains 5 clusters of alternative exclusive exons and 1 differently included penultimate exon. The alternative exons of Mhc gene encode 4 distinct regions in the myosin motor domain, that is, the N‐terminal SH3‐like domain, one lip of the nucleotide‐binding pocket, the relay, and the converter. Here, we investigated the role of the alternative regions on the motor function of locust muscle myosin. Using Sf9‐baculovirus protein expression system, we expressed and purified 5 isoforms of the locust muscle myosin heavy meromyosin (HMM), including the major isoform in the thorax dorsal longitudinal flight muscle (FL1) and 4 isoforms expressed in the abdominal intersegmental muscle (AB1 to AB4). Among these 5 HMMs, FL1‐HMM displayed the highest level of actin‐activated adenosine triphosphatase (ATPase) activity (hereafter referred as ATPase activity). To identify the alternative region(s) responsible for the elevated ATPase activity of FL1‐HMM, we produced a number of chimeras of FL1‐HMM and AB4‐HMM. Substitution with the relay of AB4‐HMM (encoded by exon‐14c) substantially decreased the ATPase activity of FL1‐HMM, and conversely, the relay of FL1‐HMM (encoded by exon‐14a) enhanced the ATPase activity of AB4‐HMM. Mutagenesis showed that the exon‐14a‐encoded residues Gly474 and Asn509 are responsible for the elevated ATPase activity of FL1‐HMM. Those results indicate that the alternative relay encoded by exon‐14a/c play a key role in regulating the ATPase activity of FL1‐HMM and AB4‐HMM.
Origin matters: Using a local reference genome improves measures in population genomics
Authors: Thorburn Doko‐Miles J. , Sagonas Kostas , Binzer‐Panchal Mahesh , Chain Frederic J. J. , Feulner Philine G. D. , Bornberg‐Bauer Erich , Reusch Thorsten B. H. , Samonte‐Padilla Irene E. , Milinski Manfred , Lenz Tobias L. , Eizaguirre Christophe
Published: July 2023

Genome sequencing enables answering fundamental questions about the genetic basis of adaptation, population structure and epigenetic mechanisms. Yet, we usually need a suitable reference genome for mapping population‐level resequencing data. In some model systems, multiple reference genomes are available, giving the challenging task of determining which reference genome best suits the data. Here, we compared the use of two different reference genomes for the three‐spined stickleback (Gasterosteus aculeatus), one novel genome derived from a European gynogenetic individual and the published reference genome of a North American individual. Specifically, we investigated the impact of using a local reference versus one generated from a distinct lineage on several common population genomics analyses. Through mapping genome resequencing data of 60 sticklebacks from across Europe and North America, we demonstrate that genetic distance among samples and the reference genomes impacts downstream analyses. Using a local reference genome increased mapping efficiency and genotyping accuracy, effectively retaining more and better data. Despite comparable distributions of the metrics generated across the genome using SNP data (i.e. π, Tajima's D and FST), window‐based statistics using different references resulted in different outlier genes and enriched gene functions. A marker‐based analysis of DNA methylation distributions had a comparably high overlap in outlier genes and functions, yet with distinct differences depending on the reference genome. Overall, our results highlight how using a local reference genome decreases reference bias to increase confidence in downstream analyses of the data. Such results have significant implications in all reference‐genome‐based population genomic analyses.
Brief, cognitive‐behavioral intervention to promote treatment seeking in adults with severe alcohol use disorder: A randomized controlled trial
Authors: Conner Kenneth R. , Maisto Stephen A. , Abar Beau , Szafranski Sarah , Chiang Andrew , Hutchison Morica , Aldalur Aileen , Stecker Tracy
Published: July 2023

Background and Aims

There is little RCT evidence that brief interventions improve treatment seeking in individuals with severe alcohol use disorder (AUD) or treatment seeking reduces alcohol use. The aim was to test the efficacy of a brief intervention to increase treatment seeking in treatment naïve adults with severe AUD and measure its effects on alcohol use.

