ABSTRACT

Lupus erythematosus (LE)-specific bullous lesions are often difficult to distinguish from other bullous diseases presenting in patients with systemic lupus erythematosus. Herein, we describe a 49-year-old woman with systemic lupus erythematosus with recurrent tense bullae on the forearms. Clinical, histopathologic, and serologic findings led to the diagnosis of LE-specific bullous lesions. We also summarize the diagnostic clues for distinguishing LE-specific bullous lesions, bullous systemic lupus erythematosus, and erythema multiforme-like lesions in LE (Rowell syndrome).

Subject(s)

Erythema Multiforme , Lupus Erythematosus, Cutaneous , Lupus Erythematosus, Systemic , Skin Diseases, Vesiculobullous , Female , Humans , Middle Aged , Blister/diagnosis , Blister/etiology , Blister/pathology , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/pathology , Erythema Multiforme/diagnosis , Erythema Multiforme/pathology , Skin Diseases, Vesiculobullous/diagnosis , Skin Diseases, Vesiculobullous/pathology , Lupus Erythematosus, Cutaneous/diagnosis , Lupus Erythematosus, Cutaneous/pathology

ABSTRACT

OBJECTIVES: This systematic review of qualitative studies explored interventions to improve student nurses' knowledge, attitudes or willingness to work with older people. Student nurses are likely to encounter older people in all health and aged care settings, however, research demonstrates that few have career aspirations in gerontological nursing. METHODS: Qualitative systematic review method based on the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Search of Medline, Embase, PsycINFO, EBSCOhost and Scopus yielded 1841 articles which were screened to include primary research about educational interventions to improve student nurses' knowledge, attitudes and/or willingness to work with older people. Data extraction was performed on the 14 included studies, and data were analysed using directed content analysis. The Mixed Methods Appraisal Tool (MMAT) was used the assess the quality of the studies. CONCLUSIONS: Educational interventions included theory or practice courses, or a combination of theory and practice. While most interventions changed nursing students' negative attitudes towards older people, few increased their willingness to work with them. Practice courses had the most significant impact on willingness to work with older people. Quality assessment revealed methodical limitations. More research is needed to better understand the elements of practice interventions that enhance student nurses' knowledge, attitudes, and willingness to work with older people, so that they can be replicated.

Subject(s)

Geriatrics , Nurses , Students, Nursing , Aged , Humans , Attitude of Health Personnel , Clinical Competence

ABSTRACT

Significance: Advancements in label-free microscopy could provide real-time, non-invasive imaging with unique sources of contrast and automated standardized analysis to characterize heterogeneous and dynamic biological processes. These tools would overcome challenges with widely used methods that are destructive (e.g., histology, flow cytometry) or lack cellular resolution (e.g., plate-based assays, whole animal bioluminescence imaging). Aim: This perspective aims to (1) justify the need for label-free microscopy to track heterogeneous cellular functions over time and space within unperturbed systems and (2) recommend improvements regarding instrumentation, image analysis, and image interpretation to address these needs. Approach: Three key research areas (cancer research, autoimmune disease, and tissue and cell engineering) are considered to support the need for label-free microscopy to characterize heterogeneity and dynamics within biological systems. Based on the strengths (e.g., multiple sources of molecular contrast, non-invasive monitoring) and weaknesses (e.g., imaging depth, image interpretation) of several label-free microscopy modalities, improvements for future imaging systems are recommended. Conclusion: Improvements in instrumentation including strategies that increase resolution and imaging speed, standardization and centralization of image analysis tools, and robust data validation and interpretation will expand the applications of label-free microscopy to study heterogeneous and dynamic biological systems.

Subject(s)

Histological Techniques , Microscopy , Animals , Flow Cytometry , Image Processing, Computer-Assisted

ABSTRACT

DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA methylation that may contribute to the pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the mutation-induced functional misregulation of DNMT3A remains unclear. Here, we report the crystal structures of the DNMT3A methyltransferase domain, revealing a molecular basis for its oligomerization behavior distinct to DNMT3B, and the enhanced intermolecular contacts caused by the R882H or R882C mutation. Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutations-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.

