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Abstract Non-masticatory labial striations on human anterior teeth are a form of cultural dental wear well recorded throughout the Pleistocene, which has been interpreted as resulting from the use of the mouth as a ‘third hand’ when processing different materials during daily activities, such as cutting meat or working hides with stone tools. Non-masticatory scratches have also been reported on the buccal surface of molars and premolars, although at a far lower frequency compared to the anterior dentition. Previous studies observed an apparent decrease through time in the occurrence of non-masticatory scratches on human teeth, with labial striations appearing to be rare for the Neolithic compared to earlier periods. This study further tests this previously observed pattern through the analysis of over 900 human teeth from 20 sites across England and Wales dating from the Upper Palaeolithic, Mesolithic, and Neolithic, to discuss the distribution and aetiology of non-masticatory striations in the British archaeological record. To record and assess the micro-morphometric characteristics of these dental alterations, macroscopic and microscopic analytical techniques were used. Results show that non-masticatory labial striations are still found on Neolithic teeth, although at a decreased frequency when compared to hunter-gatherer (Upper Palaeolithic and Mesolithic) samples. This may be partly due to changes in diets and food processing methods, as well as types of processed materials and changes in manual handling arising from the inception of the Neolithic in Britain. The sample also includes Upper Palaeolithic, Mesolithic and Neolithic teeth with non-masticatory striations likely associated with funerary practices or cannibalistic treatment of cadavers. Analyses of these marks suggest that striations inflicted during the post-mortem cutting of cadavers from cannibalism or funerary practices differ in their location and micro-morphology, compared with non-masticatory striations produced during the life of an individual using the mouth as a ‘third hand’.

Abstract Stem cells show intrinsic interferon signalling, which protects them from viral infections at all ages. In the ageing brain, interferon signalling also reduces the ability of stem cells to activate. Whether these functions are linked and at what time interferons start taking on a role in stem cell functioning is unknown. Additionally, the molecular link between interferons and activation in neural stem cells and how this relates to progenitor production is not well understood. Here we combine single‐cell transcriptomics, RiboSeq and mathematical models of interferon to show that this pathway is important for proper stem cell function at all ages in mice. Interferon orchestrates cell cycle and mTOR activity to post‐transcriptionally repress Sox2 and induces quiescence. The interferon response then decreases in the subsequent maturation states. Mathematical simulations indicate that this regulation is beneficial for the young and harmful for the old brain. Our study establishes molecular mechanisms of interferon in stem cells and interferons as genuine regulators of stem cell homeostasis and a potential therapeutic target to repair the ageing brain.

Abstract The malaria parasite, Plasmodiumfalciparum, proliferates rapidly in human erythrocytes by actively scavenging multiple carbon sources and essential nutrients from its host cell. However, a global overview of the metabolic capacity of intraerythrocytic stages is missing. Using multiplex 13C‐labelling coupled with untargeted mass spectrometry and unsupervised isotopologue grouping, we have generated a draft metabolome of P.falciparum and its host erythrocyte consisting of 911 and 577 metabolites, respectively, corresponding to 41% of metabolites and over 70% of the metabolic reaction predicted from the parasite genome. An additional 89 metabolites and 92 reactions were identified that were not predicted from genomic reconstructions, with the largest group being associated with metabolite damage‐repair systems. Validation of the draft metabolome revealed four previously uncharacterised enzymes which impact isoprenoid biosynthesis, lipid homeostasis and mitochondrial metabolism and are necessary for parasite development and proliferation. This study defines the metabolic fate of multiple carbon sources in P.falciparum, and highlights the activity of metabolite repair pathways in these rapidly growing parasite stages, opening new avenues for drug discovery.

Abstract Functional studies giving insight into the biology of circulating tumor cells (CTCs) remain scarce due to the low frequency of CTCs and lack of appropriate models. Here, we describe the characterization of a novel CTC‐derived breast cancer cell line, designated CTC‐ITB‐01, established from a patient with metastatic estrogen receptor‐positive (ER+) breast cancer, resistant to endocrine therapy. CTC‐ITB‐01 remained ER+ in culture, and copy number alteration (CNA) profiling showed high concordance between CTC‐ITB‐01 and CTCs originally present in the patient with cancer at the time point of blood draw. RNA‐sequencing data indicate that CTC‐ITB‐01 has a predominantly epithelial expression signature. Primary tumor and metastasis formation in an intraductal PDX mouse model mirrored the clinical progression of ER+ breast cancer. Downstream ER signaling was constitutively active in CTC‐ITB‐01 independent of ligand availability, and the CDK4/6 inhibitor Palbociclib strongly inhibited CTC‐ITB‐01 growth. Thus, we established a functional model that opens a new avenue to study CTC biology.

Abstract The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off‐target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first‐in‐class non‐cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR‐specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro‐inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space.

Abstract Cell‐to‐cell variability in gene expression is important for many processes in biology, including embryonic development and stem cell homeostasis. While heterogeneity of gene expression levels has been extensively studied, less attention has been paid to mRNA polyadenylation isoform choice. 3′ untranslated regions regulate mRNA fate, and their choice is tightly controlled during development, but how 3′ isoform usage varies within genetically and developmentally homogeneous cell populations has not been explored. Here, we perform genome‐wide quantification of polyadenylation site usage in single mouse embryonic and neural stem cells using a novel single‐cell transcriptomic method, BATSeq. By applying BATBayes, a statistical framework for analyzing single‐cell isoform data, we find that while the developmental state of the cell globally determines isoform usage, single cells from the same state differ in the choice of isoforms. Notably this variation exceeds random selection with equal preference in all cells, a finding that was confirmed by RNA FISH data. Variability in 3′ isoform choice has potential implications on functional cell‐to‐cell heterogeneity as well as utility in resolving cell populations.

Abstract Cancer metastasis is the main cause of cancer‐related death, and dissemination of tumor cells through the blood circulation is an important intermediate step that also exemplifies the switch from localized to systemic disease. Early detection and characterization of circulating tumor cells (CTCs) is therefore important as a general strategy to monitor and prevent the development of overt metastatic disease. Furthermore, sequential analysis of CTCs can provide clinically relevant information on the effectiveness and progression of systemic therapies (e.g., chemo‐, hormonal, or targeted therapies with antibodies or small inhibitors). Although many advances have been made regarding the detection and molecular characterization of CTCs, several challenges still exist that limit the current use of this important diagnostic approach. In this review, we discuss the biology of tumor cell dissemination, technical advances, as well as the challenges and potential clinical implications of CTC detection and characterization.

In the nutrient-poor soils of the Amazon rainforest, phosphorus (P) emerges as a critical limiting factor for ecosystem productivity. Despite these limitations, the Amazon exhibits remarkable productivity that is maintained by its efficient nutrient recycling mechanisms. Central to this process is the role of organic matter, particularly its dissolved (DOM) fraction, which serves as a crucial nutrient reservoir for both plants and microorganisms. This study delves into the dynamics of nutrient-containing DOM within the soils of two contrasting rainforest ecosystems: clayey terra firme forests, known for their robust nutrient recycling and presumed P-limitation, and sandy white-sand forests, characterized by reduced nutrient recycling capacity and presumed nitrogen (N)-limitation. Utilizing ultra-high resolution mass spectrometry (HR-MS), we analyzed the molecular composition of dissolved organic nutrient species. We evidenced nutrient limitation applying innovative concepts: (1) assessing nutrient depletion in DOM via nutrient-to-carbon ratios, (2) comparing the composition of nutrient-enriched DOM pools across soil depth profiles to infer microbial nutrient processing, and (3) examining the temporal variability of nutrient-containing DOM as an indicator of nutrient uptake and production. Our results corroborate the hypothesis of P-limitation in terra firme forests, with significant processing of N-containing DOM also observed, indicating a synergistic demand for both P and N. Surprisingly, white-sand soils exhibited no signs of N-limitation but instead sulfur (S)-limitation, a novel finding for these ecosystems. This study highlights the diversity of potential nutrient limitations in the central Amazon and the importance of the bioavailable "black box" DOM for tropical nutrient cycles. [ABSTRACT FROM AUTHOR]

