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Tracking proteasome degradation: A cross-organ analysis via intact degradomics mass spectrometry

The proteasome is a multisubunit degradation machinery that is essential for maintaining protein homeostasis by breaking down unnecessary or damaged proteins into peptides. While most of these peptides are further processed into amino acids, a subset evades complete degradation and plays key roles in biological processes such as antigen presentation, signaling, and apoptosis. However, the variability in peptide lengths and the diverse composition of proteasomes make their comprehensive identification and characterization particularly challenging. Here, we present a method that enables real-time identification of generated peptides, as well as uncleaved and partially cleaved protein substrates, revealing the processive nature of protein proteasomal degradation. Our intact degradomics workflow is based on intact mass spectrometry measurements and treats the enzymatically produced peptides as if they were generated within the mass spectrometer, akin to top–down products. We applied this approach to determine the kinetic profile of proteasome degradation and compare the real-time activity of proteasomes isolated from different mouse organs, uncovering distinct functionalities of the complex. Overall, this method offers a valuable tool for studying peptide degradation products across various proteasome configurations, while also enabling the investigation of how interacting proteins, inhibitors, and activators influence proteasome activity. Furthermore, its adaptability makes it applicable to a wide range of other proteolytic complexes, broadening its potential impact in the field.

First validity testing of GluciQuizz, a French self-questionnaire evaluating carb-counting for patients with type 1 diabetes

Objective Carbohydrate intake remains one of the most influential factors affecting post-meal glucose levels in type 1 diabetes (T1D). To individualize and optimize patient education on carbohydrate counting, it is essential to assess their knowledge of carbohydrate counting. For this purpose, we aimed to produce and validate a questionnaire for French-speaking individuals based on the American AdultCarbQuiz questionnaire (43 items). Design The translation and cross-cultural adaptation of the American questionnaire were followed by an analysis conducted by patient and diabetologist expert groups. Participants 190 participants living with T1D, Diabetologist expert group. Main outcome measure(s) Internal consistency and reliability were verified by administering the adapted French version of the questionnaire to 190 participants living with T1D. Analysis Clinical validity was verified by examining the correlation between the questionnaire score and the time in range (TIR) of these participants. Results Translation and back-translation demonstrated good consistency with the original questionnaire. Typical American food items were replaced with foods commonly consumed in France. All items were validated by both patient and diabetologist experts. After analyzing the responses of 190 participant, seven items were considered non-discriminatory and were therefore removed. Internal consistency, assessed by Cronbach’s α, was high, with α =  0.785, 95 CI [0.738–0.826]. Finally, we produced a 36 item French questionnaire named GluciQuizz. TIR correlated with the GluciQuizz score (r =  0.3; p  <  0.0001). Conclusions and implications This study validates a French-language self-administered questionnaire (GluciQuizz), which evaluates different domains of carbohydrate knowledge in a 15-minute quiz for people living with T1D.

Pollen–pistil interactions in divergent wide crosses lead to spatial and temporal pre-fertilization reproductive barrier in flax (Linum usitatissimum L.)

Deep-water corals indicate the Red Sea survived the last glacial lowstand

The Red Sea, a nascent ocean basin connected to the Indian Ocean via a shallow strait, is assumed to have experienced significant environmental changes during the last glacial period due to a sea-level drop likely exceeding 110 m. This study investigates the hypothesis that hydrodynamic restriction led to severe ecological impacts, including basin-wide extinction due to elevated salinity followed by a short time of oxygen depletion. Uranium–Thorium dating of deep-water corals (DWCs) from 26 northern Red Sea sites reveals coral growth during and after the Last Glacial sea-level lowstand, indicating tolerable seawater chemistry. Additional geochemical data show no significant difference in Red Sea chemistry or temperature between the Latest Pleistocene and Holocene. A meta-analysis of 27 deep-sea cores reveals that while planktonic foraminifera experienced local extinction, other microfossil groups seemingly persisted. These findings suggest that the Red Sea survived the last sea-level lowstand, challenging the paradigm of a complete ecological collapse and providing insights into the resilience of marine ecosystems.

