bluuebunny/crossref_metadata_2025 huggingface dataset:
A context-sensitive and non-linguistic approach to abstract concepts
Authors: Langland-Hassan Peter , Davis Charles P.
Published: December 2022

Despite the recent upsurge in research on abstract concepts, there remain puzzles at the foundation of their empirical study. These are most evident when we consider what is required to assess a person's abstract conceptual abilities without using language as a prompt or requiring it as a response—as in classic non-verbal categorization tasks, which are standardly considered tests of conceptual understanding. After distinguishing two divergent strands in the most common conception of what it is for a concept to be abstract, we argue that neither reliably captures the kind of abstraction required to successfully categorize in non-verbal tasks. We then present a new conception of concept abstractness—termed 'trial concreteness'—that is keyed to individual categorization trials. It has advantages in capturing the context-relativity of the degree of abstraction required for the application of a concept and fittingly correlates with participant success in recent experiments.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
The division of linguistic labour for offloading conceptual understanding
Authors: Andrade-Lotero Edgar J. , Ortiz-Duque Julián M. , Velasco-García Javier A. , Goldstone Robert L.
Published: December 2022

The division of linguistic labour (DLL), initially theorized by philosophers, has gained the attention of cognitive scientists in the last decade. Contrary to some controversial philosophical accounts of DLL, we propose that it is an extended mind strategy of offloading conceptual understanding onto other people. In this article, we empirically explore this proposal by providing an exploratory experimental paradigm to search for the mechanisms underwriting DLL and how they may work in practice. We developed a between-subjects experiment in which participants had to categorize two pairs of highly confusable dog breeds after receiving categorization training on just one pair of breeds. In the treatment group, participants were grouped in dyads and were allowed to interact with each other by means of the labels of these four dog breeds. In their queries to trained ‘experts’, novices frequently used labels to refer to breeds that they could not identify themselves. Experts were highly responsive to their paired novices' queries, and the rates of querying for the two members within a dyad were positively correlated. Independent categorization failure and offloading categorization success lead to subsequent increases in querying by novices, indicating adaptive use of offloading. Self-reports of breed knowledge were higher for experts within a dyad compared to isolated experts.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Interpersonal attunement in social interactions: from
collective
psychophysiology to
inter-
personalized
psychiatry and beyond
Authors: Bolis Dimitris , Dumas Guillaume , Schilbach Leonhard
Published: December 2022

In this article, we analyse social interactions, drawing on diverse points of views, ranging from dialectics, second-person neuroscience and enactivism to dynamical systems, active inference and machine learning. To this end, we define interpersonal attunement as a set of multi-scale processes of building up and materializing social expectations—put simply, anticipating and interacting with others and ourselves. While cultivating and negotiating common ground, via communication and culture-building activities, are indispensable for the survival of the individual, the relevant multi-scale mechanisms have been largely considered in isolation. Here,
collective psychophysiology
, we argue, can lend itself to the fine-tuned analysis of social interactions, without neglecting the individual. On the other hand, an interpersonal mismatch of expectations can lead to a breakdown of communication and social isolation known to negatively affect mental health. In this regard, we review psychopathology in terms of interpersonal misattunement, conceptualizing psychiatric disorders as disorders of social interaction, to describe how individual mental health is inextricably linked to social interaction. By doing so, we foresee avenues for an
inter-
personalized
psychiatry, which moves from a static spectrum of disorders to a dynamic relational space, focusing on how the multi-faceted processes of social interaction can help to promote mental health.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Kick-starting concept formation with intrinsically motivated learning: the grounding by competence acquisition hypothesis
Authors: Mannella Francesco , Tummolini Luca
Published: December 2022

Although the spontaneous origins of concepts from interaction is often given for granted, how the process can start without a fully developed sensorimotor representation system has not been sufficiently explored. Here, we offer a new hypothesis for a mechanism supporting concept formation while learning to perceive and act intentionally. We specify an architecture in which multi-modal sensory patterns are mapped in the same lower-dimensional representation space. The motor repertoire is also represented in the same space via topological mapping. We posit that the acquisition of these mappings can be mutually constrained by maximizing the convergence between sensory and motor representations during online interaction. This learning signal reflects an intrinsic motivation of competence acquisition. We propose that topological alignment via competence acquisition eventually results in a sensorimotor representation system. To assess the consistency of this hypothesis, we develop a computational model and test it in an object manipulation task. Results show that such an intrinsically motivated learning process can create a cross-modal categorization system with semantic content, which supports perception and intentional action selection, which has the resources to re-enact its own multi-modal experiences, and, on this basis, to kick-start the formation of concepts grounded in the external environment.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Cross-domain semantic alignment: concrete concepts are more abstract than you think
Authors: Liu Qiawen , Lupyan Gary
Published: December 2022