This study examined whether autistic people with siblings score higher on measures of empathy than those without siblings. Cohorts of autistic children (n = 939; mean age = 7.35 years (SD = 2.15)) and autistic adults (n = 736; mean age = 37 years (SD = 12.39)) from the Cambridge Autism Research Database (CARD) were each divided into two groups: with or without siblings. Empathy was measured using the children version of the Empathy Quotient (EQ) (parent-report) for children. For adults, the EQ (self-report version) and the Reading the Mind in the Eyes Test (RMET) were used. Contrary to the hypothesis, autistic children without siblings scored higher on EQ than those with siblings (t(283.70) = 4.20, p <.001; d = 0.50). In adults, there was no difference between autistic adults with and without siblings on both measures, but there was an interaction effect between sex and group on the RMET (f(1732) = 4.10, p = 0.04): whilst autistic males without siblings on average scored lower than females, autistic males with siblings on average performed similarly to females. Future research should investigate the possible effect of siblings on autistic males' empathy performance in a larger cohort of autistic individuals. Children's empathic abilities may be underestimated by their parents when they have siblings due to a contrast effect. [ABSTRACT FROM AUTHOR]

The long-term consequences of cancer and its therapy on the patients' immune system years after cancer-free survival remain poorly understood. Here, we present an in-depth characterization of the bone marrow immune ecosystem of multiple myeloma long-term survivors, from initial diagnosis up to 17 years following a single therapy line and cancer-free survival. Using comparative single-cell analyses combined with molecular, genomic, and functional approaches, we demonstrate that multiple myeloma long-term survivors exhibit pronounced alterations in their bone marrow microenvironment associated with impaired immunity. These immunological alterations were frequently linked to an inflammatory immune circuit fueled by the long-term persistence or resurgence of residual myeloma cells. Notably, even in the complete absence of any detectable residual disease for decades, sustained changes in the immune system were observed, suggesting an irreversible 'immunological scarring' caused by the initial exposure to the cancer and therapy. Collectively, our study provides key insights into the molecular and cellular bone marrow ecosystem of long-term survivors of multiple myeloma, revealing both reversible and irreversible alterations in the immune compartment. Understanding the immunological underpinnings of long-term survival in cancer is of high interest. Here, authors dissect the immune parameters of multiple myeloma long-term survivors following a single line of therapy longitudinally, and find sustained changes, including inflammation and impaired immune function. [ABSTRACT FROM AUTHOR]

Thyroid transcription factor 1 (TTF-1) immunohistochemistry (IHC) is routinely used for the distinction of primary pulmonary adenocarcinomas. However, TTF-1 can also occur in other malignancies. A tissue microarray containing 17,772 samples from 152 different tumor types was analyzed. Napsin-A, CK20, SATB2, FABP1, and Villin-1 IHC data were available from previous studies. TTF-1 staining was seen in 82 of 152 tumor categories including thyroidal cancers (19–100%), adenocarcinomas (94%), neuroendocrine tumors (67%) of the lung, small cell neuroendocrine carcinomas (71–80%), mesenchymal tumors (up to 42%), and thymomas (39%). Comparative analysis of TTF-1 and Napsin-A revealed a sensitivity/specificity of 94%/86% (TTF-1), 87%/98% (Napsin-A), and 85%/99.1% (TTF-1 and Napsin-A) for the distinction of pulmonary adenocarcinomas. Combined analysis of TTF-1 and enteric markers revealed a positivity for TTF-1 and at least one enteric marker in 22% of pulmonary adenocarcinomas but also a TTF-1 positivity in 6% of colorectal, 2% of pancreatic, and 3% of gastric adenocarcinomas. TTF-1 is a marker of high sensitivity but insufficient specificity for pulmonary adenocarcinomas. A small fraction of TTF-1-positive gastrointestinal adenocarcinomas represents a pitfall mimicking enteric-type pulmonary adenocarcinoma. Combined analysis of TTF-1 and Napsin-A improves the specificity of pulmonary adenocarcinoma diagnosis. [ABSTRACT FROM AUTHOR]

The ultrashort and intense pulses of X-rays produced at X-ray free electron lasers (XFELs) have enabled unique experiments on the atomic level structure and dynamics of matter, with time-resolved studies permitted in the femto- and attosecond regimes. To fully exploit them, it is paramount to obtain a comprehensive understanding of the complex nonlinear interactions that can occur at such extreme X-ray intensities. Herein, we report on the experimental observation of a resonant double-core excitation scheme in N2, where two 1σ core-level electrons are resonantly promoted to unoccupied 1 π g * molecular orbitals by a single few-femtosecond broad-bandwidth XFEL pulse. The production of these neutral two-site double core hole states is evidenced through their characteristic decay channels, which are observed in good agreement with high-level theoretical calculations. Such multi-core excitation schemes, benefiting from the high interaction cross sections and state- and site-selective nature of resonant X-ray interactions, should be generally accessible in XFEL irradiated molecules, and provide interesting opportunities for chemical analysis and for monitoring ultrafast dynamic processes. XFELs can drive multicore-ionization/excitation processes in the fs timescale of typical core-hole lifetimes in molecules. This paper reports experimental evidence of a single XFEL-pulse-driven resonant double-core excitation mechanism, producing a neutral two-site double-core-hole state in the nitrogen molecule. [ABSTRACT FROM AUTHOR]

Introduction: In sarcoidosis granulomas, monocyte-derived macrophages are activated by pro-inflammatory cytokines including TNF and IL-6. Current drug treatment for sarcoidosis aims to suppress inflammation but disabling side effects can ensue. The macrolide azithromycin may be anti-inflammatory. We aimed to determine whether treatment with azithromycin affects blood inflammatory gene expression and monocyte functions in sarcoidosis. Methods: Blood samples were collected from patients with chronic pulmonary sarcoidosis enrolled in a single arm, open label clinical trial who received oral azithromycin 250 mg once daily for 3 months. Whole blood inflammatory gene expression with or without LPS stimulation was measured using a 770-mRNA panel. Phenotypic analysis and cytokine production were conducted by flow cytometry and ELISA after 24h stimulation with growth factors and TLR ligands. mTOR activity was assessed by measuring phosphorylated S6RP. Results: Differential gene expression analysis indicated a state of heightened myeloid cell activation in sarcoidosis. Compared with controls, sarcoidosis patients showed increased LPS responses for several cytokines and chemokines. Treatment with azithromycin had minimal effect on blood gene expression overall, but supervised clustering analysis identified several chemokine genes that were upregulated. At the protein level, azithromycin treatment increased LPS-stimulated TNF and unstimulated IL-8 production. No other cytokines showed significant changes following azithromycin. Blood neutrophil counts fell during azithromycin treatment whereas mononuclear cells remained stable. Azithromycin had no detectable effects on mTOR activity or activation markers. Conclusion: Blood myeloid cells are activated in sarcoidosis, but azithromycin therapy did not suppress inflammatory gene expression or cytokine production in blood. Trial registration: EudraCT 2019-000580-24 (17 May 2019) [ABSTRACT FROM AUTHOR]

Purpose: Despite growing evidence for bilateral pelvic radiotherapy (whole pelvis RT, WPRT) there is almost no data on unilateral RT (hemi pelvis RT, HPRT) in patients with nodal recurrent prostate cancer after prostatectomy. Nevertheless, in clinical practice HPRT is sometimes used with the intention to reduce side effects compared to WPRT. Prostate-specific membrane antigen positron emission tomography / computed tomography (PSMA-PET/CT) is currently the best imaging modality in this clinical situation. This analysis compares PSMA-PET/CT based WPRT and HPRT. Methods: A propensity score matching was performed in a multi-institutional retrospective dataset of 273 patients treated with pelvic RT due to nodal recurrence (214 WPRT, 59 HPRT). In total, 102 patients (51 in each group) were included in the final analysis. Biochemical recurrence-free survival (BRFS) defined as prostate specific antigen (PSA) < post-RT nadir + 0.2ng/ml, metastasis-free survival (MFS) and nodal recurrence-free survival (NRFS) were calculated using the Kaplan-Meier method and compared using the log rank test. Results: Median follow-up was 29 months. After propensity matching, both groups were mostly well balanced. However, in the WPRT group there were still significantly more patients with additional local recurrences and biochemical persistence after prostatectomy. There were no significant differences between both groups in BRFS (p =.97), MFS (p =.43) and NRFS (p =.43). After two years, BRFS, MFS and NRFS were 61%, 86% and 88% in the WPRT group and 57%, 90% and 82% in the HPRT group, respectively. Application of a boost to lymph node metastases, a higher RT dose to the lymphatic pathways (> 50 Gy EQD2α/β=1.5 Gy) and concomitant androgen deprivation therapy (ADT) were significantly associated with longer BRFS in uni- and multivariate analysis. Conclusions: Overall, this analysis presents the outcome of HPRT in nodal recurrent prostate cancer patients and shows that it can result in a similar oncologic outcome compared to WPRT. Nevertheless, patients in the WPRT may have been at a higher risk for progression due to some persistent imbalances between the groups. Therefore, further research should prospectively evaluate which subgroups of patients are suitable for HPRT and if HPRT leads to a clinically significant reduction in toxicity. [ABSTRACT FROM AUTHOR]

