Disease States Research Articles

Mechanisms of Homoarginine: Looking Beyond Clinical Outcomes

AbstractPurposeHomoarginine (hArg) is an arginine metabolite that has been known for years, but its physiological role in the body remains poorly understood. For instance, it is well known that high hArg concentrations in the blood are protective against several disease states, yet the mechanisms behind these health benefits are unclear. This review compiles what is known about hArg, namely its synthetic pathways, its role in different diseases and conditions, and its proposed mechanisms of action in humans and experimental animals.FindingsPrevious work has identified multiple pathways that control hArg synthesis and degradation in the body. Furthermore, endogenous hArg can modulate the cardiovascular system, with decreased hArg being associated with cardiovascular complications and increased mortality. Studies also suggest that hArg could serve as a diagnostic biomarker for a variety of immune, pancreatic, renal, and hepatic dysfunctions. Finally, in women, hArg concentrations rapidly increase throughout pregnancy and there are suggestions that alterations in hArg could indicate pregnancy complications like pre‐eclampsia.SummaryHomoarginine is an under‐appreciated amino acid with potential wide‐ranging roles in systemic health, pregnancy, and pathophysiology. Although recent research has focused on its health or disease associations, there is a need for more investigations into understanding the mechanistic pathways by which hArg may operate. This could be aided using metabolomics, which provides a comprehensive approach to correlating multiple metabolites and metabolic pathways with physiological effects. Increasing our knowledge of hArg's roles in the body could pave the way for its routine use as both a diagnostic and therapeutic molecule.

Disease-State Dependent Associations Between Intrinsic Brain Function and Symptoms of Fatigue, Depression, and Anxiety in Crohn’s Disease

Abstract Background Extraintestinal symptoms (EIS) in inflammatory bowel diseases, including fatigue, depression and anxiety, are highly prevalent, but poorly understood. Alterations of brain function may contribute to EIS, but their association with disease activity is unclear. This study analyzed intrinsic neural activity (INA) of individuals with Crohn’s disease (CD) in different disease states and examined the relationship between INA and EIS. Methods Patients with CD (n = 92) and healthy controls (n = 41) underwent functional magnetic resonance brain imaging and completed symptom-specific psychometry. Temporal (amplitude of low-frequency fluctuations, ALFF) and spatial (regional homogeneity, ReHo) markers of INA were compared between CD and controls and between active (patients with active Crohn’s disease [aCD]) versus remitted (rCD) disease. Regression analyses explored disease-state-dependent associations between INA and EIS. Results Patients exhibited aberrant INA in frontotemporal, occipital, and thalamic regions. Patients with aCD exhibited lower ALFF in left subcallosal cortex and inferior temporal gyri compared to rCD. Regional homogeneity in aCD was lower in left medial orbital gyrus and higher in right superior frontal, left inferior temporal, and left precentral gyrus. Compared to rCD, aCD showed higher ALFF predominantly in superior, ventro-, and dorsolateral prefrontal regions. Distinct associations between INA and EIS were detected in patients, particularly in the remitted state. Conclusions Intrinsic brain function in patients with CD varies by disease state, with prominent frontal cortex changes in active disease. These brain activity changes are at least partly related to the magnitude of neuropsychiatric symptoms and highlight a role of disturbed brain–gut interactions in the development of EIS especially in rCD.

Fibrotic and Emphysematous Murine Lung Mechanics Under Negative-Pressure Ventilation.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and the progressive nature heightens the calamity of the disease. Despite countless existing COPD studies, lung mechanics are often reported under positive-pressure ventilation (PPV) and implications and extrapolations made from these studies pose serious restrictions as recent works have divulged disparate elastic and energetic results between PPV and more physiological negative-pressure counterparts (NPV). This non-equivalence of PPV and NPV needs to be investigated under diseased states to augment our understanding of disease mechanics. To assess the comparability of diseased pulmonary mechanics in PPV and NPV, we pose a novel study to parse out the currently entangled contributions of ventilation mode and diseased state by analyzing murine PV curves from elastase-induced emphysema and dust-induced fibrosis models under positive- and negative-pressure and exploring biomarker resolution. We find that, for emphysema, under NPV, volume, compliance (C, Cstart, Cdef), and hysteresis are increased in diseased states and that under PPV only compliance (C, Cstart) is increased. For fibrosis, under NPV, volume, compliance (C, Cinf, Cdef, K), and hysteresis are decreased whereas under PPV only volume and static compliance decreased. These significances were observed solely at higher pressures (40 cmH2O). Our nuanced conclusions indicate the detection capabilities of multiple mechanics-based biomarkers are sensitive to the ventilation mode, where NPV exhibits more altered mechanics metrics in emphysema and fibrosis compared to PPV counterparts, suggesting the resolution of biomarkers when applied under NPV research considerations may offer greater versatility.