Subject(s)

DNA (Cytosine-5-)-Methyltransferases , Leukemia, Myeloid, Acute , Humans , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methyltransferase 3A , Mutation , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , DNA Methylation/genetics , DNA/metabolism

ABSTRACT

During embryonic development, pluripotent cells assume specialized identities by adopting particular gene expression profiles. However, systematically dissecting the relative contributions of mRNA transcription and degradation to shaping those profiles remains challenging, especially within embryos with diverse cellular identities. Here, we combine single-cell RNA-Seq and metabolic labeling to capture temporal cellular transcriptomes of zebrafish embryos where newly-transcribed (zygotic) and pre-existing (maternal) mRNA can be distinguished. We introduce kinetic models to quantify mRNA transcription and degradation rates within individual cell types during their specification. These models reveal highly varied regulatory rates across thousands of genes, coordinated transcription and destruction rates for many transcripts, and link differences in degradation to specific sequence elements. They also identify cell-type-specific differences in degradation, namely selective retention of maternal transcripts within primordial germ cells and enveloping layer cells, two of the earliest specified cell types. Our study provides a quantitative approach to study mRNA regulation during a dynamic spatio-temporal response.

Subject(s)

Single-Cell Gene Expression Analysis , Zebrafish , Animals , Embryonic Development/genetics , Transcription, Genetic , RNA, Messenger/genetics , RNA, Messenger/metabolism , Gene Expression Regulation, Developmental

ABSTRACT

Existing mechanical metamaterials are typically designed to either withstand loads as a stiff structure, shape morph as a floppy mechanism, or trap energy as a multistable matter, distinct behaviours that correspond to three primary classes of macroscopic solids. Their stiffness and stability are sealed permanently into their architecture, mostly remaining immutable post-fabrication due to the invariance of zero modes. Here, we introduce an all-in-one reprogrammable class of Kagome metamaterials that enable the in-situ reprogramming of zero modes to access the apparently conflicting properties of all classes. Through the selective activation of metahinges via self-contact, their architecture can be switched to acquire on-demand rigidity, floppiness, or global multistability, bridging the seemingly uncrossable gap between structures, mechanisms, and multistable matters. We showcase the versatile generalizations of the metahinge and remarkable reprogrammability of zero modes for a range of properties including stiffness, mechanical signal guiding, buckling modes, phonon spectra, and auxeticity, opening a plethora of opportunities for all-in-one materials and devices.

ABSTRACT

Planar chiral [2.2]paracyclophanes consist of two functionalized benzene rings connected by two ethylene bridges. These organic compounds have a wide range of applications in asymmetric synthesis, as both ligands and catalysts, and in materials science, as polymers, energy materials and dyes. However, these molecules can only be accessed by enantiomer separation via (a) time-consuming chiral separations and (b) kinetic resolution approaches, often with a limited substrate scope, yielding both enantiomers. Here, we report a simple, efficient, metal-free protocol for organocatalytic desymmetrization of prochiral diformyl[2.2]paracyclophanes. Our detailed experimental mechanistic study highlights differences in the origin of enantiocontrol of pseudo-para and pseudo-gem diformyl derivatives in NHC catalyzed desymmetrizations based on whether a key Breslow intermediate is irreversibly or reversibly formed in this process. This gram-scale reaction enables a wide range of follow-up derivatizations of carbonyl groups, producing various enantiomerically pure planar chiral [2.2]paracyclophane derivatives, thereby underscoring the potential of this method.

ABSTRACT

The prevalence of Alzheimer's disease (AD) is increasing as the population ages, and patients with AD have a poor prognosis. However, knowledge on factors for predicting the survival of AD remains sparse. Here, we aimed to systematically explore predictors of AD survival. We searched the PubMed, Embase and Cochrane databases for relevant literature from inception to December 2022. Cohort and case-control studies were selected, and multivariable adjusted relative risks (RRs) were pooled by random-effects models. A total of 40,784 reports were identified, among which 64 studies involving 297,279 AD patients were included in the meta-analysis after filtering based on predetermined criteria. Four aspects, including demographic features (n = 7), clinical features or comorbidities (n = 13), rating scales (n = 3) and biomarkers (n = 3), were explored and 26 probable prognostic factors were finally investigated for AD survival. We observed that AD patients who had hyperlipidaemia (RR: 0.69) were at a lower risk of death. In contrast, male sex (RR: 1.53), movement disorders (including extrapyramidal signs) (RR: 1.60) and cancer (RR: 2.07) were detrimental to AD patient survival. However, our results did not support the involvement of education, hypertension, APOE genotype, Aß42 and t-tau in AD survival. Our study comprehensively summarized risk factors affecting survival in patients with AD, provided a better understanding on the role of different factors in the survival of AD from four dimensions, and paved the way for further research.