Emotional support from family members may have an important effect on adolescent health outcomes, and has been identified as a target for policy to protect against the impacts of poverty and other early life adversities. However, few studies have assessed the extent to which poverty and adversity themselves influence the nature of emotional support that parents can provide to adolescents. We, therefore, aimed to investigate the impact of trajectories of income poverty and family adversities, including parental mental ill health, alcohol misuse and domestic violence across childhood developmental stages on young people's relationships with their families and perceived emotional support received. We analysed longitudinal data on 10,976 children from the nationally representative UK Millennium Cohort study. Exposure trajectories of poverty and family adversities were characterised using group-based multi-trajectory models (age 9 months–14 years). The outcomes were perceived emotional support and quality of family relationships, measured by the three-item Short Social Provisions Scale (SPS-3) and levels of parent–adolescent closeness and conflict, measured at age 14. ORs and 95% CIs were estimated using multivariable logistic regression models, adjusting for potential confounding factors. At age 14, the overall prevalence of low perceived emotional support was 13% (95% CI: 12, 14). Children of mothers with lower socioeconomic status (SES) were more likely to report low emotional support, with a clear social gradient (education—degree plus: 10.3% vs. no qualifications: 15.4%). Compared with children exposed to low levels of poverty and adversity, children in the persistent adversity trajectory groups experienced higher odds of low emotional support and low-quality parent–adolescent relationship; those exposed to both persistent poverty and poor parental mental health were particularly at increased risk of experiencing poor family relationships and low perceived emotional support (adjusted odds ratio 2·2; 95% CI 1·7–2·9). Low perceived emotional support and poor family relationships in adolescence are more prevalent among socially disadvantaged children and adolescents and those experiencing social adversity. Policies to improve levels of family support for UK adolescents should focus on improving modifiable determinants such as child poverty and family mental health. [ABSTRACT FROM AUTHOR]

Introduction: Ofatumumab (Kesimpta®) is a subcutaneous CD20-targeting antibody approved in Germany in 2021 for the treatment of relapsing multiple sclerosis (RMS). After careful instruction, patients can administer the treatment themselves. We previously reported data of 101 patients (Klimas et al. in Nervenarzt 94:923–933, 2023). The objective of this longitudinal study is to explore the tolerability and acceptability of ofatumumab from a patient perspective over a follow up period of 6 months. Methods: In this prospective observational real-world study, we report follow up data of 81 patients. We evaluated sociodemographic data, disease duration, duration and side effects of ofatumumab use, expanded disability status scale (EDSS), Beck Depression Inventory II (BDI-II), Short-Form 36 (SF-36), Fatigue Scale of Motor and Cognitive Functions (FSMC), and modified Multiple Sclerosis Functional Composite Test (MSFC). In addition, we asked for subjective treatment outcomes, such as impact on quality of life, walking distance, concentration, mood, medication adherence, fatigue and the subjective course of MS on a numerical rating scale (1 = very negative; 5 = very positive). Furthermore, treatment discontinuations were recorded. Results: The average duration of ofatumumab treatment was 10 months. In comparison to previous published data of our cohort, patients reported a significant increase in headache (10% up to 26%, p = 0.004) and limb pain (5% up to 26%, p < 0.001) as persistent side effects after the injections. More patients reported a very positive effect (p < 0.0001) on quality of life. 4 confirmed relapses occurred but no EDSS worsening, and no treatment discontinuations were documented during the observation period. Discussion: As previously described, our prospective study indicates that patients have a good tolerability of ofatumumab, precisely because of the mild and few side effects at the first administration. However, the longer the observation period, the more headaches and limb pain occurred after the injections. Despite this, patients' subjective quality of life improved. There were no discontinuations during the follow-up period, with the limitation of a high loss to follow-up. [ABSTRACT FROM AUTHOR]

Purpose: Previous studies have shown a higher recurrence rate and longer operative times for thoracoscopic repair (TR) of congenital diaphragmatic hernia (CDH) compared to open repair (OR). An updated meta-analysis was conducted to re-evaluate the surgical outcomes of TR. Methods: A comprehensive literature search comparing TR and OR in neonates was performed in accordance with the PRISMA statement (PROSPERO: CRD42020166588). Results: Fourteen studies were selected for quantitative analysis, including a total of 709 patients (TR: 308 cases, OR: 401 cases). The recurrence rate was higher [Odds ratio: 4.03, 95% CI (2.21, 7.36), p < 0.001] and operative times (minutes) were longer [Mean Difference (MD): 43.96, 95% CI (24.70, 63.22), p < 0.001] for TR compared to OR. A significant reduction in the occurrence of postoperative bowel obstruction was observed in TR (5.0%) compared to OR (14.8%) [Odds ratio: 0.42, 95% CI (0.20, 0.89), p = 0.02]. Conclusions: TR remains associated with higher recurrence rates and longer operative times. However, the reduced risk of postoperative bowel obstruction suggests potential long-term benefits. This study emphasizes the importance of meticulous patient selection for TR to mitigate detrimental effects on patients with severe disease. [ABSTRACT FROM AUTHOR]

Background: We evaluated the role of dual-energy computed tomography (DECT)-based collagen maps in assessing thoracic disc degeneration. Methods: We performed a retrospective analysis of patients who underwent DECT and magnetic resonance imaging (MRI) of the thoracic spine within a 2-week period from July 2019 to October 2022. Thoracic disc degeneration was classified by three blinded radiologists into three Pfirrmann categories: no/mild (grade 1–2), moderate (grade 3–4), and severe (grade 5). The DECT performance was determined using MRI as a reference standard. Interreader reliability was assessed using intraclass correlation coefficient (ICC). Five-point Likert scales were used to assess diagnostic confidence and image quality. Results: In total, 612 intervertebral discs across 51 patients aged 68 ± 16 years (mean ± standard deviation), 28 males and 23 females, were assessed. MRI revealed 135 no/mildly degenerated discs (22.1%), 470 moderately degenerated discs (76.8%), and 7 severely degenerated discs (1.1%). DECT collagen maps achieved an overall accuracy of 1,483/1,838 (80.8%) for thoracic disc degeneration. Overall recall (sensitivity) was 331/405 (81.7%) for detecting no/mild degeneration, 1,134/1,410 (80.4%) for moderate degeneration, and 18/21 (85.7%) for severe degeneration. Interrater agreement was good (ICC = 0.89). Assessment of DECT-based collagen maps demonstrated high diagnostic confidence (median 4; interquartile range 3–4) and good image quality (median 4; interquartile range 4–4). Conclusion: DECT showed an overall 81% accuracy for disc degeneration by visualizing differences in the collagen content of thoracic discs. Relevance statement: Utilizing DECT-based collagen maps to distinguish various stages of thoracic disc degeneration could be clinically relevant for early detection of disc-related conditions. This approach may be particularly beneficial when MRI is contraindicated. Key Points: A total of 612 intervertebral discs across 51 patients were retrospectively assessed with DECT, using MRI as a reference standard. DECT-based collagen maps allowed thoracic disc degeneration assessment achieving an overall 81% accuracy with good interrater agreement (ICC = 0.89). DECT-based collagen maps could be a good alternative in the case of contraindications to MRI. [ABSTRACT FROM AUTHOR]