Chemical O‐ADP‐Ribosylations: Synthesis and Bioconjugation of ADPr‐Peptides/Proteins from NAD+

AbstractADP‐ribosylation is a complex post‐translational modification involved in key physiological processes and associated with various health and disease states. The growing interest in ADP‐ribosylation necessitates straightforward and efficient synthetic methods for the preparation of ADP‐ribosylated peptides/proteins. In this study, we report a facile reaction between nicotinamide adenine dinucleotide (NAD+) and alcohols promoted by a combination of ionic liquids, yielding up to 94 % with α : β ratios ranging from 88 : 12 to 99 : 1 and a switchable configuration selectivity. This method significantly simplifies the production of ADP‐ribosylated peptides and proteins, enabling diverse applications. It allows detailed investigation of side‐chain structure–activity relationships, facilitates two‐step clickable conjugation of ADP‐ribosyl groups to proteins, and, for the first time, enables non‐enzymatic synthesis of well‐defined ADP‐ribosylated peptides/proteins from natural counterparts and NAD+.

Disease features at diagnosis and changes in disease course severity among commercially insured patients with childhood-onset compared with adult-onset systemic lupus erythematosus

Introduction Systemic lupus erythematosus (SLE) causes widespread inflammation and damage in affected organs. Severity is determined by the type of organ systems affected and the extent of involvement. SLE occurs in childhood or adulthood and disease severity varies according to age of onset. We compared disease features and changes in disease severity over time between childhood-onset (cSLE) and adult-onset SLE (aSLE). Methods Patients 0–64 years old, newly diagnosed with SLE during 2014-2020 were identified using the MarketScan® database. A validated algorithm was used to assess disease severity. Improving severity versus baseline was defined as a transition from a higher (severe) to a lower (mild/moderate) disease state during each evaluation period. Group comparisons were made using the Pearson chi-square test for categorical and t test for continuous measures. Results A total of 10,912 patients were included. Most (89.9%) were female with a mean age of 14.2 versus 44.6 years for cSLE and aSLE groups, respectively. Patients with cSLE were more likely to have severe disease at diagnosis (38.3% vs 10.7%; p < .0001) versus aSLE. The largest reduction in SLE severity occurred during 6 to <12 months post-index with cSLE experiencing the greatest improvement (36.7% vs 19.9%; p < .0001) compared with aSLE. However, despite improvements observed over time in cSLE, this group was still more likely to have severe disease at 0 to <6 months (26.4% vs 10.5%) and 6 to <12 months (14.4% vs 8.6%) post-index compared with aSLE patients ( p < .01, all). For aSLE, the proportions of patients experiencing either an improvement or deterioration in symptoms was similar during 0 to <6 months and 6 to <12 months. However, during 12 to <24 months, nearly twice as many patients in this group experienced a deterioration in symptoms (30.1%) compared to improvement (15.6%). Conclusions Children with SLE present with greater symptom severity compared with adults. Although children were more likely to experience improvements following treatment, they had more active disease over time than aSLE patients. Disease severity remained stable for aSLE patients until the second year of follow-up, when more patients experienced a deterioration rather than improvement in symptoms.

Kisspeptin and Neurokinin B: roles in reproductive health

Kisspeptin and neurokinin B (NKB) play a key role in several physiological processes including in puberty, adult reproductive function including the menstrual cycle, as well as mediating the symptoms of menopause. Infundibular kisspeptin neurons, which co-express NKB, regulate the activity of gonadotropin releasing hormone (GnRH) neurons, and thus the physiological pulsatile secretion of GnRH from the hypothalamus. Outside of their hypothalamic reproductive roles, these peptides are implicated in several physiological functions including sexual behavior and attraction, placental function, and bone health. Over the last two decades, research findings have considerably enhanced our understanding of the physiological regulation of the hypothalamic-pituitary-gonadal (HPG) axis and identified potential therapeutic applications. For example, recognition of the role of kisspeptin as the natural inductor of ovulation has led to research investigating its use as a safer, more physiological trigger of oocyte maturation in <em>in vitro</em> fertilization (IVF) treatment. Moreover, the key role of NKB in the pathophysiology of menopausal hot flashes has led to the development of pharmacological antagonism of this pathway. Indeed, Fezolinetant, a neurokinin 3 receptor antagonist, has recently received Food and Drug Administration (FDA) approval for clinical use to treat menopausal vasomotor symptoms. Herein, we discuss the roles of kisspeptin and NKB in human physiology, including in the regulation of puberty, menstrual cyclicity, reproductive behavior, pregnancy, menopause, and bone homeostasis. We describe how perturbations of these key physiological processes can result in disease states and consider how kisspeptin and NKB could be exploited diagnostically, as well as therapeutically to treat reproductive disorders.

