Developmental and therapeutic implications of IL4ra expression for rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a solid tumor whose metastatic progression can be accelerated through interleukin-4 receptor alpha (Il4ra) mediated interaction with normal muscle stem cells (satellite cells). To understand the function of Il4ra in this tumor initiation phase of RMS, we conditionally deleted Il4ra in genetically-engineered RMS mouse models. Nullizygosity of Il4ra altered the latency, site and/or stage distribution of RMS tumors compared to IL4RA intact models. Primary tumor cell cultures taken from the genetically-engineered models then used in orthotopic allografts further defined the interaction of satellite cells and RMS tumor cells in the context of tumor initiation: in alveolar rhabdomyosarcoma (ARMS), satellite cell co-injection was necessary for Il4ra null tumor cells engraftment, whereas in embryonal rhabdomyosarcoma (ERMS), satellite cell co-injection decreased latency of engraftment of Il4ra wildtype tumor cells but not Il4ra null tumor cells. When refocusing on Il4ra wildtype tumors by single cell sequencing and cytokine studies, we have uncovered a putative signaling interplay of Il4 from T-lymphocytes being received by Il4ra + rhabdomyosarcoma tumor cells, which in turn express Ccl2, the ligand for Ccr2 and Ccr5. Taken together, these results suggest that mutations imposed during tumor initiation have different effects than genetic or therapeutic intervention imposed once tumors are already formed. We also propose that CCL2 and its cognate receptors CCR2 and/or CCR5 are potential therapeutic targets in Il4ra mediated RMS progression.

Exploring deep caries management and barriers to the use of vital pulp treatments by primary care dental practitioners.

AIM: The European Society of Endodontology outlines best practices for the management of deep caries and the pulp. Despite evidence supporting vital pulp treatments (VPTs) as predictable alternatives to conventional endodontic treatment, studies have shown they are not widely adopted in the UK. This study aimed to explore the barriers to implementation of VPTs by primary care general dental practitioners (GDPs). METHODOLOGY: Qualitative one-to-one semi-structured online interviews were conducted with purposively sampled UK GDPs. Interview transcripts were analysed using reflexive thematic analysis. Recurring themes were iteratively refined as additional transcripts were reviewed. RESULTS: Eleven participants were interviewed. A range of barriers to the provision of VPTs were identified, which aligned with two core themes: 'Motivational barriers to service provision' and 'Educational access & opportunities'. Sub-themes included lack of access to materials and equipment, deficiencies in knowledge of treatment (including protocols, outcomes and prognosis), lack of confidence (in treatment efficacy and clinical ability), time constraints and public dental service funding and remuneration. CONCLUSIONS: This study identifies barriers to the widespread adoption of VPTs among primary care GDPs in public and private settings. Economic constraints, practitioner confidence, time limitations and educational gaps are key challenges. Addressing these may require systemic changes such as policy interventions, education and improved resource allocation.

Epistasis and pleiotropy-induced variation for plant breeding.

Epistasis refers to nonallelic interaction between genes that cause bias in estimates of genetic parameters for a phenotype with interactions of two or more genes affecting the same trait. Partitioning of epistatic effects allows true estimation of the genetic parameters affecting phenotypes. Multigenic variation plays a central role in the evolution of complex characteristics, among which pleiotropy, where a single gene affects several phenotypic characters, has a large influence. While pleiotropic interactions provide functional specificity, they increase the challenge of gene discovery and functional analysis. Overcoming pleiotropy-based phenotypic trade-offs offers potential for assisting breeding for complex traits. Modelling higher order nonallelic epistatic interaction, pleiotropy and non-pleiotropy-induced variation, and genotype × environment interaction in genomic selection may provide new paths to increase the productivity and stress tolerance for next generation of crop cultivars. Advances in statistical models, software and algorithm developments, and genomic research have facilitated dissecting the nature and extent of pleiotropy and epistasis. We overview emerging approaches to exploit positive (and avoid negative) epistatic and pleiotropic interactions in a plant breeding context, including developing avenues of artificial intelligence, novel exploitation of large-scale genomics and phenomics data, and involvement of genes with minor effects to analyse epistatic interactions and pleiotropic quantitative trait loci, including missing heritability.

The association of maternal factors with the neonatal microbiota and health.