Harnessing genetic diversity in major staple crops through the development of new breeding capabilities is essential to ensure food security1. Here we examined the genetic and phenotypic diversity of the A. E. Watkins landrace collection2 of bread wheat (Triticum aestivum), a major global cereal, by whole-genome re-sequencing of 827 Watkins landraces and 208 modern cultivars and in-depth field evaluation spanning a decade. We found that modern cultivars are derived from two of the seven ancestral groups of wheat and maintain very long-range haplotype integrity. The remaining five groups represent untapped genetic sources, providing access to landrace-specific alleles and haplotypes for breeding. Linkage disequilibrium-based haplotypes and association genetics analyses link Watkins genomes to the thousands of identified high-resolution quantitative trait loci and significant marker–trait associations. Using these structured germplasm, genotyping and informatics resources, we revealed many Watkins-unique beneficial haplotypes that can confer superior traits in modern wheat. Furthermore, we assessed the phenotypic effects of 44,338 Watkins-unique haplotypes, introgressed from 143 prioritized quantitative trait loci in the context of modern cultivars, bridging the gap between landrace diversity and current breeding. This study establishes a framework for systematically utilizing genetic diversity in crop improvement to achieve sustainable food security.Genomic and phenomic screens of 827 wheat landraces from the A. E. Watkins collection provide insight into the wheat population genetic background, unlocking many agronomic traits and revealing haplotypes that could potentially be used to improve modern wheat cultivars. [ABSTRACT FROM AUTHOR]

Wheat is an important source of minerals for human nutrition and increasing grain mineral content can contribute to reducing mineral deficiencies. Here, we identify QTLs for mineral micronutrients in grain of wheat by determining the contents of six minerals in a total of eleven sample sets of three biparental populations from crosses between A.E. Watkins landraces and cv. Paragon. Twenty-three of the QTLs are mapped in two or more sample sets, with LOD scores above five in at least one set with the increasing alleles for sixteen of the QTLs being present in the landraces and seven in Paragon. Of these QTLs, the number for each mineral varies between three and five and they are located on 14 of the 21 chromosomes, with clusters on chromosomes 5A (four), 6A (three), and 7A (three). The gene content within 5 megabases of DNA on either side of the marker for the QTL with the highest LOD score is determined and the gene responsible for the strongest QTL (chromosome 5A for Ca) identified as an ATPase transporter gene (TraesCS5A02G543300) using mutagenesis. The identification of these QTLs, together with associated SNP markers and candidate genes, will facilitate the improvement of grain nutritional quality. Landraces collected 100 years ago have been used to identify novel QTLs and candidate genes for essential mineral micronutrients in wheat, demonstrating the potential of exploiting diversity in older genotypes. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to compare the incidence, severity, and burden of injury in starting and replacement players from professional men's teams of five rugby unions. Methods: Match injuries of greater than 24 h time-loss (including data on the severity, match quarter, event, body region) and player minutes of match exposure data were collated for all starting and replacement players in the men's English Premiership, Welsh Pro14 (both 2016/17–2018/19 seasons), and Australian, New Zealand, and South African Super Rugby (all 2016–2018 seasons) teams. Injury incidences and mean injury burden (incidence × days missed) were calculated, and rate ratios (RRs) (95% confidence intervals [CIs]) were used to compare injury incidence and burden between starting (reference group) and replacement players. Results: Overall injury incidence was not different between starters and replacements for all injuries (RR = 0.98, 95% CI 0.88–1.10), nor for concussions (RR = 0.85; 95% CI 0.66–1.11). Mean injury burden was higher for replacement players (RR = 1.31, 95% CI 1.17–1.46). Replacement injury incidence was lower than the starters in the third (RR = 0.68, 95% CI 0.51–0.92) and fourth (RR = 0.78, 95% CI 0.67–0.92) match quarters. Injury incidence was not different between starters and replacements for any match event or body region, but compared with starters, replacements' injury burden was higher in lower limbs (RR = 1.24, 95% CI 1.05–1.46) and in the tackled player (RR = 1.30, 95% CI 1.01–1.66). Conclusion: This study demonstrated a lower injury incidence in replacement players compared with starters in the second half of matches, with a higher injury burden for replacement players due to higher mean injury severity. [ABSTRACT FROM AUTHOR]

Background: Aquaporin-4 (AQP4) antibody-associated neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system. We have undertaken a systematic review and meta-analysis to ascertain the sex ratio and mean age of onset for AQP4 antibody associated NMOSD. We have also explored factors that impact on these demographic data. Methods: A systematic search of databases was conducted according to the PRISMA guidelines. Articles reporting sex distribution and age of onset for AQP4 antibody-associated NMSOD were reviewed. An initially inclusive approach involving exploration with regression meta-analysis was followed by an analysis of just AQP4 antibody positive cases. Results: A total of 528 articles were screened to yield 89 articles covering 19,415 individuals from 88 population samples. The female:male sex ratio was significantly influenced by the proportion of AQP4 antibody positive cases in the samples studied (p < 0.001). For AQP4 antibody-positive cases the overall estimate of the sex ratio was 8.89 (95% CI 7.78–10.15). For paediatric populations the estimate was 5.68 (95% CI 4.01–8.03) and for late-onset cases, it was 5.48 (95% CI 4.10–7.33). The mean age of onset was significantly associated with the mean life expectancy of the population sampled (p < 0.001). The mean age of onset for AQP4 antibody-positive cases in long-lived populations was 41.7 years versus 33.3 years in the remainder. Conclusions: The female:male sex ratio and the mean age of onset of AQP4 antibody-associated NMOSD are significantly higher than MS. The sex ratio increases with the proportion of cases that are positive for AQP4 antibodies and the mean age of onset increases with population life expectancy. [ABSTRACT FROM AUTHOR]

A minority of initial multiple sclerosis (MS) presentations clinically or radiologically resemble other central nervous system (CNS) pathologies, acute disseminated encephalomyelitis (ADEM) or tumefactive demyelination (atypical demyelination presentations). With the aim of better defining the long-term outcomes of this group we have performed a retrospective cohort comparison of atypical demyelination versus 'typical' MS presentations. Twenty-seven cases with atypical presentations (both first and subsequent demyelinating events) were identified and compared with typical MS cases. Disease features analysed included relapse rates, disability severity, whole brain and lesion volumes, lesion number and distribution. Atypical cases represented 3.9% of all MS cases. There was considerable overlap in the magnetic resonance imaging (MRI) features of ADEM-like and tumefactive demyelination cases. ADEM-like cases tended to be younger but not significantly so. Atypical cases showed a trend towards higher peak expanded disability severity score (EDSS) score at the time of their atypical presentation. Motor, cranial nerve, cerebellar, cerebral and multifocal presentations were all more common in atypical cases, and less likely to present with optic neuritis. Cerebrospinal fluid (CSF) white cell counts were higher in atypical cases (p = 0.002). One atypical case was associated with peripheral blood myelin oligodendrocyte glycoprotein (MOG) antibodies, but subsequent clinical and radiological course was in keeping with MS. There was no difference in long-term clinical outcomes including annualised relapse rates (ARR), brain volume, lesion numbers or lesion distributions. Atypical demyelination cases were more likely to receive high potency disease modifying therapy early in the course of their illness. Despite the severity of initial illness, our cohort analysis suggests that atypical demyelination presentations do not confer a higher risk of long-term adverse outcomes. [ABSTRACT FROM AUTHOR]

Exposure to alkaline stress is common in aquatic practices. The present research investigated the detrimental impacts of rearing Nile tilapia under alkaline water stress by investigating the liver function indices and transcriptomic profile. A 30-day study was conducted on 160 fish (16.02 ± 0.14 g) split into four groups, each with four replicates. Group 1 (G1) and G2 were fed on a basal diet fortified with 0 and 75 g/kg diet camel whey protein hydrolysates (CWP) and reared in freshwater (carbonate alkalinity = 1.4 mmol/L, pH = 7.19). Moreover, G3 and G4 were fed on a basal diet enriched with 0 and 75 g/kg diet CWP and reared in alkaline water (carbonate alkalinity = 23.8 mmol/L; pH = 8.65). The outcomes revealed elevated lipid indices (triglycerides, cholesterol, low- and high-density lipoproteins) and liver enzymes (alanine and aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase) with lowered protein indices (total protein, albumin, and globulin) in alkaline-reared fish. Moreover, oxidative stress was initiated through lowered antioxidant enzymes (superoxide dismutase, catalase, and reduced glutathione) and higher malondialdehyde in the alkaline-exposed fish. Alkaline stress induced the activation of the mechanistic target of rapamycin and MAPK pathway (mitogen-activated protein kinase, c-Jun NH terminal kinase, and MAPK-1) with down-regulation of the autophagy-related genes (ATG-5, ATG-7, and ATG-13) and cathepsin B expression. Feeding on a CWP-supplemented diet resulted in significant modulation of the lipid profile, liver enzyme activity, and improvement in protein indices and antioxidant enzyme activity. Furthermore, modulation of the transcriptomic profile of the hepatic tissue of the alkaline-exposed fish was noticed due to feeding on a CWP-supplemented diet. Overall, CWP dietary addition at a level of 75 g/kg diet can alleviate the alkaline stress exposure in Nile tilapia. These outcomes could contribute to understanding the physiological circumstances of Nile tilapia when reared in alkaline water as well as provide a novel dietary additive for mitigating the bad consequences due to alkaline-stress exposure. [ABSTRACT FROM AUTHOR]