We can easily evaluate similarities between concepts within semantic domains, e.g. doctor and nurse, or violin and piano. Here, we show that people are also able to evaluate similarities across domains, e.g. aligning doctors with pianos and nurses with violins. We argue that understanding how people do this is important for understanding conceptual organization and the ubiquity of metaphorical language. We asked people to answer questions of the form ‘If a nurse were an animal, they would be a(n) …’ (Experiments 1 and 2) and asked them to explain the basis for their response (Experiment 1). People converged to a surprising degree (e.g. 20% answered ‘cat’). In Experiment 3, we presented people with cross-domain mappings of the form ‘If a nurse were an animal, they would be a cat’ and asked them to indicate how good each mapping was. The results showed that the targets people chose and their goodness ratings of a given response were predicted by similarity along abstract semantic dimensions such as valence, speed and genderedness. Reliance on such dimensions was also the most common explanation for their responses. Altogether, we show that people can evaluate similarity between very different domains in predictable ways, suggesting either that seemingly concrete concepts are represented along relatively abstract dimensions (e.g. weak–strong) or that they can be readily projected onto these dimensions.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Whole-exome sequencing study identifies genes associated with Alzheimer’s disease and related dementias
Authors: Gao Xiaoyi Raymond , Chiariglione Marion , Arch Alexander J.
Published: December 2022

Alzheimer’s disease (AD) is the most common form of late-onset neurodegenerative disease. Previous genome-wide association studies have identified numerous common genetic variants associated with AD. The contribution of rare variants to AD remains to be uncovered. AD-by-proxy, based on parental AD status, showed superior statistical power boost in recent AD studies. Using the UK Biobank (UKB) 368,865 whole-exome sequences of white British ancestry and AD-by-proxy (57,976 proxy AD cases and 310,889 non-AD proxy controls), we conducted the largest exome-wide association study of proxy AD to date. We identified 38 novel genes harboring rare variants for AD, such asANKRD36(P= 6.02 × 10−31),MMP13(P= 1.08 × 10−6),TUBA4A(P= 7.15 × 10−12), andZNF296(P= 4.19 × 10−14), demonstrating the power boost of aggregating rare variants and utilizing AD-by-proxy in gene discovery. We further replicated these genes in the FinnGen dataset. Notably,MMP13is a current drug target for AD andTUBA4Ais a drug target for cognitive impairment in clinical trials. These results expand our knowledge of the genetic architecture of AD, especially the role of rare variants, and potential drug targets for AD.
Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids
Authors: Stewart Romal , Yan Kexin , Ellis Sevannah A. , Bishop Cameron , Dumenil Troy , Tang Bing , Nguyen Wilson , Larcher Thibaut , Parry Rhys , Jun Sng Julian De , Khromykh Alexander A. , Sullivan Robert K. P. , Lor Mary , Meunier Frédéric A. , Rawle Daniel J. , Suhrbier Andreas
Published: December 2022

The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described, although whether such attenuation is retained for later variants like BA.5 and XBB remains controversial. We show that BA.5 and XBB isolates were significantly more pathogenic in K18-hACE2 mice than a BA.1 isolate, showing increased neuroinvasiveness, resulting in fulminant brain infection and mortality, similar to that seen for original ancestral isolates. BA.5 also infected human cortical brain organoids to a greater extent than the BA.1 and original ancestral isolates. In the brains of mice, neurons were the main target of infection, and in human organoids neuronal progenitor cells and immature neurons were infected. Although fulminant brain infection is not a feature of COVID-19, evidence for brain infection and brain damage in some COVID-19 patients with severe disease is becoming compelling, with the results herein suggesting that evolving omicron variants may have increasing intrinsic neuropathogenic potential.
HOW DO WE INDUCE LABOURS IN SPAIN? RESULTS OF THE INDUCESPAÑA SURVEY
Authors: del Barrio Fernández Pablo , Medina Mallen María del Carmen , Alonso Saiz Rubén , Álvarez Suberviola Edurne , Álvarez Colomo Cristina , Batllori Badia Emma , Dueñas Carazo María Begoña , Benítez Cano Elena , Bernardo Vega Rut , Boza Novo Patricia , Castro Portillo Laura , Comas Rovira Montserrat , Díaz Meca Lucía , Fernández Fernández Camino , Fernández Buhigas Irene , Fernández Menéndez Sara , Garrido Luque M. Belén , Gastaca Abásolo Irene , Llano Fontela Ruth , Llordella Sarmiento Ivanna , Llull Gomila Marina , López Pérez Rocío , Meca Casbas Marta Ruth , Muñoz Abellana Begoña , Muñoz Carmona Víctor , Orizales Lago Carmen María , Orozco Fernández Rodrigo , Ortiz Herrera María Caridad , Peña Salas María Soledad , Pérez Álvarez Sara , Prats Rodríguez Pilar , Puertas Prieto Alberto , Puerto Tamayo Linda Grace , Rodríguez López Silvia , Rodríguez Pradera Susana , Sabench Carreras Cristina , Soldevilla Pérez Susana , Suarez Arana María , Pintado Paredes Elena , Carrasco Catena Mª Amparo , Martínez-Pérez Óscar
Published: December 2022

Background

Induction of labour (IDP) is the artificial initiation of labour with the goal of achieving a vaginal delivery. IDP is one of the most frequently performed obstetric procedures in the world. Recent data indicate a highly variable percentage of induction depending on the country.

Methods

A descriptive study was carried out on different aspects that are part of the ITP process through a survey prepared according to the Delphi method distributed among the 37 participating hospitals from June to October 2021.