The human microbiome plays a crucial role in human health. However, the influence of maternal factors on the neonatal microbiota remains obscure. Herein, our observations suggest that the neonatal microbiotas, particularly the buccal microbiota, change rapidly within 24-48 h of birth but begin to stabilize by 48-72 h after parturition. Network analysis clustered over 200 maternal factors into thirteen distinct groups, and most associated factors were in the same group. Multiple maternal factor groups were associated with the neonatal buccal, rectal, and stool microbiotas. Particularly, a higher maternal inflammatory state and a lower maternal socioeconomic position were associated with a higher alpha diversity of the neonatal buccal microbiota and beta diversity of the neonatal stool microbiota was influenced by maternal diet and cesarean section by 24-72 h postpartum. The risk of admission of a neonate to the newborn intensive care unit was associated with preterm birth as well as higher cytokine levels and probably higher alpha diversity of the maternal buccal microbiota.

Elemental Composition of Commercially Available Cannabis Rolling Papers.

With the recent legalization of cannabis in multiple jurisdictions and widespread use as a medical treatment, there has been an increased focus on product safety and the potential impacts of contaminants on human health. One factor that has received little attention is the possible exposure to potentially hazardous levels of toxic elements from rolling (smoking) papers. The elemental composition of rolling papers is largely unregulated, with a minority of jurisdictions regulating papers only when they are part of a final cannabis product. This study reports the concentrations of 26 elements in commercially available rolling papers and estimates potential maximum exposures relative to USP232 and ICH Q3D dosages in pharmaceutical compounds. Exposure estimates indicate that the concentrations of several elements in some products, particularly Cu, Cr, and V, may present a potential hazard to frequent users. Several elements, including Ag, Ca, Ba, Cu, Ti, Cr, Sb, and possibly others, are likely present in elevated quantities in some papers due to product design and manufacturing processes. Our results further suggest that Cu-based pigments are used by a number of manufacturers and that regular use of these products might result in exposures as high as 4.5-11 times the maximum exposure limits. Further research to quantify the contribution of rolling papers to elemental exposure under realistic smoking conditions is warranted.

Root canal re-treatment with gutta percha - which techniques influence success?

OBJECTIVE: A systematic review and meta-analysis of the literature was carried out assessing the success rate of root canal retreatment using gutta percha. DATA SOURCES: Four of the largest databases were used to identify existing literature with no date or language restrictions. PubMed, Cochrane, ScienceDirect, Scopus and other additional sources were searched. Grey literature was also reviewed. STUDY SELECTION: Two authors, with Master's degrees in endodontics and with extensive university teaching experience, were selected to screen the databases to identify suitable studies. In case the authors were not able to agree during the study selection process, a third investigator was consulted. Specific inclusion and exclusion criteria were outlined and adhered to in the study selection. Two randomised controlled trials, seven single arm prospective studies and one single arm ambispective study published before the 10th of December 2022 were included. These studies evaluated the success of root canal re-treatment, obturated with gutta percha with at least a 1-year follow-up. Nine of the studies were published between 1998 and 2022. Seven studies were conducted in Europe, one in North America and one in Asia. DATA EXTRACTION AND SYNTHESIS: Standard Cochrane methods to assess interval validity were used. Risk of bias in individual studies was assessed using The Newcastle-Ottawa quality assessment scale (NOS) for single-arm studies, and the Cochrane risk of bias tool (RoB2) was used for randomised controlled trials. Outcome measures were standardised as either success or failure of root canal retreatment. Success was classified into 2 different criteria: Strict criteria = absence of clinical signs and symptoms and radiographically normal periodontal ligament space; and Loose criteria = absence of clinical signs and symptoms and absence or reduction of apical radiolucency in the control radiograph. Statistical analysis was undertaken using R software and the Freeman-Turkey transformation was performed. Results were visualised using forest plots. Heterogeneity between studies was measured using the Cochrane Q test and I2 values. RESULTS: Whilst following strict criteria, the success rate of non-surgical root canal retreatment obturated with gutta percha was 71% for 1-3 years follow-up (95% CI, 0.66-0.77) and 77% for 4-5 years follow-up (95% CI, 0.67-0.86). Heterogeneity was moderate (I2 = 61.4) and low (I2 = 0.0), respectively. Factors reducing the success rate of root canal re-retreatment under the strict criteria were older patients, mandibular teeth, molar teeth, the presence of a peri-apical radiolucency, teeth with a previous radiolucency, large peri-apical radiolucency's, higher initial periapical index scores and multiple visit-retreatments. Following the loose criteria, the success rate of non-surgical root canal re-treatment obturated with gutta percha was 87% for 1-3 years follow-up (95% CI, 0.79-0.93) with significant heterogeneity across the studies (I2 = 88.5%). Factors influencing the success rate under the loose criteria were large periapical lesions >5 mm and higher initial periapical index (PAI) scores. CONCLUSIONS: Non-surgical root canal retreatment results in favourable outcomes. However, there are several factors which can result in a lower success rate: the presence and size of a periapical radiolucency, a higher initial PAI score, multiple-visit retreatments, and the size and position of the tooth.