In this study, Moringa oleifera seed protein hydrolysate (MSPH) was included in the diet of Nile tilapia, Oreochromis niloticus, as a protein supplement for 90 days. Fish (n = 250, weighing 30.37 ± 0.05 g) were received diets with five inclusion levels of MSPH: 0, 33, 66, 99, and 132 g kg−1 diet (MSPH0, MSPH33, MSPH66, MSPH99, and MSPH132), respectively, with MSPH0 serving as the control diet. Compared to MSPH0, a pronounced improvement in the final body weight (FBW), total weight gain (TWG), specific growth rate % (SGR %), feed conversion ratio (FCR), protein efficacy ratio (PER), and average daily weight gain (ADWG) was noticed in all MSPH groups, with MSPH132 showing the highest values. The improvement was by 6.41, 18.18, 34.22, and 47.05% for FBW, 9.87, 27.40, 51.39, and 70.46% for TWG, and 4.80, 15.20, 34.40, and 38.40% for FCR in the MSPH33, MSPH66, MSPH99, and MSPH132 groups, respectively. The intestinal histo-morphometric and hematological indices of O. niloticus were significantly improved by MSPH levels. The total proteins and albumin were enhanced considerably by dietary MSPH (66 to 132 g kg−1 diet), while the globulin was enhanced by MSPH (99 to 132 g kg−1 diet). MSPH diets significantly enhanced the hepatic antioxidant enzymes and serum total antioxidant capacity and reduced malondialdehyde level. MSPH dietary inclusion did not alter the hepatorenal functions and their tissue integrity except for mild tubular adenomatous regenerative changes in the kidney of the MSPH132 group. In conclusion, the MSPH at a level up to 99 g kg−1 diet could be used as a dietary inclusion in O. niloticus. These findings contribute to the sustainability of the Nile tilapia culture sector. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women, and incidence rates are rising, it is thought in part, due to increasing levels of obesity. Endocrine therapy (ET) remains the cornerstone of systemic therapy for early and advanced oestrogen receptor-positive (ER +) breast cancer, but despite treatment advances, it is becoming more evident that obesity and insulin resistance are associated with worse outcomes. Here, we describe the current understanding of the relationship between both obesity and diabetes and the prevalence and outcomes for ER+ breast cancer. We also discuss the mechanisms associated with resistance to ET and the relationship to treatment toxicity. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusions Level of Evidence Lateralisation of the proximal apex of the quadriceps tendon relative to the mechanical axis or external rotation relative to the femoral shaft can be accurately measured and is strongly associated with patella maltracking. The aim of this study was to first assess the association between preoperative quadriceps tendon alignment (QTA) and the patient‐reported outcomes (PROMs) of total knee replacement, and second, determine the influence of component position on outcomes in patients with preoperative quadriceps tendon malalignment (QTM).A retrospective analysis of prospectively collected data was performed. All patients had preoperative and postoperative CT scans performed. PROMs were collected preoperatively and at 1 year postoperatively. QTA was measured by the quadriceps tendon axial angle (QTAx). The preoperative and postoperative coronal and axial alignment were measured. Femoral component rotation was measured relative to the preoperative posterior condyles.Analysis was conducted on 388 cases and the mean preoperative QTAx was 6.2° externally rotated (standard deviation 12.0°). QTM (QTAx > 14°) was identified in 76 (19.8%) patients. The diagnosis of QTM was associated with reduced patient outcomes including Forgotten Joint Score (60.2 vs. 51.2, p = 0.008), EuroQol Visual Analogue Scale (81.3 vs. 75.7, p = 0.009), KOOS‐12 (80.3 vs. 73.3, p = 0.001) and reduced PASS percentages for all KOOS subscales. In patients with preoperative QTM, femoral component external rotation >2° was associated with improved PROMs when compared to patients with <2° of femoral rotation. This included a clinically significant difference in the improvement of KOOS‐12 (11.7 points, p = 0.013) and improved PASS percentages in all KOOS subscales. There was no association between coronal alignment or tibial axial alignment and outcomes.Quadriceps malalignment is a common cause for poorer patient outcomes following total knee replacement. This can be avoided by externally rotating the femoral component to accommodate the deformity in the extensor mechanism.Level III, case‐control study. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusions Level of Evidence The stability of the graft in the bony tunnels is of utmost importance in the anterior cruciate ligament reconstruction (ACLR) since it ensures safe healing at the tendon‐bone interface. The hypothesis was that when a double tibial fixation was used in ACLR with a short graft of autologous hamstrings, tibial tunnel bone re‐growth and better graft integration would be observed at short‐term follow‐up.The analysis included a cohort of 112 patients after a primary ACLR with hamstring tendons who underwent postoperative magnetic resonance imaging (MRI) 3.0‐Tesla (3.0‐T) 6 months after the surgery. The patients were divided into three groups based on the tibial fixation technique: 40 had a screw (group S), 35 had a screw and cortical button (group S + B) and 37 had a screw and anchor (group S + A). Two orthopaedic specialists independently evaluated the images, who measured the screw‐free tunnel space, and assessed the presence of bone filling in the free tunnel. Furthermore, Ge's protocol was used to determine the graft healing in the tunnel.In 94 patients a screw‐free tunnel space was detected, and a filling of the tunnel was reported in 80.85% of the cases (76 patients), being partial in 15.79% (12 patients) and complete in 84.21% (64 patients). Patients who presented better graft integration (Ge1) had significantly higher values of screw‐free tunnel length compared to the other ones who had lower graft integration (Ge3)(p < 0.05).At 6 months postoperative MRI, tibial tunnel bone re‐growth and graft‐tunnel tibial integration after hamstring ACLR is significantly associated with the presence of free space between the anterior tibial cortex and the most distal portion of the interference screw, hence the use of a short and proximalized interference screw is suggested to restore bone stock after hamstring ACLR.Level IV retrospective comparative cohort study. [ABSTRACT FROM AUTHOR]

Purpose: Computer-aided design (CAD) and computer-aided manufacturing (CAM) techniques have paved the way for single-step resections and cranio-orbital reconstructions with patient specific implants in spheno-orbital tumors. Here, we present our interdisciplinary maxillofacial and neurosurgical workflow and a case series of patients treated with this integrated approach. Methods: Patients, who underwent single-step resection of benign spheno-orbital tumors and cranio-orbital reconstruction with polyetheretherketone (PEEK) patient specific implants (PSI) from 2019 to 2024 in our institution were included. Three dimensional models of the tumor, the skull, the implants and the cutting guides were integrated into intraoperative neuronavigation and 3D printed at the point of care (POC) for surgical planning. Clinical data was retrospectively analyzed, pre- and postoperative Exophthalmic index (EI) was radiologically determined. Results: Eleven patients met inclusion criteria. Meningioma WHO grade 1 was the most common tumor entity (81.8%). In a majority of patients, exophthalmos was the presenting sign (63.6%). Postoperative cranial imaging revealed an optimal position of the PEEK implants with regredient EI in 88.9%. Four (36.4%) patients, of whom two (50%) had undergone prior tumor resections, suffered from surgical complications. The most commonly recorded complication was impaired wound healing (n = 2). Tumor recurrence was observed in one (9.1%) patient at six months follow-up. Conclusions: Single-step resection and reconstruction in spheno-orbital tumors with PEEK PSIs is feasible and combines surgical expertise, virtual implant design and 3D printing techniques. Favorable aesthetical, visual and oncological outcomes were achieved in this cohort, despite a significant risk for postoperative complications. [ABSTRACT FROM AUTHOR]