Subject(s)

Alzheimer Disease , Humans , Male , Alzheimer Disease/genetics , Biomarkers , Risk Factors , Genotype , Case-Control Studies , Amyloid beta-Peptides/genetics , tau Proteins/genetics

ABSTRACT

Collective cooperation is essential for many social and biological systems, yet understanding how it evolves remains a challenge. Previous investigations report that the ubiquitous heterogeneous individual connections hinder cooperation by assuming individuals update strategies at identical rates. Here we develop a general framework by allowing individuals to update strategies at personalised rates, and provide the precise mathematical condition under which universal cooperation is favoured. Combining analytical and numerical calculations on synthetic and empirical networks, we find that when individuals' update rates vary inversely with their number of connections, heterogeneous connections actually outperform homogeneous ones in promoting cooperation. This surprising property undercuts the conventional wisdom that heterogeneous structure is generally antagonistic to cooperation and, further helps develop an efficient algorithm OptUpRat to optimise collective cooperation by designing individuals' update rates in any population structure. Our findings provide a unifying framework to understand the interplay between structural heterogeneity, behavioural rhythms, and cooperation.

Subject(s)

Biological Evolution , Cooperative Behavior , Humans , Game Theory , Algorithms

ABSTRACT

Several studies have suggested the imprinting of SARS-CoV-2 immunity by original immune challenge without addressing the formation of the de novo response to successive antigen exposures. As this is crucial for the development of the original antigenic sin, we assessed the immune response against the mutated epitopes of omicron SARS-CoV-2 after vaccine breakthrough. Our data demonstrate a robust humoral response in thrice-vaccinated individuals following omicron breakthrough which is a recall of vaccine-induced memory. The humoral and memory B cell responses against the altered regions of the omicron surface proteins are impaired. The T cell responses to mutated epitopes of the omicron spike protein are present due to the high cross-reactivity of vaccine-induced T cells rather than the formation of a de novo response. Our findings, therefore, underpin the speculation that the imprinting of SARS-CoV-2 immunity by vaccination may lead to the development of original antigenic sin if future variants overcome the vaccine-induced immunity.

Subject(s)

Breakthrough Infections , Vaccines , Humans , Vaccination , Epitopes , SARS-CoV-2 , Immunity , Antibodies, Viral , Antibodies, Neutralizing

ABSTRACT

Bell nonlocality refers to correlations between two distant, entangled particles that challenge classical notions of local causality. Beyond its foundational significance, nonlocality is crucial for device-independent technologies like quantum key distribution and randomness generation. Nonlocality quickly deteriorates in the presence of noise, and restoring nonlocal correlations requires additional resources. These often come in the form of many instances of the input state and joint measurements, incurring a significant resource overhead. Here, we experimentally demonstrate that single copies of Bell-local states, incapable of violating any standard Bell inequality, can give rise to nonlocality after being embedded into a quantum network of multiple parties. We subject the initial entangled state to a quantum channel that broadcasts part of the state to two independent receivers and certify the nonlocality in the resulting network by violating a tailored Bell-like inequality. We obtain these results without making any assumptions about the prepared states, the quantum channel, or the validity of quantum theory. Our findings have fundamental implications for nonlocality and enable the practical use of nonlocal correlations in real-world applications, even in scenarios dominated by noise.