Results

The mean induction rate was 30.6%. The average rate of caesarean sections was 21.4%. 75% of the centers had a rate higher than 20% and only in 1 center was it lower than 15%. In 11 centers they were not available to use misoprostol and in 4 centers they did not have oxytocin as PDI. Mechanical methods were available in 23 hospitals. In 16 centers they had a double Cook balloon; in 5 they used a Foley catheter and in 2 hospitals they used both devices. In 4 hospitals they used mechanical methods simultaneously with prostaglandins. In all but 5 centers, continuous monitoring was performed in low-risk pregnancies, at least for the first hour. In these 5 centers, windows of 20 minutes were carried out from the start of the induction
Post-mortem Nasopharyngeal Microbiome Analysis of Zambian Infants with and without Respiratory Syncytial Virus Disease: A Nested Case Control Study
Authors: McClintock Jessica , Odom-Mabey Aubrey R. , Kebere Nitsueh , Ismail Arshad , Mwananyanda Lawrence , Gill Christopher J. , MacLeod William B. , Pieciak Rachel C. , Lapidot Rotem , Johnson W. Evan
Published: December 2022

Background

Respiratory Syncytial Virus (RSV) is the most common cause of bronchiolitis and lower respiratory tract infections in children in their first year of life, disproportionately affecting infants in developing countries. Previous studies have found that the nasopharyngeal microbiome of infants with RSV infection has specific characteristics that correlate with disease severity, including lower biodiversity, perturbations of the microbiota and differences in relative abundance. These studies have focused on infants seen in clinical or hospital settings, predominantly in developed countries.

Methods

We conducted a nested case control study within a random sample of 50 deceased RSV+ infants with age at death ranging from 4 days to 6 months and 50 matched deceased RSV-infants who were all previously enrolled in the Zambia Pertussis and RSV Infant Mortality Estimation (ZPRIME) study. All infants died within the community or within 48 hours of facility admittance. As part of the ZPRIME study procedures, all decedents underwent one-time, post-mortem nasopharyngeal sampling. The current analysis explored the differences between the nasopharyngeal microbiome profiles of RSV+ and RSV-decedents using 16S ribosomal DNA sequencing.

Results

We found thatMoraxellawas more abundant in the nasopharyngeal microbiome of RSV+ decedents than in RSV-decedents. Additionally,GemellaandStaphylococcuswere less abundant in RSV+ decedents than in RSV-decedents.

Conclusion

These results support previously reported findings of the association between the nasopharyngeal microbiome and RSV and suggest that changes in the abundance of these microbes are likely specific to RSV and may correlate with mortality associated with the disease.
Understanding the current and future usage of donor human milk in hospitals: an online survey of UK neonatal units
Authors: Shenker NS , Griffin S , Hamill-Keays J , Thomson M , Simpson J , Weaver G
Published: December 2022

Objective

The use of donor human milk (DHM) where there is a shortfall of maternal milk can benefit both infant and maternal outcomes but DHM supply is not always assured. This study aimed to understand current DHM usage in UK neonatal units and potential future demand to inform service planning.

Design/Setting

An online survey was disseminated to all UK neonatal units using SmartSurvey or by telephone between February and April 2022 after development alongside neonatal unit teams.

Results

Surveys were completed by 55.4% units (108/195; 18 Level 1, 47 Level 2, 41 Level 3; cot numbers 9-56) from all thirteen Operational Delivery Networks. Only four units reported not using DHM, and another two units only if infants are transferred on DHM feeds. There was marked diversity in DHM implementation and usage. Five of six units with their own milk bank had needed to source milk from an external milk bank in the last year. Ninety units (84.9%) considered DHM was sometimes (n=35) or always (n=55) supportive of maternal breastfeeding, and rarely supportive by three (2.9%). Usage was predicted to increase by 37 units (34.9%), driven by parental preference, clinical trials, and improved evidence.

Conclusions

These findings support the assumption that UK hospital DHM demand will increase after updated recommendations from the WHO and British Association of Perinatal Medicine. This data will help policymakers and milk banks to plan strategic service delivery, alongside ongoing cost-benefit analyses, donor recruitment strategies and infrastructure planning to ensure equity of assured access to DHM nationally.

What’s known, what does this study add?

What is already known on this topic

Updated recommendations from WHO and BAPM are likely to increase demand for donor human milk provision from human milk banks, but there have been no recent data collected on baseline usage criteria, enteral feeding guidelines, and anticipated future use.

What this study adds

This national survey of UK neonatal units highlights variability in DHM provision, and reasons for demand spikes that will be helpful for modelling future services. Almost 85% of neonatal units responded that DHM availability was supportive of maternal lactation support. DHM demand is likely to increase further in the next 2 years.

How this study might affect research, practice or policy

Understanding demand variability will help in planning nationally equitable human milk bank services, and support the development of robust national service continuity planning. The study also highlights variability in practice, often in single regions, raising concerns related to health equity, staffing limitations and uncertainty in DHM implementation.
Additive interaction and mediation-interaction decomposition: DNA methylation age acceleration, education, and cognitive impairment in the Health and Retirement Study
Authors: Ware Erin B. , Higgins Cesar , Harris Sean , Fisher Jonah D. , Bakulski Kelly M.
Published: December 2022

Importance

Dementia represents a significant and increasing public health burden. DNA methylation age acceleration may be associated with dementia and dementia risk factors, such as education, but investigating their impact on dementia is necessary.