Community emergency management policy in China using a policy text tool

Systematically analyzing the current status and problems of the Community Emergency Management Policy (CEMP) system in China and proposing practical suggestions that are conducive to subsequent policy formulation and improvement are important for improving community emergency management capabilities and levels and promoting sustainable community development. Based on the two-dimensional analysis framework of “policy tools–policy objectives”, this paper draws from content analysis and social network analysis, quantitatively analyzing the CEMP texts at the national level from 2004 to 2024. The results show that the CEMP system in China has essentially taken shape, but there are still some problems, such as the uneven use of policy tools, the unbalanced internal structure of policy tools, the large distribution gap of policy objective elements, and the adaptability between policy tools and policy objectives, which needs to be improved. Given these results, we suggest 1) Appropriately increasing the frequency of using demand-type policy tools and effectively optimizing the internal structure of the three main types of policy tools; 2) Comprehensively deepening the reform of CEMP objectives; and 3) Reasonably improving the adaptability between policy tools and objectives.

Short-term overloading exercise attenuates articular chondrocyte features partly via synovium–cartilage interactions mediated by inhibin subunit beta A

OsNLP3 and OsPHR2 orchestrate direct and mycorrhizal pathways for nitrate uptake by regulating NAR2.1–NRT2s complexes in rice

Nitrogen (N) is the most important essential nutrient required by plants. Most land plants have evolved two N uptake pathways, a direct root pathway and a symbiotic pathway, via association with arbuscular mycorrhizal (AM) fungi. However, the interaction between the two pathways is ambiguous. Here, we report that OsNAR2.1–OsNRT2s, the nitrate (NO 3 − ) transporter complexes with crucial roles in direct NO 3 − uptake, are also recruited for symbiotic NO 3 − uptake. OsNAR2.1 and OsNRT2.1/2.2 are coregulated by NIN-like protein 3 (OsNLP3), a key regulator in NO 3 − signaling, and OsPHR2, a major regulator of phosphate starvation responses. More importantly, AM symbiosis induces expression of OsNAR2.1 – OsNRT2s, OsNLP3, and OsSPX4 , encoding an intracellular Pi sensor, in arbuscular-containing cells, but weakens their expression in the epidermis. OsNAR2.1 and OsNLP3 can activate both mycorrhizal NO 3 − uptake and mycorrhization efficiency. Overall, we demonstrate that OsNLP3 and OsPHR2 orchestrate the direct and mycorrhizal NO 3 − uptake pathways by regulating the NAR2.1–NRT2s complexes in rice.

Comparison of leg length discrepancy after total hip arthroplasty: Direct anterior and posterior lateral approach

Background Leg length discrepancy (LLD) after total hip arthroplasty (THA) is a clinical entity that deteriorates clinical outcomes and patients’ satisfaction. Few articles have compared LLD after THA by different surgical approaches. Methods A total of 358 consecutive patients who underwent primary THA between January 2016 and November 2018 were retrospectively reviewed. All 4 surgeons performed THA through both direct anterior approach (DAA) and posterior lateral approach (PLA). The primary outcome measurement was LLD. LLD was measured on post-operative anteroposterior bilateral hip radiograph. The secondary outcomes were acetabular abduction, acetabular anteversion, perceived LLD (pLLD) and HHS at 6 weeks, 1 year and 5 years. Intergroup analyses were performed using the Chi-square test for enumeration data and the independent sample t-test for quantitative data. Results There was no inter-group difference in terms of patients’ demographics. The DAA group had decreased LLD compared to the PLA group (3.0 ± 5.9mm vs. 4.2 ± 4.5mm, p = 0.027). Meanwhile, the DAA group had a smaller acetabular anteversion than the PLA group (12.9 ± 2.9 vs. 18.4 ± 2.9, p < 0.01). At 6-week follow-up, the DAA group had higher HHS (82.2 + 6.2 vs. 80.5 + 6.6, p = 0.015) and less pLLD (P = 0.001) compared to the PLA group. Conclusions DAA results in more accurate leg length equalization, reduced pLLD, and improved short-term outcomes compared with PLA.