Combination therapy of low-dose radiotherapy and immunotherapy in advanced metastatic nasopharyngeal carcinoma: a case report and literature review.

Nasopharyngeal cancer (NPC) is a common head and neck malignant tumor, which is difficult to treat at the advanced NPC due to its occult and high metastatic potential to the cervical lymph nodes and distant organs. Low-dose radiotherapy (LDRT) is increasingly being investigated for potential cancer treatment. When combined with immune checkpoint inhibitors, LDRT has been shown to significantly improve the immune microenvironment of tumors, thereby promote the immune attack on tumor cells. However, the therapeutic effect of LDRT combined with immunotherapy in advanced NPC is not well understood. We report a case of a 31-year-old man was diagnosed with advanced metastatic nasopharnygeal non-keratinizing carcinoma (T4N3M1 stage IVb AJCC8th). The patient was treated with a high-dose of radiation therapy combined with LDRT and immunotherapy to inhibit tumor cell proliferation and activate the body's immune system. The initial treatment procedure was as follows: chemotherapy regimen (nedaplatin + docetaxel + fluorouracil) induction, followed by radical radiotherapy for the primary lesion, LDRT for the L5 vertebral body metastasis, and concurrent use of low-dose capecitabine beat chemotherapy and toripalimab immunotherapy. The patient was also administered with human granulocyte-macrophage colony-stimulating factor and aspirin to enhance the immune function. This combination therapy approach alleviated patient symptoms, improved bone changes in the L5 vertebral body and resolved the tumor without any adverse effects signals. The progression-free survival (PFS) has reached 27 months and he is currently stable without tumor recurrence. The combination of chemotherapy and LDRT with aspirin and human granulocyte macrophage colony-stimulating factor improved the disease state of advanced NPC cancer, effectively reducing the level of tumor markers, enhanced the immune function without significant adverse reactions.

Human physiological and psychological health maintenance through physical activity

Maintaining physical well-being and controlling several illnesses, including depression, cancer, diabetes, osteoporosis, hypertension, obesity, and cardiovascular disease, need regular physical activity. It has the potential to enhance endothelial function, which is impacted by smoking, age, and chronic illness. Adults who engage in aerobic exercise have better vascular function, which assists people with a variety of illnesses. Research has concentrated on the processes that lower the likelihood and severity of specific disease states, as well as the connection between physical exercise and cardiovascular disease.

How I Treat Anemia in Myelofibrosis.

Anemia is a common consequence of myelofibrosis. The treatment of myelofibrosis-associated anemia is complicated by a multifactorial pathobiology, as well as a lack of therapies that result in normalization of the bone marrow and complete restoration of its function. Established agents that are used to treat anemia in other bone marrow failure states such as myelodysplastic syndromes and aplastic anemia, are used for the treatment of myelofibrosis-associated anemia. However, there has been rapid development of new anemia-directed therapies; some of which have garnered regulatory approval. In addition to adopting therapies from other disease states, better understating of the root causes of myelofibrosis-associated anemia has positioned the field to be on the cutting edge of new anemia treatments, spearheading the advancement of agents that work on the hepcidin pathway to improve red cell production.