Design

Parallel group, non‐pharmacologic RCT with intervention (n = 197) and active control (n = 203) conditions, with blinded assessors conducting follow‐ups at 1, 3 and 6 months.

Setting

Online recruitment in a 17‐county region of upstate New York, USA.

Participants

Inclusion criteria consisted of ages ≥18 years, Alcohol Use Disorders Identification Test score ≥16, exceeds recommended limits for alcohol use and no history of AUD treatment. n = 400; 50% female; 79% white; mean age, 40.7; mean education, 14.6 years.

Intervention and comparator

One‐session telephone‐delivered interventions: Cognitive‐Behavioral Therapy for Treatment Seeking (CBT‐TS; intervention), review of a National Institute on Alcohol Abuse and Alcoholism pamphlet on AUD treatment (control).

Measurements

Self‐report of any AUD treatment use over 3 months (primary outcome) and two standard measures of alcohol use over 6 months (secondary outcomes).

Findings

Intent‐to‐treat analyses were used. Assessment follow‐up rates were ≥93%. Any alcohol‐related treatment use over 3‐month follow‐up was obtained by 38 (19%) intervention participants and 36 (18%) control participants, a non‐significant difference, χ2 [1] = 0.16, P = 0.689. Secondary analysis showed a significant interaction term between sex and intervention assignment (β = −1.197, P = 0.027). The interaction suggested CBT‐TS was effective in men (22% vs 13%), although the evidence was somewhat weak (P = 0.071), and it was not effective in women (17% vs 24%).

Conclusions

A one‐session cognitive‐behavioral therapy intervention to increase treatment seeking in treatment naïve adults with severe alcohol use disorder did not increase treatment seeking.
Anthropometrics of neonates born to mothers with PCOS with metformin or placebo exposure in utero
Authors: Nilsen Guro Ørndal , Simpson Melanie Rae , Hanem Liv Guro Engen , Løvvik Tone Shetelig , Ødegård Rønnaug , Stokkeland Live Marie T. , Andersen Marianne Skovsager , Juliusson Petur Benedikt , Vanky Eszter
Published: July 2023

Introduction

Fetal growth may be affected by both maternal polycystic ovary syndrome (PCOS) and metformin therapy. Here, we explore the effect of intrauterine metformin exposure on birth anthropometrics of infants born to women with PCOS. We also investigated whether the effect of metformin on birth anthropometrics is modified by maternal pre‐pregnancy body mass index, PCOS hyperandrogenic phenotype, serum androgen levels, preconception use of metformin and offspring sex. Additionally, we assessed newborn anthropometrics in relation to a national reference population.

Material and methods

Individual data from three randomized controlled triasl were pooled. The randomized controlled trials investigated the effects of metformin in pregnant women with PCOS. In all, 397 and 403 were randomized to the metformin and placebo groups, respectively. A Scandinavian growth reference was used to calculate sex and gestational age adjusted z‐scores. Linear regression models were used to estimate the effect of metformin on offspring z‐scores of head circumference, birth length, birthweight, placental weight, body mass index, ponderal index and birthweight:placental weight ratio. S‐testosterone, s‐androstenedione, and s‐sex‐hormone binding globulin from four timepoints in pregnancy were analyzed.

Results

Compared with the PCOS‐placebo group, newborns in the PCOS‐metformin group had larger head circumference (head circumference z‐score: mean difference = 0.25, 95% CI = 0.11– 0.40). This effect of metformin on head circumference z‐score was particularly observed among offspring of overweight/obese mothers and mothers with hyperandrogenic PCOS‐phenotype. We observed no difference in other anthropometric measures between the metformin and placebo groups or any clear interaction between maternal androgen levels and metformin. Newborns in the PCOS‐placebo group were shorter than in the reference population (birth length z‐score: mean = −0.04, 95% CI = –0.05 to −0.03), but head circumference and birthweight were similar.