Objective

To evaluate the association of educational attainment on dementia and cognitive impairment through DNA methylation age acceleration, while accommodating exposure-mediator interaction effects.

Design

In the 2016 Health and Retirement Study wave, we evaluated six epigenetic clocks, including GrimAge, with Langa-Weir classified dementia, cognitive impairment non-dementia, and normal cognition. Age acceleration was the residual between chronological age of participants and DNA methylation clock, dichotomized at zero. To understand the joint association of low education (≤12 years) and DNA methylation age acceleration in relation to cognitive impairment, we used weighted logistic regression and calculated interaction on the additive scale adjusting for chronological age, sex, race/ethnicity, and cell type composition. We performed four-way mediation and interaction decomposition analysis to estimate the: 1) controlled direct effect of education on cognition, 2) interaction reference, 3) interaction mediation, and 4) the pure indirect effect of DNA methylation age acceleration on cognition.

Setting

Analysis was conducted on a subsample of Health and Retirement Study participants in the 2016 Venous Blood Study (N=3,724).

Results

Both GrimAge acceleration (OR=1.6 95%CI 1.3 – 2.1) and low educational attainment (OR=2.4 95%CI 1.9 – 3.0) were associated with higher odds of cognitive impairment, non-dementia in a mutually adjusted logistic model. We found additive interaction associations between low education and GrimAge acceleration on dementia. We observed that 6-8% of the association of education on dementia was mediated through GrimAge acceleration. While mediation effects were small, the portion of the association of education due to additive interaction with GrimAge acceleration was between 23.6 and 29.2%.

Conclusions and Relevance

Accelerated DNA methylation age was associated with increased odds of cognitive impairment and we observed more than additive interaction effects between education and age acceleration on dementia. These results support the interplay of social disadvantage and biological aging processes on impaired cognition.
An allelic series rare variant association test for candidate gene discovery
Authors: McCaw Zachary R , O’Dushlaine Colm , Somineni Hari , Bereket Michael , Klein Christoph , Karaletsos Theofanis , Casale Francesco Paolo , Koller Daphne , Soare Thomas W
Published: December 2022

Allelic series are of candidate therapeutic interest due to the existence of a dose-response relationship between the functionality of a gene and the degree or severity of a phenotype. We define an allelic series as a gene in which increasingly deleterious mutations lead to increasingly large phenotypic effects, and develop a gene-based rare variant association test specifically targeted for the identification of allelic series. Building on the well-known burden and sequence kernel association (SKAT) tests, we specify a variety of association models, covering different genetic architectures, and integrate these into a COding-variant Allelic Series Test (COAST). Through extensive simulations, we confirm that COAST maintains the type I error and improves power when the pattern of coding-variant effect sizes increases monotonically with mutational severity. We applied COAST to identify allelic series for 4 circulating lipid traits and 5 cell count traits among 145,735 subjects with available whole exome sequencing data from the UK Biobank. Compared with optimal SKAT (SKAT-O), COAST identified 29% more Bonferroni significant associations with circulating lipid traits, on average, and 82% more with cell count traits. All of the gene-trait associations identified by COAST have corroborating evidence either from rare-variant associations in the full cohort (Genebass,N= 400K), or from common variant associations in the GWAS catalog. In addition to detecting many gene-trait associations present in Genebass using only a fraction (36.9%) of the sample, COAST detects associations, such asANGPTL4with triglycerides, that are absent from Genebass but which have clear common variant support.
Determinants of Motor Neuron Functional Subtypes Important for Locomotor Speed
Authors: D’Elia Kristen P. , Hameedy Hanna , Goldblatt Dena , Frazel Paul , Kriese Mercer , Zhu Yunlu , Hamling Kyla R. , Kawakami Koichi , Liddelow Shane A. , Schoppik David , Dasen Jeremy S.
Published: December 2022

Locomotion requires precise control of the strength and speed of muscle contraction and is achieved by recruiting functionally-distinct subtypes of motor neurons (MNs). MNs are essential to movement and differentially susceptible in disease, but little is known about how MNs acquire functional subtype-specific features during development. Using single-cell RNA profiling in embryonic and larval zebrafish, we identify novel and conserved molecular signatures for MN functional subtypes, and identify genes expressed in both early post-mitotic and mature MNs. Assessing MN development in genetic mutants, we define a molecular program essential for MN functional subtype specification. Two evolutionarily-conserved transcription factors, Prdm16 and Mecom, are both functional subtype-specific determinants integral for fast MN development. Loss ofprdm16ormecomcauses fast MNs to develop transcriptional profiles and innervation similar to slow MNs. These results reveal the molecular diversity of vertebrate axial MNs and demonstrate that functional subtypes are specified through intrinsic transcriptional codes.
Spatiotemporal profiling of a dominant coral’s photo-endosymbiotic assemblage indicates that acclimation is supported by phenotypic plasticity of single cells
Authors: Anthony CJ , Lock C , Taylor BM , Bentlage B
Published: December 2022