The value of metagenomic next-generation sequencing in the diagnosis of fever of unknown origin

Fever of unknown origin (FUO) caused by infection is a disease state characterized by complex pathogens and remains a diagnostic dilemma. Metagenomic next-generation sequencing (mNGS) technology is a promising diagnostic tool for identifying pathogenic microbes of FUO caused by infection. Little is known about the clinical impact of mNGS in the etiological diagnosis of FUO. This study focuses on the value of mNGS in the etiologic diagnosis of FUO by diagnostic performance, further clarifying the value of mNGS in clinical management. In a single-centre retrospective cohort study, 263 FUO patients who underwent both mNGS and culture at the First Affiliated Hospital of Nanchang University were enrolled from December 2020 to February 2023. The sensitivity and specificity of culture and mNGS were analyzed based on the final clinical diagnosis as the gold standard to assess the diagnostic value of mNGS in FUO cases. Among the 263 patients, 69.96%(184/263) cases were diagnosed as infectious diseases, of which lower respiratory tract infections were the most common, accounting for 53.26%(98/184). 30.04%(79/263) cases had a diagnosis of non-infectious disease. From these cases, mNGS identified 150 true-positive cases, 21 false-positive cases, 58 true-negative cases, and 34 false-negative cases. The sensitivity of mNGS in infection diagnosis was much higher than that of culture [81.52%(150/184) vs. 47.28%(87/184)], but the specificity was the opposite[73.42%(58/79) vs. 84.81%(67/79)]. mNGS had a receiver operating characteristic (ROC) curve of 0.775 for infectious disease, which was significantly higher than that of culture (0.661, P < 0.05). mNGS detection revealed that bacteria were the most commonly identified potential pathogens. The top causative pathogens identified were Acinetobacter baumannii. Of the 263 patients with FUO, clinical management of 48.67% (128/263) patients was positively affected by mNGS, and 51.33% (135/263) patients were not affected by mNGS(P = 0.1074). To sum up, infectious diseases are the principal cause of FUO. mNGS could significantly improve the detected pathogen spectrum of FUO caused by infection. However, the FUO disease spectrum is relatively broad, including a large number of non-infectious diseases. Therefore, Further investigation is warranted into the specific clinical scenarios for which mNGS may offer the greatest clinical diagnostic value.

Unravelling the impact of SARS-CoV-2 on hemostatic and complement systems: a systems immunology perspective

The hemostatic system prevents and stops bleeding, maintaining circulatory integrity after injury. It directly interacts with the complement system, which is key to innate immunity. In coronavirus disease 2019 (COVID-19), dysregulation of the hemostatic and complement systems has been associated with several complications. To understand the essential balance between activation and regulation of these systems, a quantitative systems immunology model can be established. The dynamics of the components are examined under three distinct conditions: the disease state representing symptomatic COVID-19 state, an intervened disease state marked by reduced levels of regulators, and drug interventions including heparin, tranexamic acid, avdoralimab, garadacimab, and tocilizumab. Simulation results highlight key components affected, including thrombin, tissue plasminogen activator, plasmin, fibrin degradation products, interleukin 6 (IL-6), the IL-6 and IL-6R complex, and the terminal complement complex (C5b-9). We explored that the decreased levels of complement factor H and C1-inhibitor significantly elevate these components, whereas tissue factor pathway inhibitor and alpha-2-macroglobulin have more modest effects. Furthermore, our analysis reveals that drug interventions have a restorative impact on these factors. Notably, targeting thrombin and plasmin in the early stages of thrombosis and fibrinolysis can improve the overall system. Additionally, the regulation of C5b-9 could aid in lysing the virus and/or infected cells. In conclusion, this study explains the regulatory mechanisms of the hemostatic and complement systems and illustrates how the biopathway machinery sustains the balance between activation and inhibition. The knowledge that we have acquired could contribute to designing therapies that target the hemostatic and complement systems.

Dialogue mechanisms between astrocytic and neuronal networks: A whole-brain modelling approach.

Astrocytes critically shape whole-brain structure and function by forming extensive gap junctional networks that intimately and actively interact with neurons. Despite their importance, existing computational models of whole-brain activity ignore the roles of astrocytes while primarily focusing on neurons. Addressing this oversight, we introduce a biophysical neural mass network model, designed to capture the dynamic interplay between astrocytes and neurons via glutamatergic and GABAergic transmission pathways. This network model proposes that neural dynamics are constrained by a two-layered structural network interconnecting both astrocytic and neuronal populations, allowing us to investigate astrocytes' modulatory influences on whole-brain activity and emerging functional connectivity patterns. By developing a simulation methodology, informed by bifurcation and multilayer network theories, we demonstrate that the dialogue between astrocytic and neuronal networks manifests over fast-slow fluctuation mechanisms as well as through phase-amplitude connectivity processes. The findings from our research represent a significant leap forward in the modeling of glial-neuronal collaboration, promising deeper insights into their collaborative roles across health and disease states.