Major efforts in human neuroimaging strive to understand individual differences and find biomarkers for clinical applications by predicting behavioural phenotypes from brain imaging data. To identify generalisable and replicable brain-behaviour prediction models, sufficient measurement reliability is essential. However, the selection of prediction targets is predominantly guided by scientific interest or data availability rather than psychometric considerations. Here, we demonstrate the impact of low reliability in behavioural phenotypes on out-of-sample prediction performance. Using simulated and empirical data from four large-scale datasets, we find that reliability levels common across many phenotypes can markedly limit the ability to link brain and behaviour. Next, using 5000 participants from the UK Biobank, we show that only highly reliable data can fully benefit from increasing sample sizes from hundreds to thousands of participants. Our findings highlight the importance of measurement reliability for identifying meaningful brain–behaviour associations from individual differences and underscore the need for greater emphasis on psychometrics in future research. Our ability to identify associations between behaviour and brain imaging is important for uncovering markers of cognition and disease. Here, the authors illustrate the importance of the reliability of behavioural measurements to accurately investigate brain-behaviour associations using machine learning. [ABSTRACT FROM AUTHOR]

Synaptic mechanisms that contribute to human memory consolidation remain largely unexplored. Consolidation critically relies on sleep. During slow wave sleep, neurons exhibit characteristic membrane potential oscillations known as UP and DOWN states. Coupling of memory reactivation to these slow oscillations promotes consolidation, though the underlying mechanisms remain elusive. Here, we performed axonal and multineuron patch-clamp recordings in acute human brain slices, obtained from neurosurgeries, to show that sleep-like UP and DOWN states modulate axonal action potentials and temporarily enhance synaptic transmission between neocortical pyramidal neurons. Synaptic enhancement by UP and DOWN state sequences facilitates recruitment of postsynaptic action potentials, which in turn results in long-term stabilization of synaptic strength. In contrast, synapses undergo lasting depression if presynaptic neurons fail to recruit postsynaptic action potentials. Our study offers a mechanistic explanation for how coupling of neural activity to slow waves can cause synaptic consolidation, with potential implications for brain stimulation strategies targeting memory performance. Whether and how slow wave activity (SWA) and the underlying membrane potential UP and DOWN states initiate mechanisms that augment memory functions in humans are not fully understood. Here authors used multineuron patch-clamp in alive human brain tissue, resected during neurosurgeries, to show that membrane potential UP/DOWN states, which mimic neural sleep activity, modulate axonal action potentials to boost synaptic strength and plasticity. [ABSTRACT FROM AUTHOR]

During their final transformation, insects emerge from the pupal case and deploy their wings within minutes. The wings deploy from a compact origami structure, to form a planar and rigid blade that allows the insect to fly. Deployment is powered by a rapid increase in internal pressure, and by the subsequent flow of hemolymph into the deployable wing structure. Using a combination of imaging techniques, we characterize the internal and external structure of the wing in Drosophila melanogaster, the unfolding kinematics at the organ scale, and the hemolymph flow during deployment. We find that, beyond the mere unfolding of the macroscopic folds, wing deployment also involves wing expansion, with the stretching of epithelial cells and the unwrinkling of the cuticle enveloping the wing. A quantitative computational model, incorporating mechanical measurements of the viscoelastic properties and microstructure of the wing, predicts the existence of an operating point for deployment and captures the dynamics of the process. This model shows that insects exploit material and geometric nonlinearities to achieve rapid and efficient reconfiguration of soft deployable structures. Upon emerging from their pupal case, insects swiftly deploy their wings from a compact origami-like structure to a fully extended blade. Here, authors use a combination of imaging and mechanical tests to model the kinematics and dynamics of wing deployment in Drosophila. [ABSTRACT FROM AUTHOR]

Isomerisation through stereochemical changes and modulation in bond order conjugation are processes that occur ubiquitously in diverse chemical systems and for photochromic spirocompounds, it imparts them their functionality as phototransformable molecules. However, these transformations have been notoriously challenging to observe in crystals due to steric hindrance but are necessary ingredients for the development of reversible spiro-based crystalline devices. Here, we report the detection of spectroscopic signatures of merocyanine due to photoisomerisation within crystalline spiropyran following 266 nm excitation. Our femtosecond spectroscopy experiments reveal bond breaking, isomerisation and increase in bond order conjugation towards the formation of merocynine on a sub-2 ps time scale. They further unveil a lifetime of several picoseconds for the initial open ring intermediate with subsequent relaxation to mercocyanine, with established back connversion pathways, which make the system highly reversible in the solid state. Supporting femtosecond electron diffraction studies suggest that lattice strain favours the return of photoproduct to the closed spiroform. Our work thus paves the way for novel ultrafast applications from spiropyran-derived compounds. Steric hindrance in crystals can prevent activity of photochromic compounds. Here, the authors show reversible isomerization in spiropyran crystals even in the presence of photoinduced mechanical strain using ultrafast spectroscopy techniques. [ABSTRACT FROM AUTHOR]

Paratyphoid B fever (PTB) is caused by an invasive lineage (phylogroup 1, PG1) of Salmonella enterica serotype Paratyphi B (SPB). However, little was known about the global population structure, geographic distribution, and evolution of this pathogen. Here, we report a whole-genome analysis of 568 historical and contemporary SPB PG1 isolates, obtained globally, between 1898 and 2021. We show that this pathogen existed in the 13th century, subsequently diversifying into 11 lineages and 38 genotypes with strong phylogeographic patterns. Following its discovery in 1896, it circulated across Europe until the 1970s, after which it was mostly reimported into Europe from South America, the Middle East, South Asia, and North Africa. Antimicrobial resistance recently emerged in various genotypes of SPB PG1, mostly through mutations of the quinolone-resistance-determining regions of gyrA and gyrB. This study provides an unprecedented insight into SPB PG1 and essential genomic tools for identifying and tracking this pathogen, thereby facilitating the global genomic surveillance of PTB. Hawkey et al. provide insights into the spatio-temporal distribution and genetic diversity of Salmonella Paratyphi B — the agent of paratyphoid B fever — and report a genotyping scheme facilitating the international surveillance of this pathogen. [ABSTRACT FROM AUTHOR]

Organofluorine mass balance approaches are increasingly applied to investigate the occurrence of per- and polyfluoroalkyl substances (PFAS) and other organofluorines in environmental samples more comprehensively. Usually, complex samples prevent the identification and quantification of every fluorine-containing molecule. Consequently, large unidentified fractions between fluorine sum parameters such as extractable organic fluorine (EOF) and the sum of quantified analytes are frequently reported. We propose using oxidative conversion to separate (unidentified) weakly fluorinated compounds (e.g., pesticides, pharmaceuticals) from PFAA-precursors (perfluoroalkyl chain lengths ≥ C6). We show with three organofluorine model substances (flufenamic acid, diflufenican, pantoprazole) that CF3-groups or aromatic fluorine can be quantitatively converted to inorganic fluoride and trifluoroacetic acid (TFA) by applying PhotoTOP oxidation (UV/TiO2). The principle of fluorine separation in mixtures is demonstrated by the oxidation of the three weakly fluorinated compounds together with the PFAA-precursor 6:2/6:2 fluorotelomer mercaptoalkyl phosphate diester (FTMAP). After oxidation, the products F− and TFA were separated from PFCAs (> C4) by SPE, and the fractions were analyzed individually. Closed mass balances both with and without the addition of organic matrix were achieved. Eventually, the fluorine balance was verified by total fluorine measurements with combustion ion chromatography (CIC). The proposed methods should be considered a proof of concept to potentially explain unidentified fractions of the EOF, especially if compounds with low fluorine content such as pesticides, pharmaceuticals, and their transformation products contribute largely to the EOF. Future studies are needed to show the applicability to the complexity of environmental samples. [ABSTRACT FROM AUTHOR]