ABSTRACT

Decidual macrophages (dMϕs) play critical roles in regulation of immune-microhomeostasis at maternal-fetal interface during pregnancy, but the underlying molecular mechanisms are still unclear. In this study, it was found that litter size and fetal weight were significantly reduced, whereas the rate of embryo resorption was increased in miR-3074-5p knock-in (3074-KI) pregnant mice, compared to that of wild-type (WT) pregnant mice. Plasma levels of pro-inflammatory cytokines in 3074-KI pregnant mice were also significantly elevated compared to WT pregnant mice at GD7.5. The quantity of M1-Mϕs in uterine tissues of 3074-KI pregnant mice was significantly increased compared to WT pregnant mice at GD13.5. Estrogen receptor-α (ERα) was validated to be a target of miR-3074-5p. Either miR-3074-5p overexpression or ERα knockdown promoted transcriptional activity of NF-κB/p65, induced M1-polarization and pyroptosis of THP1-derived Mϕs, accompanied with increased intracellular levels of cleaved Caspase-1, cleaved IL-1ß, NLRP3, cleaved GSDMD and ASC aggregation. Furthermore, ERα could not only bind to NLRP3 or ASC directly, but also inhibit the interaction between NLRP3 and ASC. The endometrial miR-3074-5p expression level at the middle secretory stage of repeated implantation failure (RIF) patients was significantly decreased compared to that of control fertile women. These data indicated that miR-3074-5p could promote M1 polarization and pyroptosis of Mϕs via activation of NLRP3 inflammasome by targeting ERα, and the dysregulation of miR-3074-5p expression in dMϕs might damage the embryo implantation and placentation by interfering with inflammatory microenvironment at the maternal-fetal interface during early pregnancy.

ABSTRACT

Invasive species significantly impact biodiversity and ecosystem services, yet understanding these effects at large spatial scales remains a challenge. Our study addresses this gap by assessing the current and potential future risks posed by 94 invasive species to seven key ecosystem services in Europe. We demonstrate widespread potential impacts, particularly on outdoor recreation, habitat maintenance, crop provisioning, and soil and nitrogen retention. Exposure to invasive species was higher in areas with lower provision of ecosystem services, particularly for regulating and cultural services. Exposure was also high in areas where ecosystem contributions to crop provision and nitrogen retention were at their highest. Notably, regions vital for ecosystem services currently have low invasion suitability, but face an average 77% increase in potential invasion area. Here we show that, while high-value ecosystem service areas at the highest risk represent a small fraction of Europe (0-13%), they are disproportionally important for service conservation. Our study underscores the importance of monitoring and protecting these hotspots to align management strategies with international biodiversity targets, considering both invasion vulnerability and ecosystem service sustainability.

Subject(s)

Ecosystem , Introduced Species , Biodiversity , Conservation of Natural Resources , Europe , Nitrogen , Animals

ABSTRACT

Manipulating surface charge, electric field, and plasma afterglow in a non-equilibrium plasma is critical to control plasma-surface interaction for plasma catalysis and manufacturing. Here, we show enhancements of surface charge, electric field during breakdown, and afterglow by ferroelectric barrier discharge. The results show that the ferroelectrics manifest spontaneous electric polarization to increase the surface charge by two orders of magnitude compared to discharge with an alumina barrier. Time-resolved in-situ electric field measurements reveal that the fast polarization of ferroelectrics enhances the electric field during the breakdown in streamer discharge and doubles the electric field compared to the dielectric barrier discharge. Moreover, due to the existence of surface charge, the ferroelectric electrode extends the afterglow time and makes discharge sustained longer when alternating the external electric field polarity. The present results show that ferroelectric barrier discharge offers a promising technique to tune plasma properties for efficient plasma catalysis and electrified manufacturing.

ABSTRACT

The senescence of fruit is a complex physiological process, with various cell types within the pericarp, making it highly challenging to elucidate their individual roles in fruit senescence. In this study, a single-cell expression atlas of the pericarp of pitaya (Hylocereus undatus) is constructed, revealing exocarp and mesocarp cells undergoing the most significant changes during the fruit senescence process. Pseudotime analysis establishes cellular differentiation and gene expression trajectories during senescence. Early-stage oxidative stress imbalance is followed by the activation of resistance in exocarp cells, subsequently senescence-associated proteins accumulate in the mesocarp cells at late-stage senescence. The central role of the early response factor HuCMB1 is unveiled in the senescence regulatory network. This study provides a spatiotemporal perspective for a deeper understanding of the dynamic senescence process in plants.