RNA-binding proteins as versatile metabolic regulators

Metabolic shifts are a hallmark of numerous biological processes, including the differentiation of stem cells along a specific lineage and the activation of diverse cell types, such as immune cells. This review examines the intricate energy metabolic alterations that occur in diverse biological settings, from embryonic development to adult tissue homoeostasis and disease states. In particular, we emphasise the regulatory function of RNA-binding proteins (RBPs) in coordinating these metabolic shifts and examine how they modulate key pathways, such as glycolysis and oxidative phosphorylation, to meet the dynamic cellular energy demands. This review highlights the various mechanisms by which RBPs regulate these changes, ranging from active involvement in the post-transcriptional regulation of metabolically relevant genes to alteration of an RBP’s function by specific RNAs, metabolites or growth factors. Finally, we consider how ageing and disease affect the function of RBPs and how RBPs can disrupt the delicate balance of metabolic regulation. Taken together, this review provides a comprehensive overview of the critical interplay between RBPs and metabolism and offers insights into potential therapeutic targets for regenerative medicine and age-related diseases.

CFTR mutation is associated with bone differentiation abnormalities in cystic fibrosis.

Cystic Fibrosis-related Bone Disease is an emerging challenge faced by 50 % of adult people with cystic fibrosis (CF). The multifactorial causes of this comorbidity remain elusive. However, congenital bone defects have been observed in animal models with CFTR mutations, suggesting its importance. The role of CFTR in bone cells development is unknown. Studies from human cells remain somewhat controversial depending on the cells used and the disease state of the patients from which the cells derived. Therefore, we investigated the role of CFTR in osteoblast development using induced pluripotent stem cells generated from homozygous CF donors for F508del and non-CF controls. This approach allows for a clear understanding towards how the CFTR mutation may influence osteoblast differentiation independently from other confounding factors. We observed a lower capacity of differentiation in CF cells as compared to control, already from mesenchymal stem cells (MSC) stage, whereby they retained expression of the pluripotency marker OCT4. Furthermore, our results demonstrated a delayed osteoblast commitment and altered expression of specific markers, such as an increased RANKL/OPG ratio and decreased BMP2, suggesting a potentially perturbed bone homeostasis associated with CFTR mutation. This is the first study of its kind, clearly demonstrating a role for CFTR mutation in delaying osteoblast differentiation and/or regeneration.

IL-33, a neutrophil extracellular trap-related gene involved in the progression of diabetic kidney disease.

Chronic inflammation is well recognized as a key factor related to renal function deterioration in patients with diabetic kidney disease (DKD). Neutrophil extracellular traps (NETs) play an important role in amplifying inflammation. With respect to NET-related genes, the aim of this study was to explore the mechanism of DKD progression and therefore identify potential intervention targets. Hub NET-related DEGs were screened via differential expression analysis and three machine learning methods, namely, LASSO, SVM-RFE and random forest. Consensus clustering was performed to analyze NET-related subtypes in DKD patients. KEGG enrichment analysis, GSEA, GSVA, ssGSEA and ESTIMATE were conducted to explore the molecular features of DKD patient subtypes. Leveraging single-nucleus RNA-seq datasets, the "scissor" and "bisqueRNA" algorithms were applied to identify the composition of renal cell types in DKD patient subtypes. Soft clustering analysis was performed to obtain gene groups with similar expression patterns during the development and progression of DKD. The correlations between hub NET-related DEGs and clinical parameters were mined from the Nephroseq V5 database. The core gene among the hub NET-related DEGs was selected by calculating semantic similarity. "Cellchat" algorithm, immunostaining, ELISA and flow cytometry were performed to explore the expression and function of the core gene. The Drug-Gene Interaction Database (DGIdb) was searched to identify candidate drugs. Six hub NET-related DEGs, namely, ACTN1, ITGB2, IL33, HRG, NFIL3 and CLEC4E, were identified. On the basis of these 6 genes, DKD patients were classified into 2 clusters. Cluster 1 patients, with higher NET scores, were evidently more immune-activating than those of cluster 2. Markedly increased numbers of immune cells, fibroblasts and proinflammatory proximal tubular cells were observed in cluster 1 but not in cluster 2. Cluster 1 also represented a more clinically advanced disease state. Among the 6 hub NET-related DEGs, the mRNA expression of ACTN1, ITGB2, IL33 and HRG was correlated with the eGFR. By semantic similarity analysis, IL33 was considered a central gene among the 6 genes. Cell-cell communication analysis further indicated that intercellular interactions via IL-33 were enhanced in DKD. Serum IL-33 concentration was negatively correlated with eGFR. IHC staining revealed that IL-33 expression was upregulated in the tubular epithelium in DKD patients. Supernatants from inflammatory tubular epithelial cells can increase MPO in neutrophils, whereas addition of anti-IL-33 antibody attenuated this phenotype. We identified 2 distinct NET-related subtypes in DKD patients, in which one subgroup was apparently more inflammatory and associated with a more severe clinical state. A significantly increased level of IL-33 in this inflammatory patient subgroup may play a role in aggravating inflammation via the IL-33-ST2 axis.