Bench blasting is commonly used in open-pit coal mines because it effectively increases coal production and aids in overburden removal. However, uncontrolled blasting can generate significant vibrations and accelerations, which may lead to slope failure if the magnitude of permanent displacement exceeds its critical value. A prevalent method for calculating the dynamic factor of safety (FoS) of a slope due to blasting is the pseudo-static approach; however, this method tends to be overly conservative. In this study, we utilized Newmark’s sliding block method and the strength reduction factor (SRF) to assess the dynamic FoS of slopes by evaluating the permanent displacement caused by bench blasting. We based our seismic input on a complete vibration waveform obtained through signature hole analysis of a specific bench blast design. The dynamic FoS was defined as the SRF threshold that resulted in a critical slope displacement of 50 mm. The case study was conducted at Borneo Indo Bara, one of Indonesia’s largest open-pit coal mines located in South Borneo Province. We analyzed four sidewall slopes that were subjected to repeated blasting events. The results indicated that the slope’s LOM design could tolerate blasting vibrations corresponding to a peak particle acceleration (PPA) of up to 0.41 g, which yielded a dynamic FoS of 1.35. This value is significantly higher than the pseudo-static approach, which indicated a pseudo-static FoS of 1.04 for a PPA of 0.12 g. Furthermore, this study assists mining practitioners in predicting the allowable number of blast events to prevent slope failure and recommends avoiding blast events with a scaled distance of less than 8 m/kg1/2 to prevent sudden slope failures. In conclusion, the study highlights the importance of the integrated approach that combines signature hole analysis, Newmark’s sliding block method, and the SRF approach for evaluating the dynamic FoS of mine slopes subjected to bench blasting. The results of this study can offer valuable insights for mining engineers engaged in bench blasting to adopt the proposed integrated approach, which is still overlooked in Indonesia’s open pit blasting practices. [ABSTRACT FROM AUTHOR]

X-Linked myotubular myopathy (XLMTM) is characterized by severe skeletal muscle weakness and reduced life expectancy. The pathomechanism and the impact of non-muscular defects affecting survival, such as liver dysfunction, are poorly understood. Here, we investigated organ-specific effects of XLMTM using the Mtm1−/y mouse model. We performed RNA-sequencing to identify a common mechanism in different skeletal muscles, and to explore potential phenotypes and compensatory mechanisms in the heart and the liver. The cardiac and hepatic function and structural integrity were assessed both in vivo and in vitro. Our findings revealed no defects in liver function or morphology. A disease signature common to several skeletal muscles highlighted dysregulation of muscle development, inflammation, cell adhesion and oxidative phosphorylation as key pathomechanisms. The heart displayed only mild functional alterations without obvious structural defects. Transcriptomic analyses revealed an opposite dysregulation of mitochondrial function, cell adhesion and beta integrin trafficking pathways in cardiac muscle compared to skeletal muscles. Despite this dysregulation, biochemical and cellular experiments demonstrated that these pathways were strongly affected in skeletal muscle and normal in cardiac muscle. Moreover, biomarkers reflecting the molecular activity of MTM1, such as PtdIns3P and dynamin 2 levels, were increased in the skeletal muscles but not in cardiac muscle. Overall, these data suggest a compensatory mechanism preserving cardiac function, pointing to potential therapeutic targets to cure the severe skeletal muscle defects in XLMTM. [ABSTRACT FROM AUTHOR]

The signal amplification by reversible exchange process (SABRE) enhances NMR signals by unlocking hidden polarization in parahydrogen through interactions with to-be-hyperpolarized substrate molecules when both are transiently bound to an Ir-based organometallic catalyst. Recent efforts focus on optimizing polarization transfer from parahydrogen-derived hydride ligands to the substrate in SABRE. However, this requires quantitative information on ligand exchange rates, which common NMR techniques struggle to provide. Here, we introduce an experimental spin order transfer sequence, with readout occurring at 15N nuclei directly interacting with the catalyst. Enhanced 15N NMR signals overcome sensitivity challenges, encoding substrate dissociation rates. This methodology enables robust data fitting to ligand exchange models, yielding substrate dissociation rate constants with higher precision than classical 1D and 2D 1H NMR approaches. This refinement improves the accuracy of key activation enthalpy ΔH‡ and entropy ΔS‡ estimates. Furthermore, the higher chemical shift dispersion provided by enhanced 15N NMR reveals the kinetics of substrate dissociation for acetonitrile and metronidazole, previously inaccessible via 1H NMR due to small chemical shift differences between free and Ir-bound substrates. The presented approach can be successfully applied not only to isotopically enriched substrates but also to compounds with natural abundance of the to-be-hyperpolarized heteronuclei. Current efforts to enhance NMR signals using the signal amplification by reversible exchange (SABRE) focus on optimizing polarization transfer from parahydrogen-derived hydride ligands to the substrate, but this requires quantitative information on ligand exchange rates, which common NMR techniques struggle to provide. Here, the authors introduce an experimental spin order transfer sequence with readout occurring at hyperpolarization-enhanced 15N nuclei that are directly interacting with the SABRE catalyst, enabling robust evaluation of ligand chemical exchange. [ABSTRACT FROM AUTHOR]

Speaker-conditioned target speaker extraction aims at estimating the target speaker from a mixture of speakers utilizing auxiliary information about the target speaker. In this paper, we consider a single-channel target speaker extraction system consisting of a speaker embedder network and a speaker separator network. Instead of using standard long short-term memory (LSTM) cells in the separator network, we propose two variants of LSTM cells that are customized for speaker-conditioned target speaker extraction. The first variant customizes both the forget gate and input gate of the LSTM cell, aiming at retaining only relevant features related to target speaker and disregarding the interfering speakers by simultaneously resetting and updating the cell state using the speaker embedding. For the second variant, we introduce a new gate within the LSTM cell, referred to as auxiliary-modulation gate. This gate modulates the information processing during cell state reset, aiming at learning the long-term and short-term discriminative features of the target speaker. Both in unidirectional and bidirectional mode, experimental results on 2-speaker mixtures, 3-speaker mixtures, and noisy mixtures (containing 1, 2, or 3 speakers) show that both proposed variants of LSTM cells outperform the standard LSTM cells for target speaker extraction, where the best performance is obtained using the auxiliary-gated LSTM cells. [ABSTRACT FROM AUTHOR]

For almost two decades now, scientists have increasingly focused on the occurrence of microplastic particles (MPs) in the environment and their impact on environmental and human health. Currently, the variety of analytical methods used in microplastic research result in data of different quality. This largely hampers comparability between data sets and consequently prevents a reliable risk assessment. In this context, the lack of suitable reference microplastic particles (RMPs) that can be added as an internal standard in an exactly known number further prevents quality assessment of, and harmonization in terms of comparability between different analytical methods. Although this challenge has been widely recognized, the availability of RMPs is currently limited to commercially available particles in the form of micro-beads or -fragments (powders). Manual addition of such RMPs to samples in a precisely defined number as an internal standard is inefficient and the alternative use of MP suspensions does not allow for the addition of an exactly defined particle number. The optimum solution to solve this issue would be RMPs embedded in an easy-to-use soluble matrix in exact numbers. This would allow for evaluating analytical quality during microplastic analysis as well as establishing harmonization in terms of comparability between different methods. In the present study we focused on the development of such RMPs. We used computerized numerical controlled (CNC) milling to produce small diameter plastic columns followed by gelatine embedment and subsequent cryosectioning. This results in gelatin slices containing an exactly defined number of RMPs with well-defined size, shape and polymer type / chemical composition that can be added to a sample easily with the dissolution of the gelatine. We successfully produced square shaped RMPs in a size range of 125–1000 μm of five different polymers. The overall size-deviation of the RMPs never exceeded ± 11.2% from the mean value of a set of particles. The highest percentage mass-deviation was 25.5% from the mean value of a set of 125 × 125 × 20 μm polystyrene (PS) RMPs. Our approach allows for the production of RMPs tailored to specific needs of all different analytical methods used in current microplastic research. Beyond analytical method validation, these RMPs furthermore open possibilities for experiments on MPs in different fields. [ABSTRACT FROM AUTHOR]

Little is known about the sources of parenting stress and the coping strategies adopted by parents of children with attention deficit hyperactivity disorder (ADHD) in China. The current study aimed to explore the stress and coping strategies adopted by Chinese parents using stress-coping theories. A qualitative study was conducted on fifteen parents whose children, aged between 7 and 11 years (from primary school grades one to five), had received a formal diagnosis of ADHD. The findings revealed that Chinese parents use individual, family and school coping strategies to cope with their stress. The themes that emerged from the data included five types of stressors and eight coping strategies. The choice of the strategy adopted by the parents was influenced by cultural and environmental factors; in particular, family coping strategies required the availability of a supportive spouse and a supportive family culture. Similarly, school coping strategies required the availability of school involvement opportunities and school support resources. Since the support offered by teachers and mental health professionals such as school counsellors and social workers can be strengthened, this study recommends ways to strengthen the support provided to parents of children with ADHD. Highlights: This study examined the coping methods adopted by Chinese parents whose children have ADHD within the Chinese cultural, social and educational context. The results revealed that the children's symptoms, parents' personality traits and perception, extra family burden and additional family conflict as the primary sources of the parental stress. Whereas parents employed individual, family and school coping strategies in reacting to the stressors. Chinese parents were more self-critical in a collectivist culture and they engaged in self-reflection, self-criticism and self-regulation as a stress coping process. Chinese parents felt the lack of social and school support, especially the pressure from teachers' criticism and the lack of empathy for their children. They expect to get some social resources to help them. [ABSTRACT FROM AUTHOR]