Negative pressure wound therapy promotes wound healing by down-regulating miR-155 expression in granulation tissue of diabetic foot ulcers

A long-distance inhibitory system regulates haustoria numbers in parasitic plants

The ability of parasitic plants to withdraw nutrients from their hosts depends on the formation of an infective structure known as the haustorium. How parasites regulate their haustoria numbers is poorly understood, and here, we uncovered that existing haustoria in the facultative parasitic plants Phtheirospermum japonicum and Parentucellia viscosa suppressed the formation of new haustoria located on distant roots. Using Phtheirospermum, we found that this effect depended on the formation of mature haustoria and could be induced through the application of external nutrients. To understand the molecular basis of this root plasticity, we analyzed hormone response and found that existing infections upregulated cytokinin-responsive genes first at the haustoria and then more distantly in Phtheirospermum shoots. We observed that infections increased endogenous cytokinin levels in Phtheirospermum roots and shoots, and this increase appeared relevant since local treatments with exogenous cytokinins blocked the formation of both locally and distantly formed haustoria. In addition, local overexpression of a cytokinin-degrading enzyme in Phtheirospermum prevented this systemic interhaustoria repression and increased haustoria numbers locally. We propose that a long-distance signal produced by haustoria negatively regulates future haustoria, and in Phtheirospermum , such a signaling system is mediated by a local increase in cytokinin to regulate haustoria numbers and balance nutrient acquisition.

Widespread dissemination of Salmonella, Escherichia coli and Campylobacter resistant to medically important antimicrobials in the poultry production continuum in Canada

The Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS) monitors Escherichia coli, Salmonella and Campylobacter and their resistance to antimicrobials in broiler chickens at the farm and slaughter plant levels. In response to many years of CIPARS’ observations and farmers’ data, the Chicken Farmers of Canada implemented a strategy to reduce antimicrobial use in 2014. As resistance genes can be transmitted vertically from parents to their offspring, a study was conducted in broiler breeder flocks to assess the frequency of target bacteria, their antimicrobial resistance (AMR) and to obtain a comprehensive picture of AMR in poultry production. Spent breeder flocks slaughtered between 2018 and 2021 were sampled and data from broiler flocks at the farm and slaughter plants were assessed. Salmonella was most frequently detected in farm broiler chickens (46%), while Campylobacter was most frequently detected in broiler breeders (73%). In Campylobacter, high levels (20–24%) of ciprofloxacin resistance were found across the three production stages, and was highest in farm broiler chickens (24%). In E. coli, an indicator organism, low-level ceftriaxone resistance and occasional isolates that were non-susceptible to ciprofloxacin were noted. Using the indicator, fully susceptible E. coli, broiler breeders had the highest frequency (54%) compared to farm (36%) and slaughtered (35%) broiler chickens. In Salmonella broiler breeders had the highest resistance to most antimicrobials tested.Fully susceptible Salmonella was lowest in broiler breeders (16%) compared to farm (42%) and slaughtered (42%) broiler chickens. Salmonella serovars differed between the production stages, but S. Kentucky was the most predominant. Resistance to critically important antimicrobials in human medicine and regional variations in resistance profiles were observed. This study suggests that broiler breeders carry foodborne bacteria resistant to antimicrobials used in human medicine, demonstrating their role in the maintenance of AMR in poultry and the need to adopt a harmonized sector-wide AMU strategy.

Advanced financial security system using smart contract in private ethereum consortium blockchain with hybrid optimization strategy

Options for student loan repayment matter

Document review of the paper-based implementation of the Framework and strategy for disability and rehabilitation in Gauteng, South Africa