Conclusions

Larger head circumference was observed at birth in metformin‐exposed offspring of mothers with PCOS. PCOS‐offspring were also shorter, with a similar birthweight to the reference population, indirectly indicating higher weight‐to‐height ratio at birth.
Converging old and new carbon frontiers in northern Australia
Authors: Neale Timothy , Dahlgren Kari , Howey Kirsty , Kearnes Matthew
Published: July 2023

Over the past 15 years, international climate policy and governance practice have shifted from a linear model of carbon emissions management to a circular model. Whereas the former primarily focused on reducing absolute emissions, the latter focuses on balancing emissions sources and sinks. Australia, a major global exporter of ‘old’ carbon resources such as coal, has actively embraced circular carbon policies and their related ‘new’ carbon resources such as carbon credits. Focusing on Australia's Northern Territory as a site of old and new carbon economies, where government administrators have actively sought to host carbon circulations and loops, this paper examines three interlinked cases to illustrate the interdependencies generated through circular carbon policies. Identifying how sources, sinks, and the mediation of relations between them all constitute key contemporary carbon frontiers, we conclude by calling for a research agenda that analyses ‘old’ and ‘new’ carbon economies as a co‐produced assemblage rather than as isolated zones.
A Self-Censoring Model for Multivariate Nonignorable Nonmonotone Missing Data
Authors: Li Yilin , Miao Wang , Shpitser Ilya , Tchetgen Tchetgen Eric J.
Published: July 2023

We introduce an itemwise modeling approach called “self-censoring” for multivariate nonignorable nonmonotone missing data, where the missingness process of each outcome can be affected by its own value and associated with missingness indicators of other outcomes, while conditionally independent of the other outcomes. The self-censoring model complements previous graphical approaches for the analysis of multivariate nonignorable missing data. It is identified under a completeness condition stating that any variability in one outcome can be captured by variability in the other outcomes among complete cases. For estimation, we propose a suite of semiparametric estimators including doubly robust estimators that deliver valid inferences under partial misspecification of the full-data distribution. We also provide a novel and flexible global sensitivity analysis procedure anchored at the self-censoring. We evaluate the performance of the proposed methods with simulations and apply them to analyze a study about the effect of highly active antiretroviral therapy on preterm delivery of HIV-positive mothers.
Obesity is associated with poor outcomes of corticosteroid treatment in patients with primary immune thrombocytopenia
Authors: Zhang Xiaoyu , Liu Qiang , Liu Anli , Leng Shaoqiu , Wang Xiaolin , Zhao Ruxia , Sheng Zi , Feng Qi , Yang Xiaorong , Wang Shuwen , Hou Ming , Peng Jun , Feng Gege
Published: July 2023

Emerging evidence has demonstrated that obesity impacts multiple immune‐related diseases. It remains unclear whether and how obesity alters treatment outcomes in patients with primary immune thrombocytopenia (ITP). Thus, we retrospectively investigated 214 treatment‐naïve patients who received standard high‐dose dexamethasone therapy in Qilu Hospital. Patients with obesity showed significantly lower overall initial response (underweight vs. normal vs. overweight vs. obese: 85.7% vs. 85.2% vs. 72.0% vs. 52.3%, p = 0.001) and initial complete response ([CR], 71.4% vs. 70.4% vs. 53.3% vs. 27.3%, p < 0.001) rates. The same trend was observed in the 6‐month sustained response (63.6% vs. 52.3% vs. 35.6% vs. 22.7%, p = 0.03) and sustained CR (36.4% vs. 44.6% vs. 24.4% vs. 9.1%, p = 0.01). The Kaplan–Meier analysis revealed a shortened duration of remission in the obese group (median duration of remission, not reached vs. 16 months vs. 2 months vs. 1 month, p = 0.002). In multivariate regression analysis, obesity was independently associated with poor initial and sustained responses, and an increased risk for relapse. In conclusion, obesity is a negative predictor for outcomes of corticosteroid treatment. A stratified strategy according to body mass index status may facilitate the precision management of ITP.
Machine learning approaches for predicting 5‐year breast cancer survival: A multicenter study
Authors: Nguyen Quynh Thi Nhu , Nguyen Phung‐Anh , Wang Chun‐Jung , Phuc Phan Thanh , Lin Ruo‐Kai , Hung Chin‐Sheng , Kuo Nei‐Hui , Cheng Yu‐Wen , Lin Shwu‐Jiuan , Hsieh Zong‐You , Cheng Chi‐Tsun , Hsu Min‐Huei , Hsu Jason C.
Published: July 2023