Coral-associated dinoflagellates (Symbiodiniaceae) are photosynthetic endosymbionts that influence coral acclimation and adaptation, as indicated by photo-physiological plasticity (phenotypic variance) in response to environmental change. Symbiont shuffling (shifts in endosymbiont community composition), changes in endosymbiont cell density, and phenotypic plasticity have all been proposed as mechanisms to adjust to environmental change. However, few studies have been able to partition which of the three strategies were responsible for observed phenotypic variance. Therefore, we quantified the biodiversity, cell density, and phenotypic variance of single cells forAcropora pulchra-associated Symbiodiniaceae assemblages. Using a combination of metabarcoding and flow cytometry, we simultaneously characterized Symbiodiniaceae assemblages at the community (biodiversity), population (cell density), and individual level (phenotype) under natural environmental conditions to determine whether phenotypic variation of Symbiodiniaceae communities is concomitant with either symbiont shuffling, changes in cell density, or phenotypic plasticity. Symbiodiniaceae assemblages displayed season-specific phenotypic variance, while biodiversity was geographically structured and cell density showed limited data structure. Based on these patterns, we reveal that phenotypic plasticity of individual Symbiodiniaceae cells is the source of a phenotypic variation, thus indicating that phenotypic plasticity is a mechanism for rapid acclimation to mild environmental change.
Genomics of turions from the Greater Duckweed reveal its pathways for dormancy and reemergence strategy
Authors: Pasaribu Buntora , Acosta Kenneth , Aylward Anthony , Liang Yuanxue , Abramson Bradley W. , Colt Kelly , Nolan T. Hartwick , Shanklin John , Michael Todd P. , Lam Eric
Published: December 2022

Over 15 families of aquatic plants are known to use a strategy of developmental switching upon environmental stress to produce dormant propagules called turions. However, few molecular details for turion biology have been elucidated due to the difficulties in isolating high-quality nucleic acids from this tissue. We successfully developed a new protocol to isolate high-quality transcripts and carried out RNA-seq analysis of mature turions from the Greater DuckweedSpirodela polyrhiza. Comparison of turion transcriptome to that of fronds, the actively growing leaf-like tissue, were carried out.

Bioinformatic analysis of high confidence, differentially expressed transcripts between frond and mature turion tissues revealed major pathways related to stress tolerance, starch and lipid metabolism, and dormancy that are mobilized to reprogram frond meristems for turion differentiation.

We identified the key genes that are likely to drive starch and lipid accumulation during turion formation, as well as in pathways for starch and lipid utilization upon turion germination. Comparison of genome-wide cytosine methylation levels also revealed evidence for epigenetic changes in the formation of turion tissues.

Similarities between turions and seeds provided evidence that key regulators for seed maturation and germination have been retooled for their function in turion biology.
Extrapolating Heterogeneous Time-Series Gene Expression Data using Sagittarius
Authors: Woicik Addie , Zhang Mingxin , Chan Janelle , Ma Jianzhu , Wang Sheng
Published: December 2022

Understanding the temporal dynamics of gene expression is crucial for developmental biology, tumor biology, and biogerontology. However, some timepoints remain challenging to measure in the lab, particularly during very early or very late stages of a biological process. Here we propose Sagittarius, a transformer-based model that can accurately simulate gene expression profiles at timepoints outside of the range of times measured in the lab. The key idea behind Sagittarius is to learn a shared reference space for time series measurements, thereby explicitly modeling unaligned timepoints and conditional batch effects between time series, and making the model widely applicable to diverse biological settings. We show Sagittarius’s promising performance when extrapolating mammalian developmental gene expression, simulating drug-induced expression at unmeasured dose and treatment times, and augmenting datasets to accurately predict drug sensitivity. We also used Sagittarius to extrapolate mutation profiles for early-stage cancer patients, which enabled us to discover a gene set connected to the Hedgehog signaling pathway that may be related to tumorigenesis in sarcoma patients, includingPTCH1,ARID2, andMYCBP2. By augmenting experimental temporal datasets with crucial but difficult-to-measure extrapolated datapoints, Sagittarius enables deeper insights into the temporal dynamics of heterogeneous transcriptomic processes and can be broadly applied to biological time series extrapolation.
Difference in determinants and changing patterns of plant community composition with and without grazing across semi-arid and arid regions in Mongolian steppe
Authors: Ishii Naohiro I. , Nishimura Issei , Qi Yulan , Batdelger Gantsetseg , Kagami Maiko , Takimoto Gaku , Sasaki Takehiro
Published: December 2022