Cicer super-pangenome provides insights into species evolution and agronomic trait loci for crop improvement in chickpea.

Chickpea (Cicer arietinum L.)-an important legume crop cultivated in arid and semiarid regions-has limited genetic diversity. Efforts are being undertaken to broaden its diversity by utilizing its wild relatives, which remain largely unexplored. Here, we present the Cicer super-pangenome based on the de novo genome assemblies of eight annual Cicer wild species. We identified 24,827 gene families, including 14,748 core, 2,958 softcore, 6,212 dispensable and 909 species-specific gene families. The dispensable genome was enriched for genes related to key agronomic traits. Structural variations between cultivated and wild genomes were used to construct a graph-based genome, revealing variations in genes affecting traits such as flowering time, vernalization and disease resistance. These variations will facilitate the transfer of valuable traits from wild Cicer species into elite chickpea varieties through marker-assisted selection or gene-editing. This study offers valuable insights into the genetic diversity and potential avenues for crop improvement in chickpea.

The complex relationship between disease resistance and yield in crops.

In plants, growth and defence are controlled by many molecular pathways that are antagonistic to one another. This results in a 'growth-defence trade-off', where plants temporarily reduce growth in response to pests or diseases. Due to this antagonism, genetic variants that improve resistance often reduce growth and vice versa. Therefore, in natural populations, the most disease resistant individuals are often the slowest growing. In crops, slow growth may translate into a yield penalty, but resistance is essential for protecting yield in the presence of disease. Therefore, plant breeders must balance these traits to ensure optimal yield potential and yield stability. In crops, both qualitative and quantitative disease resistance are often linked with genetic variants that cause yield penalties, but this is not always the case. Furthermore, both crop yield and disease resistance are complex traits influenced by many aspects of the plant's physiology, morphology and environment, and the relationship between the molecular growth-defence trade-off and disease resistance-yield antagonism is not well-understood. In this article, we highlight research from the last 2 years on the molecular mechanistic basis of the antagonism between defence and growth. We then discuss the interaction between disease resistance and crop yield from a breeding perspective, outlining the complexity and nuances of this relationship and where research can aid practical methods for simultaneous improvement of yield potential and disease resistance.

Unbiased metastatic niche-labeling identifies estrogen receptor-positive macrophages as a barrier of T cell infiltration during bone colonization.

Microenvironment niches determine cellular fates of metastatic cancer cells. However, robust and unbiased approaches to identify niche components and their molecular profiles are lacking. We established Sortase A-Based Microenvironment Niche Tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastatic colonization. SAMENT was applied to multiple cancer models colonizing the same organ and the same cancer to different organs. Common metastatic niche features include macrophage enrichment and T cell depletion. Macrophage niches are phenotypically diverse between different organs. In bone, macrophages express the estrogen receptor alpha (ERα) and exhibit active ERα signaling in male and female hosts. Conditional knockout of Esr1 in macrophages significantly retarded bone colonization by allowing T cell infiltration. ERα expression was also discovered in human bone metastases of both genders. Collectively, we identified a unique population of ERα+ macrophages in the metastatic niche and functionally tied ERα signaling in macrophages to T cell exclusion during metastatic colonization. HIGHLIGHTS: SAMENT is a robust metastatic niche-labeling approach amenable to single-cell omics.Metastatic niches are typically enriched with macrophages and depleted of T cells.Direct interaction with cancer cells induces ERα expression in niche macrophages. Knockout of Esr1 in macrophages allows T cell infiltration and retards bone colonization.