The study used clinical data to develop a prediction model for breast cancer survival. Breast cancer prognostic factors were explored using machine learning techniques. We conducted a retrospective study using data from the Taipei Medical University Clinical Research Database, which contains electronic medical records from three affiliated hospitals in Taiwan. The study included female patients aged over 20 years who were diagnosed with primary breast cancer and had medical records in hospitals between January 1, 2009 and December 31, 2020. The data were divided into training and external testing datasets. Nine different machine learning algorithms were applied to develop the models. The performances of the algorithms were measured using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and F1‐score. A total of 3914 patients were included in the study. The highest AUC of 0.95 was observed with the artificial neural network model (accuracy, 0.90; sensitivity, 0.71; specificity, 0.73; PPV, 0.28; NPV, 0.94; and F1‐score, 0.37). Other models showed relatively high AUC, ranging from 0.75 to 0.83. According to the optimal model results, cancer stage, tumor size, diagnosis age, surgery, and body mass index were the most critical factors for predicting breast cancer survival. The study successfully established accurate 5‐year survival predictive models for breast cancer. Furthermore, the study found key factors that could affect breast cancer survival in Taiwanese women. Its results might be used as a reference for the clinical practice of breast cancer treatment.
Discovery of novel TRPV1 modulators through machine learning‐based molecular docking and molecular similarity searching
Authors: Wei Xinmiao , Yang Qifan , Yang Zhijiang , Huang Tengxin , Yang Hang , Wang Liangliang , Pan Li , Ding Junjie
Published: July 2023

The transient receptor potential vanilloid 1 (TRPV1) channel belongs to the transient receptor potential channel superfamily and participates in many physiological processes. TRPV1 modulators (both agonists and antagonists) can effectively inhibit pain caused by various factors and have curative effects in various diseases, such as itch, cancer, and cardiovascular diseases. Therefore, the development of TRPV1 channel modulators is of great importance. In this study, the structure‐based virtual screening and ligand‐based virtual screening methods were used to screen compound databases respectively. In the structure‐based virtual screening route, a full‐length human TRPV1 protein was first constructed, three molecular docking methods with different precisions were performed based on the hTRPV1 structure, and a machine learning‐based rescoring model by the XGBoost algorithm was constructed to enrich active compounds. In the ligand‐based virtual screening route, the ROCS program was used for 3D shape similarity searching and the EON program was used for electrostatic similarity searching. Final 77 compounds were selected from two routes for in vitro assays. The results showed that 8 of them were identified as active compounds, including three hits with IC50 values close to capsazepine. In addition, one hit is a partial agonist with both agonistic and antagonistic activity. The mechanisms of some active compounds were investigated by molecular dynamics simulation, which explained their agonism or antagonism.
Beyond ARIA: Will e‐diaries replace retrospective questionnaires in measuring the severity of allergic rhinitis in clinical research and daily practice?
Authors: Matricardi Paolo M. , Sousa‐Pinto Bernardo , Dramburg Stephanie , Bousquet Jean
Published: July 2023

Retrospective questionnaires are used since decades to assess the severity and/or control of allergic diseases. Applications on smartphones have recently facilitated the use of prospective clinical diaries, based on questionnaires filled every day by the patient. Once limited to clinical trials, these e‐diaries, based on validated disease control scores and visual analogue scales, permit a quantitative day‐by‐day measure free of recall bias. Given the advantages of this procedure, its use could be extended to the daily clinical practice. E‐diaries may facilitate (1) a more precise identification of the culprit allergen in the diagnostic work‐up of poly‐sensitized patients, (2) the stratification of patients for treatment, (3) the follow‐up of the patients under treatment for optimized shared decision‐making, and (4) a careful assessment of preventive therapies. While a few apps are being used in scientific studies, consensus on their use in daily practice should be reached and guidelines for specialists should be elaborated by scientific associations.