Aridity, edaphic variables related to aridity, and livestock grazing are major drivers of plant community composition across dryland grasslands. With accounting these factors, little is known about differences in determinants and changing patterns along aridity gradients with different average of aridity. Thus, the comparative investigations of communities without and with grazing in semi-arid and arid regions are suitable to clarify the difference in compositional responses along aridity gradients between potential vegetations and degraded ones with grazing. We investigated compositional changes of communities without/with grazing in semi-arid (north) /arid (south) regions across Mongolia. The compositional changes based on Bray-Curtis dissimilarity were investigated by generalized dissimilarity modeling, including geographic distance, aridity, soil pH, and sand and clay contents as independent variables. The determinants and changing patterns of community composition were compared among the four groups. Aridity had significant impacts on community composition regardless of the regions and the absence/presence of grazing. However, without the dependency on grazing, the difference in response patterns was observed between the regions. The compositional change was steeper especially at the upper edge of aridity rather than the lower edge in the arid region. This indicates the vulnerability of plant communities to aridity shifts due to future climate change in desert steppe of Mongolia. In addition, regardless of the regions, the effects of soil pH on community composition were eliminated by grazing. Because soil pH indirectly affected by aridity shifts can have impacts on community composition of potential vegetations without grazing, the long-term monitoring of vegetation dynamics needs observations of both of communities without and with grazing.
Ca2+and cAMP open differentially dilating synaptic fusion pores
Authors: Bulgari Dinara , Cavolo Samantha L. , Schmidt Brigitte F. , Buchan Katherine , Bruchez Marcel P. , Deitcher David L. , Levitan Edwin S.
Published: December 2022

Neuronal dense-core vesicles (DCVs) contain neuropeptides and much larger proteins that affect synaptic growth and plasticity. Rather than using full collapse exocytosis that is common in endocrine cells, DCVs at a native intact synapse, theDrosophilaneuromuscular junction, release their contents via fusion pores formed by kiss and run exocytosis. Here fluorogen activating protein (FAP) imaging reveals the permeability range of synaptic DCV fusion pores and then shows that this constraint is circumvented by cAMP-induced extra fusions with dilating pores that result in DCV emptying. These Ca2+-independent full fusions require PKA-R2, a PKA phosphorylation site on the fusion clamp protein complexin and the acute presynaptic function of Rugose/Neurobeachin, a PKA-R2 anchor implicated in learning and autism. Therefore, localized Ca2+-independent cAMP signaling opens dilating fusion pores to release large cargo proteins that cannot pass through the narrower fusion pores that normally dominate spontaneous and Ca2+-evoked synaptic protein release. Hence, two independent exocytosis triggers (Ca2+and cAMP) vary the composition of released proteins at the synapse by differentially adjusting DCV fusion pores.
An apicomplexan bromodomain, TgBDP1 associates with diverse epigenetic factors to regulate essential transcriptional processes inToxoplasma gondii
Authors: Fleck Krista , McNutt Seth , Chu Feixia , Jeffers Victoria
Published: December 2022

The protozoan pathogenToxoplasma gondiirelies on tight regulation of gene expression to invade and establish infection in its host. The divergent gene regulatory mechanisms ofToxoplasmaand related apicomplexan pathogens rely heavily on regulators of chromatin structure and histone modifications. The important contribution of histone acetylation forToxoplasmain both acute and chronic infection has been demonstrated, where histone acetylation increases at active gene loci. However, the direct consequences of specific histone acetylation marks and the chromatin pathway that influences transcriptional regulation in response to the modification is unclear. As a reader of lysine acetylation, the bromodomain serves as a mediator between the acetylated histone and transcriptional regulators. Here we show that the bromodomain protein TgBDP1 which is conserved amongst Apicomplexa and within the Alveolata superphylum, is essential forToxoplasmaasexual proliferation. Using CUT&TAG we demonstrate that TgBDP1 is recruited to transcriptional start sites of a large proportion of parasite genes. Transcriptional profiling during TgBDP1 knockdown revealed that loss of TgBDP1 leads to major dysregulation of gene expression, implying multiple roles for TgBDP1 in both gene activation and repression. This is supported by interactome analysis of TgBDP1 demonstrating that TgBDP1 forms a core complex with two other bromodomain proteins and an ApiAP2 factor. This core complex appears to interact with other epigenetic factors such as nucleosome remodelling complexes. We conclude that TgBDP1 interacts with diverse epigenetic regulators to exert opposing influences on gene expression in theToxoplasmatachyzoite.

Histone acetylation is critical for proper regulation of gene expression in the single celled eukaryotic pathogenToxoplasma gondii. Bromodomain proteins are “readers” of histone acetylation and may link the modified chromatin to transcription factors. Here, we show that the bromodomain protein TgBDP1 is essential for parasite survival and that loss of TgBDP1 results in global dysregulation of gene expression. TgBDP1 is recruited to the promoter region of a large proportion of parasite genes, forms a core complex with two other bromodomain proteins and interacts with different transcriptional regulatory complexes. We conclude that TgBDP1 is a key factor for sensing specific histone modifications to influence multiple facets of transcriptional regulation inToxoplasma gondii.
Folic acid-loaded chitosan nanoparticles: Cytotoxicity, acute and sub-acute oral toxicity and bioavailability in Wistar rats
Authors: Fathima Eram , Kumar Shashank , Patil M M , Khanum Farhath , Anand T
Published: December 2022