Biodiversity is central for restoration.

The global restoration agenda can help solve the biodiversity extinction crisis by regenerating biodiversity-rich ecosystems, maximising conservation benefits using natural regeneration. Yet, conservation is rarely the core objective of restoration, and biodiversity is often neglected in restoration projects targeted towards carbon sequestration or enhancing ecosystem services for improved local livelihoods. Here, we synthesise evidence to show that promoting biodiversity in restoration planning and delivery is integral to delivering other long-term restoration aims, such as carbon sequestration, timber production, enhanced local farm yields, reduced soil erosion, recovered hydrological services and improved human health. For each of these restoration goals, biodiversity must be a keystone objective to the entire process. Biodiversity integration requires improved evidence and action, delivered via a socio-ecological process operating at landscape scales and backed by supportive regulations and finance. Conceiving restoration and biodiversity conservation as synergistic, mutually reinforcing partners is critical for humanity's bids to tackle the global crises of climate change, land degradation and biodiversity extinction.

Serogroup B Invasive Meningococcal Disease in Older Adults Identified by Genomic Surveillance, England, 2022-2023.

We report a cluster of serogroup B invasive meningococcal disease identified via genomic surveillance in older adults in England and describe the public health responses. Genomic surveillance is critical for supporting public health investigations and detecting the growing threat of serogroup B Neisseria meningitidis infections in older adults.

Technological Development and Advances for Constructing and Analyzing Plant Pangenomes.

A pangenome captures the genomic diversity for a species, derived from a collection of genetic sequences of diverse populations. Advances in sequencing technologies have given rise to three primary methods for pangenome construction and analysis: de novo assembly and comparison, reference genome-based iterative assembly, and graph-based pangenome construction. Each method presents advantages and challenges in processing varying amounts and structures of DNA sequencing data. With the emergence of high-quality genome assemblies and advanced bioinformatic tools, the graph-based pangenome is emerging as an advanced reference for exploring the biological and functional implications of genetic variations.

Other Secondary Headaches: Odontogenic Pain and Other Painful Orofacial Conditions.

This article discusses extremely common odontogenic pain conditions, which may occasionally present to the neurology clinic mimicking headache, and other uncommon orofacial pain conditions, which may do the same. Typical presentations, investigative strategies, and management are discussed, as well as highlighting key diagnostic criteria and the importance of involving oral or dental specialists where diagnostic uncertainty exists.

Ecology: A few species dominate forest tree abundance pan-tropically.

An analysis of over 1 million old-growth tropical forest trees reveals that ∼2.2% of species comprise 50% of the individuals in Africa, Amazonia, and Southeast Asia, suggesting that the ecological mechanisms underpinning tree community assembly are ubiquitous across the tropics.

Conflicts and opportunities for commercial tree plantation expansion and biodiversity restoration across Brazil.

Substantial global restoration commitments are occurring alongside a rapid expansion in land-hungry tropical commodities, including to supply increasing demand for wood products. Future commercial tree plantations may deliver high timber yields, shrinking the footprint of production forestry, but there is an as-yet unquantified risk that plantations may expand into priority restoration areas, with marked environmental costs. Focusing on Brazil-a country of exceptional restoration importance and one of the largest tropical timber producers-we use random forest models and information on the economic, social, and spatial drivers of historic commercial tree plantation expansion to estimate and map the probability of future monoculture tree plantation expansion between 2020 and 2030. We then evaluate potential plantation-restoration conflicts and opportunities at national and biome-scales and under different future production and restoration pathways. Our simulations show that of 2.8 Mha of future plantation expansion (equivalent to plantation expansion 2010-2020), ~78,000 ha (3%) is forecast to occur in the top 1% of restoration priority areas for terrestrial vertebrates, with ~547,500 ha (20%) and ~1,300,000 ha (46%) in the top 10% and 30% of priority areas, respectively. Just ~459,000 ha (16%) of expansion is forecast within low-restoration areas (bottom 30% restoration priorities), and the first 1 Mha of plantation expansion is likely to have disproportionate impacts, with potential restoration-plantation overlap starkest in the Atlantic Forest but prominent in the Pampas and Cerrado as well. Our findings suggest that robust, coherent land-use policies must be deployed to ensure that significant trade-offs between restoration and production objectives are navigated, and that commodity expansion does not undermine the most tractable conservation gains under emerging global restoration agendas. They also highlight the potentially significant role an engaged forestry sector could play in improving biodiversity outcomes in restoration projects in Brazil, and presumably elsewhere.