Subject(s)

Cactaceae , Fruit , Fruit/genetics , Proteins/genetics , Cactaceae/genetics , Sequence Analysis, RNA

ABSTRACT

The present study aims to examine the characteristics of a composite material composed of glass/madar fibers and porcelain particles, which are reinforced with epoxy. A compression molding technique achieves the fabrication of this composite. A comprehensive characterization was conducted by employing a mixture of analytical techniques, including X-ray Diffraction (XRD), mechanical testing, Scanning Electron Microscopy (SEM), Dynamic Mechanical Analysis (DMA), and Thermogravimetric Analysis (TGA). The composition of the composite was determined using X-ray diffraction (XRD) analysis, which demonstrated the successful integration of porcelain fillers. The material exhibited notable mechanical properties, rendering it appropriate for utilization in structural applications. The utilization of SEM facilitated the examination of the microstructure of the composite material, thereby providing a deeper understanding of the interactions between the fibers and the matrix. DMA results revealed the glass/madar composite contained 4.2% higher viscoelastic properties when the addition of porcelain filler, thermal stability was improved up to the maximum temperature of 357 °C. This study provided significant insights into the properties of a hybrid epoxy composite consisting of glass/madar fibers reinforced porcelain particles.

ABSTRACT

Solute structure and its evolution in supersaturated aqueous solutions are key clues to understand Ostwald's step rule. Here, we measure the structural evolution of solute molecules in highly supersaturated solutions of KH2PO4 (KDP) and NH4H2PO4 (ADP) using a combination of electrostatic levitation and synchrotron X-ray scattering. The measurement reveals the existence of a solution-solution transition in KDP solution, caused by changing molecular symmetries and structural evolution of the solution with supersaturation. Moreover, we find that the molecular symmetry of H2PO4- impacts on phase selection. These findings manifest that molecular symmetry and its structural evolution can govern the crystallization pathways in aqueous solutions, explaining the microscopic origin of Ostwald's step rule.

ABSTRACT

Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.

Subject(s)

Colonic Neoplasms , Indoles , Interleukin-11 , Humans , Interleukin-11/therapeutic use , Cell Line, Tumor , Interleukin-6/metabolism , Cytokine Receptor gp130/metabolism , Colonic Neoplasms/drug therapy , Apoptosis

ABSTRACT

The presence of autoantibodies is a defining feature of many autoimmune diseases. The number of unique autoantibody clones is conceivably limited by immune tolerance mechanisms, but unknown due to limitations of the currently applied technologies. Here, we introduce an autoantigen-specific liquid chromatography-mass spectrometry-based IgG1 Fab profiling approach using the anti-citrullinated protein antibody (ACPA) repertoire in rheumatoid arthritis (RA) as an example. We show that each patient harbors a unique and diverse ACPA IgG1 repertoire dominated by only a few antibody clones. In contrast to the total plasma IgG1 antibody repertoire, the ACPA IgG1 sub-repertoire is characterised by an expansion of antibodies that harbor one, two or even more Fab glycans, and different glycovariants of the same clone can be detected. Together, our data indicate that the autoantibody response in a prominent human autoimmune disease is complex, unique to each patient and dominated by a relatively low number of clones.

Subject(s)

Arthritis, Rheumatoid , Autoantibodies , Humans , Anti-Citrullinated Protein Antibodies , Immunoglobulin G , Autoantigens

ABSTRACT

Species assemblage composition of marine microfossils offers the possibility to investigate ecological and climatological change on time scales inaccessible using conventional observations. Planktonic foraminifera - calcareous zooplankton - have an excellent fossil record and are used extensively in palaeoecology and palaeoceanography. During the Last Glacial Maximum (LGM; 19,000 - 23,000 years ago), the climate was in a radically different state. This period is therefore a key target to investigate climate and biodiversity under different conditions than today. Studying LGM climate and ecosystems indeed has a long history, yet the most recent global synthesis of planktonic foraminifera assemblage composition is now nearly two decades old. Here we present the ForCenS-LGM dataset with 2,365 species assemblage samples collected using standardised methods and with harmonised taxonomy. The data originate from marine sediments from 664 sites and present a more than 50% increase in coverage compared to previous work. The taxonomy is compatible with the most recent global core top dataset, enabling direct investigation of temporal changes in foraminifera biogeography and facilitating seawater temperature reconstructions.

Subject(s)

Foraminifera , Fossils , Zooplankton , Animals , Biodiversity , Ecosystem