The study aims to develop folic acid-loaded chitosan nanoparticles (FA-Chi-NPs) as the vitamin is sensitive to heat and light and to investigate the safety of FA-Chi-NPsin vitroandin vivo. The prepared formulation showed an average diameter of 191.7 ± 2 nm with a zeta potential of + 52 ± 4 mV and PDI of 0.195 ± 0.03. The encapsulation efficiency was found to be 80%.In vitrocytotoxicity assays revealed that FA-Chi-NPs had no cytotoxic effect on Caco-2 cells. Acute-toxicity and subacute-toxicity of FA-Chi-NPs (0.4, 2, and 4 mg/kg body weight) revealed no mortality, and no gross morphological abnormalities were noticed. There were no dose-dependent toxic effects of free folic acid (FA) and FA-Chi-NPs in haematological, histological, plasma biochemical indices, oxidative stress enzymes, or other parameters when compared to the control group(s). The plasma and tissue levels of FA from FA-Chi-NPs were significantly higher. Results demonstrated enhanced bioavailability of FA from FA-Chi-NPs with no toxicity.

Practical applications

In the current study, nanoencapsulation is used as a potential approach to enhance folic acid bioavailability. The results showed that encapsulating folic acid in chitosan improved bioavailability with no apparent adverse effects, and thus chitosan could be a promising polymer for safe folic acid delivery.
Blood meals from ‘dead-end’ vertebrate hosts enhance transmission potential of malaria-infected mosquitoes
Authors: Pathak Ashutosh K. , Shiau Justine C. , de Freitas Cury Rafael Sadock , Kyle Dennis E.
Published: December 2022

Ingestion of an additional blood meal(s) by mosquitoes can accelerate parasite migration to the salivary glands in infected mosquitoes. Most studies, however, offer blood from the same vertebrate host species as the original challenge (for e.g., human for primary and additional blood meals). Here, we show a second blood meal from bovine and canine hosts can also enhance sporozoite migration inAnopheles stephensimosquitoes infected with the human- and rodent-restrictedPlasmodium falciparumandP. bergheirespectively. The extrinsic incubation period (time to sporozoite appearance in salivary glands) showed more consistent reductions with blood from human and bovine donors than canine blood, although the latter’s effect may be confounded by the toxicity, albeit non-specific, associated with the anticoagulant used to collect whole blood from donors. The complex patterns of enhancement highlight the limitations of a laboratory system but are nonetheless reminiscent of parasite host-specificity and mosquito adaptations, and the genetic predisposition ofAn. stephensifor bovine blood. We suggest that in natural settings, a blood meal from any vertebrate host could accentuate the risk of human infections byP. falciparum, although our observations should also be applicable to other species ofPlasmodiumand indeed other vector-borne diseases such as arboviruses for instance.

Graphical Abstract

HIGHLIGHTS

Plasmodium falciparumandP. bergheicause malaria in humans and rodents, respectively.

They are vectored byAnophelesspecies that can also imbibe blood from other vertebrate species.

Parasite development is enhanced after another blood meal, usually from the same host (e.g., human).

Here, bovine, and canine blood also enhanced development ofPlasmodiumspecies inAn. stephensi.

In natural settings, blood from any host could enhance development of vector transmitted parasites.
Targeting riboswitches with beta-axial substituted cobalamins
Authors: Lennon Shelby R. , Wierzba Aleksandra J. , Siwik Shea H. , Gryko Dorota , Palmer Amy E. , Batey Robert T.
Published: December 2022

RNA-targeting small molecule therapeutics an emerging field hindered by an incomplete understanding of the basic principles governing RNA-ligand interactions. One way to advance our knowledge in this area is to study model systems where these interactions are better understood, such as riboswitches. Riboswitches bind a wide array of small molecules with high affinity and selectivity, providing a wealth of information on how RNA recognizes ligands through diverse structures. The cobalamin-sensing riboswitch is a particularly useful model system as similar sequences show highly specialized binding preferences for different biological forms of cobalamin. This riboswitch is also widely dispersed across bacteria and therefore holds strong potential as an antibiotic target. Many synthetic cobalamin forms have been developed for various purposes including therapeutics, but their interaction with cobalamin riboswitches is yet to be explored. In this study, we characterize the interactions of eleven cobalamin derivatives with three representative cobalamin riboswitches usingin vitrobinding experiments (both chemical footprinting and a fluorescence-based assay) and a cell-based reporter assay. The derivatives show productive interactions with two of the three riboswitches, demonstrating simultaneously plasticity and selectivity within these RNAs. The observed plasticity is partially achieved through a novel structural rearrangement within the ligand binding pocket, providing insight into how similar RNA structures can be targeted in the future. As the derivatives also showin vivofunctionality, they serve as several potential lead compounds for further drug development.
PROSTATA: Protein Stability Assessment using Transformers
Authors: Umerenkov Dmitriy , Shashkova Tatiana I. , Strashnov Pavel V. , Nikolaev Fedor , Sindeeva Maria , Ivanisenko Nikita V. , Kardymon Olga L.
Published: December 2022