Hypertonic Aerosols Hydrate Airways Longer and Reduce Acidification Risk with Nonpermeating Cation and Permeating Anion Salts.

Background: Hyperosmolar aerosols appear to promote or suppress upper airway dysfunction caused by dehydration in a composition-dependent manner. We sought to explore this composition dependence experimentally, in an interventional human clinical study, and theoretically, by numerical analysis of upper airway ion and water transport. Methods: In a double-blinded, placebo-controlled clinical study, phonation threshold pressure (PTP) was measured prenasal and postnasal inhalation of hypertonic aerosols of NaCl, KCl, CaCl2, and MgCl2 in seven human subjects. Numerical analysis of water and solute exchanges in the upper airways following deposition of these same aerosols was performed using a mathematical model previously described in the literature. Results: PTP decreased by 9%-22% relative to baseline (p < 0.05) for all salts within the first 30 minutes postadministration, indicating effective laryngeal hydration. Only MgCl2 reduced PTP beyond 90 minutes (21% below baseline at 2 hours postadministration). By numerical analysis, we determined that, while airway water volume up to 15 minutes postdeposition is dictated by osmolarity, after 30 minutes, divalent cation salts, such as MgCl2, better retain airway surface liquid (ASL) volume by slow paracellular clearance of the divalent cation. Fall of CFTR chloride flux with rise in ASL height, a promoter of airway acidification, appears to be a signature of permeating cation (NaCl) and nonpermeating anion (mannitol) aerosol deposition. For hypertonic aerosols that lack permeating cation and include permeating anion (CaCl2 and MgCl2), this acid-trigger signature does not exist. Conclusions: Nonpermeating cation and permeating anion hypertonic aerosols appear to hydrate upper airways longer and, rather than provoke, may reduce laryngeal dysfunction such as cough and bronchoconstriction.

CD8+ T-cell metabolism is related to cerebrovascular reactivity in middle-aged adults.

Cerebrovascular reactivity (CVR) decreases with advancing age, contributing to increased risk of cognitive impairment; however, the mechanisms underlying the age-related decrease in CVR are incompletely understood. Age-related changes to T cells, such as impaired mitochondrial respiration, increased inflammation, likely contribute to peripheral and cerebrovascular dysfunction in animals. However, whether T-cell mitochondrial respiration is related to cerebrovascular function in humans is not known. Therefore, we hypothesized that peripheral T-cell mitochondrial respiration would be positively associated with CVR and that T-cell glycolytic metabolism would be negatively associated with CVR. Twenty middle-aged adults (58 ± 5 yr) were recruited for this study. T cells were separated from peripheral blood mononuclear cells. Cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR, a marker of glycolytic activity) were measured using extracellular flux analysis. CVR was quantified using the breath-hold index (BHI), which reflects the change in blood velocity in the middle-cerebral artery (MCAv) during a 30-s breath-hold. In contrast to our hypothesis, we found that basal OCR in CD8+ T cells (ß = -0.59, R2 = 0.27, P = 0.019) was negatively associated with BHI. However, in accordance with our hypothesis, we found that basal ECAR (ß = -2.20, R2 = 0.29, P = 0.015) and maximum ECAR (ß = -50, R2 = 0.24, P = 0.029) were negatively associated with BHI in CD8+ T cells. There were no associations observed in CD4+ T cells. These associations appeared to be primarily mediated by an association with the pressor response to the breath-hold test. Overall, our findings suggest that CD8+ T-cell respiration and glycolytic activity may influence CVR in humans.NEW & NOTEWORTHY Peripheral T-cell metabolism is related to in vivo cerebrovascular reactivity in humans. Higher glycolytic metabolism in CD8+ T cells was associated with lower cerebrovascular reactivity to a breath-hold in middle-aged adults, which is possibly reflective of a more proinflammatory state in midlife.