Background The prevalence of disability is on the rise globally and in South Africa, with a high number of unmet needs and poor actualisation of the health rights of persons with disabilities. A tool to realise these rights is health policy, such as the framework and strategy for disability and rehabilitation (2015-2022)(FSDR). There are limited data on the implementation outcomes of the FSDR. Objective To review the implementation of the FSDR according to the paper-based provincial reports. Methods The study conducted a document review and utilised a concurrent mixed-method design, combining qualitative and quantitative data extracted from paper-based evaluation templates developed by the South African National Department of Health (NDoH). The qualitative analysis involved thematic coding using the RE-AIM framework to examine the FSDR’s implementation across eight provinces, while quantitative data, such as frequencies and percentages, provided supplementary insights. Results The quantitative results revealed that 87% of the reports from provinces reported physical accessibility to the FSDR, and 62% of provinces received training on the implementation of the FSDR. Only two out of eight provinces have conducted monitoring and evaluation since implementing the FSDR in 2015. Qualitative findings revealed poor reach and adoption of the FSDR owing to a lack of implementation training for end users. The lack of indicators resulted in poor maintenance of the FSDR, as well as the lack of human resources and equipment which resulted in the reduced efficacy of the FSDR. Conclusion The FSDR has not achieved its full level of implementation due to numerous barriers, such as lack of resources, human capacity, and training on implementation.

Author Correction: Faces of different socio-cultural identities impact emotional meaning learning for L2 words

Agouti and BMP signaling drive a naturally occurring fate conversion of melanophores to leucophores in zebrafish

The often-distinctive pigment patterns of vertebrates are varied in form and function and depend on several types of pigment cells derived from embryonic neural crest or latent stem cells of neural crest origin. These cells and the patterns they produce have been useful for uncovering features of differentiation and morphogenesis that underlie adult phenotypes, and they offer opportunities to discover how patterns and the cell types themselves have diversified. In zebrafish, a body pattern of stripes arises by self-organizing interactions among three types of pigment cells. Yet these fish also exhibit white ornamentation on their fins that depends on the transdifferentiation of black melanophores to white cells, “melanoleucophores.” To identify mechanisms underlying this conversion we used ultrastructural, transcriptomic, mutational, and other approaches. We show that melanophore–melanoleucophore transition depends on regional BMP signals transduced through noncanonical receptors (Rgmb-Neo1a-Lrig2) as well as BMP-dependent signaling by Agouti genes, asip1 and asip2b . These signals lead to expression of transcription factor genes including foxd3 and runx3 that are necessary to induce loss of melanin, curtail new melanin production, and deploy a pathway for accumulating guanine crystals that, together, confer a white phenotype. These analyses uncover an important role for positional information in specifying ornamentation in zebrafish and show how tissue environmental cues and an altered gene regulatory program have allowed terminal addition of a distinct phenotype to a preexisting cell type.

Impacts of a prolonged marine heatwave and chronic local human disturbance on juvenile coral assemblages

Coral reefs are threatened by climate change and chronic local human disturbances. Although some laboratory studies have investigated the effects of combined stressors, such as nutrient enrichment and heat stress, on growth and survival of early life stage corals, in situ studies remain limited. To assess the influence of multiple stressors on juvenile corals, we quantified densities of corals ≤ 5 cm at 18 forereef sites with different exposure levels to underlying chronic local human disturbance before, during, and after the 2015-2016 El Niño. This marine heatwave caused prolonged heat stress and devastating losses of coral cover on the shallow forereef’s of Kiritimati, in the central equatorial Pacific Ocean. Here, we enumerated a total of 7732 juvenile corals from 13 different families. Over 80% of corals were from four families: 70% from Agariciidae, Merulinidae, or Poritidae, which all have stress-tolerant life history strategies, and 11% from Acroporidae which has a competitive life-history strategy. Both local disturbance and heat stress were significantly negatively related to juvenile coral densities. Prior to the heatwave, juvenile densities were on average 72% lower at the most disturbed sites (7.2 ±  1.9 m -2 ) compared to the least disturbed ones (15.3 ±  3.8 m -2 ). Overall, juvenile corals had a lower bleaching prevalence and lower mortality during the heatwave when compared to their adult counterparts. Still, the heatwave resulted in the loss of half (49%) of all juvenile corals, with those corals with competitive or weedy life history strategies undergoing greater declines than stress-tolerant ones. Although juvenile coral densities increased slightly in the year following the heatwave, the effect was statistically non-significant. Our results highlight the influence of chronic local anthropogenic and marine heatwaves on juvenile coral densities.