Accurate prediction of change in protein stability due to point mutations is an attractive goal that remains unachieved. Despite the high interest in this area, little consideration has been given to the transformer architecture, which is dominant in many fields of machine learning. In this work, we introduce PROSTATA, a predictive model built in knowledge transfer fashion on a new curated dataset. PROSTATA demonstrates superiority over existing solutions based on neural networks. We show that the large margin of improvement is due to both the architecture of the model and the quality of the new training data set. This work opens up opportunities for developing new lightweight and accurate models for protein stability assessment. PROSTATA is available athttps://github.com/AIRI-Institute/PROSTATA.
Biosynthesis of Kratom Opioids
Authors: Kim Kyunhee , Shahsavarani Mohammadamin , Oswaldo Garza-García Jorge Jonathan , Carlisle Jack Edward , Guo Jun , De Luca Vincenzo , Qu Yang
Published: December 2022

Mitragyna speciosa(kratom) derived monoterpenoid indole alkaloids (MIAs) such as mitragynine and 7-hydroxymitragynine are a new class of opioids with a corynanthe MIA pharmacophore that is responsible for their significantly reduced side effects and superior safety profiles. While botanical kratom has been historically used for stimulation and pain management in Southeast Asia, the biosynthesis of kratom MIAs is not known. In this study, we identified and characterized 9 reductases bearing various degrees of demethyldihydrocoryanthine/demethylcorynantheidine synthase activity and a new SABATH type methyltransferase that catalyzes highly unusual non-aromatic enol methylation from kratom and several other species, which are required in kratom opioids biosynthesis. With unnatural substrate 4-hydroxytryptamine, we further showed the biosynthesis of mitragynine and its epimer speciogynine using these characterized enzymes. The promiscuity of kratom opioid biosynthetic enzymes suggests that derivatives and analogs of kratom opioids may be manufactured in heterologous systems with appropriate enzymes and substrates.
Quantitative measures of topographic and divergent/convergent connectivity in diffusion MRI of the human cerebral cortex
Authors: Shi Liang , Woodward Alexander , Igarashi Jun
Published: December 2022

Spatial features of connections, such as topography and divergence/convergence, reflect the information-processing mechanisms crucial for understanding and modeling the brain. However, this has not yet been comprehensively investigated. Using diffusion Magnetic Resonance Imaging (dMRI) data, we developed a topographic factor (TF) and divergence/convergence factor (DC) to quantitatively explore the spatial connectivity patterns of one entire hemisphere of the human cerebral cortex. In the analysis, the early sensory areas, which are located far away from the center of the cerebral cortex, exhibited high topographic connectivity. In contrast, the limbic system, which is located proximal to the center, showed high divergence/convergence in two types of connectivity: one region to another region at the region-to-region level, and one region to all other regions at the global level. Topography had anti-correlation with divergence/convergence over the cerebral cortex, and the two types of divergence/convergence displayed positive correlation with each other. These results suggest that topographic and divergent/convergent connectivity are spatially organized with respect to cytoarchitecture over the cerebral cortex to optimize energy efficiency and information transfer performance in the cerebral cortex.
Peering down the sink: A review of isoprene metabolism by bacteria
Authors: Dawson Robin A. , Crombie Andrew T. , Jansen Robert S. , Smith Thomas J. , Nichol Tim , Murrell Colin
Published: December 2022

Isoprene (2‐methyl‐1,3‐butadiene) is emitted to the atmosphere each year in sufficient quantities to rival methane (>500 Tg C yr−1), primarily due to emission by trees and other plants. Chemical reactions of isoprene with other atmospheric compounds, such as hydroxyl radicals and inorganic nitrogen species (NOx), have implications for global warming and local air quality, respectively. For many years, it has been estimated that soil‐dwelling bacteria consume a significant amount of isoprene (~20 Tg C yr−1), but the mechanisms underlying the biological sink for isoprene have been poorly understood. Studies have indicated or confirmed the ability of diverse bacterial genera to degrade isoprene, whether by the canonical iso‐type isoprene degradation pathway or through other less well‐characterized mechanisms. Here, we review current knowledge of isoprene metabolism and highlight key areas for further research. In particular, examples of isoprene‐degraders that do not utilize the isoprene monooxygenase have been identified in recent years. This has fascinating implications both for the mechanism of isoprene uptake by bacteria, and also for the ecology of isoprene‐degraders in the environments.
Pseudomonas aeruginosa and its multiple strategies to access iron
Authors: Schalk Isabelle J. , Perraud Quentin
Published: December 2022

Pseudomonas aeruginosa is a ubiquitous bacterium found in many natural and man‐made environments. It is also a pathogen for plants, animals, and humans. As for almost all living organisms, iron is an essential nutrient for the growth of P. aeruginosa. The bacterium has evolved complex systems to access iron and maintain its homeostasis to survive in diverse natural and dynamic host environments. To access ferric iron, P. aeruginosa is able to produce two siderophores (pyoverdine and pyochelin), as well as use a variety of siderophores produced by other bacteria (mycobactins, enterobactin, ferrioxamine, ferrichrome, vibriobactin, aerobactin, rhizobactin and schizokinen). Furthermore, it can also use citrate, in addition to catecholamine neuromediators and plant‐derived mono catechols, as siderophores. The P. aeruginosa genome also encodes three heme‐uptake pathways (heme being an iron source) and one ferrous iron acquisition pathway. This review aims to summarize current knowledge concerning the molecular mechanisms involved in all the iron and heme acquisition strategies used by P. aeruginosa.