There has been increasing interest in understanding the higher education experiences of students who spent time 'in care' as children, who tend to have to overcome strong barriers to educational success. Care-experienced students often thrive in higher education, although little is currently known about those who build on this success to pursue their own academic career. This study sought to explore the educational trajectories and working lives of care-experienced academics in the UK for the first time. We used an online survey to identify potential interview participants, leading to 21 semi-structured online interviews. This article reports the findings from five of the eight themes developed through thematic analysis, focusing primarily on the diverse pathways into and through academic careers. We used Archer's concepts of reflexivity and the 'internal conversation' to explore agency, enablements and constraints. Most participants highlighted the disrupted nature of their schooling, although school was a place of safety and success for some. Pathways into higher education were heterogeneous, including a group who had used their 'expertise through experience' to forge academic careers in disciplines like social work and psychology. Career precarity was common and particularly challenging without family 'safety nets'. Our participants tended to show high levels of self-reliance and/or willingness to seek help, coupled with a scepticism around long-term planning. We argue that these factors are shaped by early lives and lead to specific forms of reflexivity, concluding that universities need to recognise care experience as a status deserving of additional career support. [ABSTRACT FROM AUTHOR]

COVID-19 is no longer considered a global public health emergency, yet it persists in communities and continues to cause illness, particularly in the vulnerable. New variants of SARS-CoV-2 (the virus that causes COVID-19) are highly transmissible but are generally associated with mild symptoms. People who are vulnerable and people who have not yet been vaccinated should still be encouraged to get vaccinated. The vaccines approved for emergency use by the World Health Organization include inactivated, mRNA-based, adenovirus vector-based and protein subunit-based vaccines. These vaccines still protect against severe illness but provide limited protection for symptomatic illness. To prevent transmission of COVID-19, new vaccines may be required. [ABSTRACT FROM AUTHOR]

The Bacille Calmette-Guerin (BCG) vaccine is one of the most widely used vaccines in the world for the prevention of tuberculosis. Its immunological capacity also includes epigenetic reprogramming, activation of T cells and inflammatory responses. Although the main usage of the vaccine is the prevention of tuberculosis, different works have shown that the effect of BCG can go beyond the peripheral immune response and be linked to the central nervous system by modulating the immune system at the level of the brain. This review therefore aims to describe the BCG vaccine, its origin, its relationship with the immune system, and its involvement at the brain level. [ABSTRACT FROM AUTHOR]

While organic matter (OM) interactions in the water column prevent iron (Fe) precipitation and sedimentation, Fe also acts as a precursor of aggregation and a vector of OM to sediments. This study aims to characterize Fe–OM interactions to understand the role of Fe in promoting aggregation and transport of OM. Samples of Fe and OM were collected from water, settling material, and sediment along a gradient starting from the inlet and continuing offshore within a boreal lake. Fe speciation was determined using X-ray absorption spectroscopy (XAS), and the chemical composition of OM was assessed using Diffuse reflectance infrared Fourier transform spectroscopy (DRIFT IR) and Nuclear magnetic resonance spectroscopy (NMR). The results show a decrease in Fe and OM concentrations in the water column with increasing distance from the inlet. Winter sampling revealed a shift in Fe speciation from dominance of organically complexed Fe to an increase in Fe(oxy)hydroxide, accompanied by a loss of aromatic and carboxylate function of OM. Summer sampling revealed no significant changes along the gradient, with Fe(oxy)hydroxide and carbohydrates dominating the water phase. Interestingly, settling particles and surface sediments were dominated by Fe(oxy)hydroxides and aliphatic OM. We propose that phototransformation may be an important process that influences the interaction between Fe and OM and, as a consequence, their fate along the spatial gradient. Our study suggests a photochemically induced loss of carboxylate groups, reflected by an increased carbohydrate-to-carboxylate ratio along the gradient, particularly in winter, and generally lower levels during summer. Loss of carboxylate function promotes the formation of Fe(oxy)hydroxides, which in turn, facilitates the aggregation and sinking of OM, particularly aliphatic components. These insights contribute to a broader understanding of carbon cycling and storage in lakes. Future studies should assess the significance of photochemical processes to OM burial and it how may change given trends in Fe and OM in northern regions. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to prove new fine regularity results for nonlocal drift-diffusion equations via pointwise potential estimates. Our analysis requires only minimal assumptions on the divergence free drift term, enabling us to include drifts of critical order belonging merely to BMO. In particular, our results allow us to derive new estimates for the dissipative surface quasi-geostrophic equation. [ABSTRACT FROM AUTHOR]

In this review paper, we provide a brief overview of the recent advances in the continuum modeling of gas–particle flows. First, we focus on the kinetic theory-based two-fluid models, which have become a valuable tool to investigate small-scale moderately dense turbulent gas–particle flows. Second, the continuum description is quite restrictive with respect to the maximum grid spacing, and large-scale simulations usually employ coarse mesh resolutions to keep the analyses practicable. Such coarse-graining inevitably neglects the small unresolved scales, which requires additional modeling. Here, filtered two-fluid models have been applied successfully to a variety gas–solid flow problems. Finally, we give a condensed outline about future research challenges for the continuum modeling of gas–particle flows. [ABSTRACT FROM AUTHOR]

Intracerebral haemorrhage (ICH) is a devastating condition associated with high mortality and substantial residual disability among survivors. Effective treatments for the acute stages of ICH are limited. However, promising findings from randomized trials of therapeutic strategies, including acute care bundles that target anticoagulation therapies, blood pressure control and other physiological parameters, and trials of minimally invasive neurosurgical procedures have led to renewed optimism that patient outcomes can be improved. Currently ongoing areas of research for acute treatment include anti-inflammatory and haemostatic treatments. The implementation of effective secondary prevention strategies requires an understanding of the aetiology of ICH, which involves vascular and brain parenchymal imaging; the use of neuroimaging markers of cerebral small vessel disease improves classification with prognostic relevance. Other data underline the importance of preventing not only recurrent ICH but also ischaemic stroke and cardiovascular events in survivors of ICH. Ongoing and planned randomized controlled trials will assess the efficacy of prevention strategies, including antiplatelet agents, oral anticoagulants or left atrial appendage occlusion (in patients with concomitant atrial fibrillation), and optimal management of long-term blood pressure and statin use. Together, these advances herald a new era of improved understanding and effective interventions to reduce the burden of ICH. Effective treatments for the acute stages of intracerebral haemorrhage are currently limited. In this Review, the authors consider advances in therapeutic strategies and neurosurgical procedures, including acute care bundles, that promise a new era of interventions. Key points: Intracerebral haemorrhage (ICH) is a common and severe type of stroke associated with severe morbidity and mortality. Advances in acute treatment of ICH, including ultra-early blood pressure control, anticoagulation reversal and minimally invasive neurosurgical procedures, have great potential to improve patient outcomes; bundled approaches might have particular value in acute settings. Diagnosis of the underlying aetiology of ICH is crucial for understanding the cause; diagnosis usually requires both vascular and structural (magnetic resonance) imaging. The most important aetiologies of ICH include arteriolosclerosis, cerebral amyloid angiopathy and macrovascular causes. ICH aetiology must be determined to assess the risk of recurrent ICH and other vascular events, which informs the use of individualized secondary prevention strategies and decisions on the use of antiplatelet or anticoagulant treatments for other indications. [ABSTRACT FROM AUTHOR]

The editorial discusses advancements in nuclear medicine, particularly in the context of neuroendocrine tumors (NETs), drawing parallels to the Star Wars series. It highlights the use of radioligands and nuclear imaging techniques, such as SSTR imaging and peptide receptor radionuclide therapy (PRRT), in diagnosing and treating NETs. The editorial also explores recent developments in NET management, including molecular targeted therapies, PRRT, chemotherapy, and potential combination therapies, emphasizing the importance of personalized treatment strategies. Ongoing research and clinical trials aim to further improve diagnostic accuracy and treatment outcomes for patients with NETs. [Extracted from the article]