Identification of a novel unfolded protein response related signature for predicting the prognosis of acute myeloid leukemia

Antagonizing <i>cis-</i> regulatory elements of a conserved flowering gene mediate developmental robustness

Developmental transitions require precise temporal and spatial control of gene expression. In plants, such regulation is critical for flower formation, which involves the progressive maturation of stem cell populations within shoot meristems to floral meristems, followed by rapid sequential differentiation into floral organs. Across plant taxa, these transitions are orchestrated by the F-box transcriptional cofactor gene UNUSUAL FLORAL ORGANS ( UFO ). The conserved and pleiotropic functions of UFO offer a useful framework for investigating how evolutionary processes have shaped the intricate cis- regulation of key developmental genes. By pinpointing a conserved promoter sequence in an accessible chromatin region of the tomato ortholog of UFO , we engineered in vivo a series of cis- regulatory alleles that caused both loss- and gain-of-function floral defects. These mutant phenotypes were linked to disruptions in predicted transcription factor binding sites for known transcriptional activators and repressors. Allelic combinations revealed dosage-dependent interactions between opposing alleles, influencing the penetrance and expressivity of gain-of-function phenotypes. These phenotypic differences support that robustness in tomato flower development requires precise temporal control of UFO expression dosage. Bridging our analysis to Arabidopsis , we found that although homologous sequences to the tomato regulatory region are dispersed within the UFO promoter, they maintain similar control over floral development. However, phenotypes from disrupting these sequences differ due to the differing expression patterns of UFO . Our study underscores the complex cis- regulatory control of dynamic developmental genes and demonstrates that critical short stretches of regulatory sequences that recruit both activating and repressing machinery are conserved to maintain developmental robustness.

Epidemiology of reported serious adverse drug reactions due to anti-infectives using nationwide database of Thailand

Serious Adverse Drug Reactions (ADRs) can cause a longer stay, which can result in fatal outcomes. Understanding the prognostic factors for the serious ADRs play a vital role in developing appropriate serious ADR prevention strategies. This study aimed to analyze nationwide database in Thailand to identify predisposing factors associated with the serious ADRs, explore drug exposure, distribution of serious ADRs, types of ADRs, and classify the determinants of serious ADR due to anti-infective in Thailand. The national database of anti-infective-induced ADRs from January 2012 to December 2021 in Thailand’s 77 provinces, Thai Vigibase at the Health Product Vigilance Center (HPVC), was considered. After pre-processing, frequencies and percentages were used to investigate the distribution of ADR seriousness. To determine the significance of the independent variables on the seriousness of anti-infective-induced ADRs, logistic regression and the Classification and Regression Tree (CART) model were performed. A p-value &lt; 0.05 was considered statistically significant. A total of 82,333 ADR cases, of which 20,692 were serious ADRs (25.13%). Serious ADRs is statistically associated with region, gender, ethnicity, age, type of patient, history of drug allergy, chronic disease and dose frequency (p-value &lt; 0.001). The most commonly reported serious ADRs were in the South region of Thailand (OR = 1.92, 95% CI = 1.88–1.97), followed by the North region (OR = 1.68, 95% CI = 1.64–1.71) of Thailand. Gender and history of drug allergy were also statistically associated with the seriousness of ADRs (p-value = 0.001). Reported ADRs revealed that patients were males (OR =  1.11, 95% CI = 1.11–1.13) and those with a prior history of drug allergy (OR = 1.22, 95% CI = 1.20–1.24) were more likely to experience serious ADRs. The risk of having an ADR reported as serious was significantly higher in patients aged 60 and over (OR = 1.42, 95% CI = 1.39–1.46) and patients aged 40–59 years (OR = 1.34, 95% CI = 1.31–1.37) compared to patients aged 0–19 years. IPD patients most commonly associated with serious ADRs. The results of this study will enable healthcare professionals to use caution when prescribing to those groups. Furthermore, developing a reporting system to reduce serious ADR evidence, such as software with electronic prescribing databases or applications that enable efficient detection of ADRs in high-risk groups, was critical in order to closely monitor and improve patient safety.