A Consistent Lack of Consistency: Definitions, Evidentiary Expectations and Potential Use of Meaningful Change Data in Clinical Outcome Assessments Across Stakeholders. Results from a DIA Working Group Literature Review and Survey.

Clinical outcome assessments (COAs) measure how patients feel or function and can be used to understand which patients experience benefits of treatment and which do not. Interpretation of COA data is influenced by how meaningful change is defined. We aimed to compare how different stakeholders define, assess, and use meaningful change for decisions that impact patients. A targeted literature review was undertaken in July 2021 using Medline, Embase, online grey literature search engines, and stakeholder organization websites. Additionally, a stakeholder survey on meaningful change was fielded between March and June 2023. Both quantitative and qualitative methods were used to analyze responses and identify key themes. The literature review resulted in 86 references. These revealed different approaches to define, measure and validate meaningful change. There were 248 survey responses. Many respondents felt the terminology and methods for defining meaningful change are confusing. Respondents also emphasized the importance of distinguishing within-patient and between-group change, and defining meaningfulness from the patient perspective (most patients and caregivers do not share a similar definition of meaningfulness as their healthcare professionals). Four key recommendations for defining, establishing, and interpreting meaningful change estimates for COAs are: (1) Be clear on the type of "meaningful change" that is discussed or needed for a COA, (2) Ensure the "patient voice" is informing meaningful change estimates/definitions, (3) Acknowledge that a meaningful change estimate for a COA may differ between populations, diseases, and disease states, and (4) Disseminate data in a way that reduces ambiguity.

Digital Profiling of Tumor Extracellular Vesicle-Associated RNAs Directly from Unprocessed Blood Plasma.

Tumor-derived extracellular vesicle (tEV)-associated RNAs hold promise as diagnostic biomarkers, but their clinical use is hindered by the rarity of tEVs among nontumor EVs. Here, we present EV-CLIP, a highly sensitive droplet-based digital method for profiling EV RNA. EV-CLIP utilizes the fusion of EVs with charged liposomes (CLIPs) in a microfluidic chip. Optimized CLIP surface charge enables exceptional sensitivity and selectivity for EV-derived miRNAs and mRNAs. This approach streamlines detection with minimal plasma volume (20 μL) and eliminates the need for prior EV isolation or RNA preparation, preventing loss of EVs or RNA. In testing with 83 patient samples, EV-CLIP detected EGFR L858R and T790M mutations with high AUC values of 1.0000 and 0.9784, respectively. Its success in serial monitoring during chemotherapy highlights its potential for precise quantification of rare EV subpopulations, facilitating the exploration of single EV RNA content and enhancing understanding of diverse EV populations in various disease states.

Design and characterization of a micro RNA-200c detecting Broccoli fluorescent light-up aptamer.

In the last decade the important role of small non-coding RNAs such as micro RNAs (miRs) in gene regulation in healthy and disease states became more and more evident. The miR-200-family of miRs has been shown to play a critical role in many diseases such as cancer and neurodegenerative disorders and could be potentially important for diagnosis and treatment. However, the size of miRs of about ~21-23nt provide challenges for their investigation. Here we report the conversion and optimization of the Broccoli fluorescent light-up RNA-aptamer into a specific sensor for miR-200c using a strand-displacement design principle. This aptamer can differentiate miR-200c from its family members whose sequence differ by more than one nucleotide. By adding this in vitro transcribed aptamer to RNA extracts from human cells, we can detect miR-200c in vitro in a plate reader assay.

Effects of periodontal disease on the proteomic profile of the periodontal ligament.

Periodontal disease affects over 1 billion people globally. This study investigated how periodontitis affects the protein profile of the periodontal ligament (PDL) in rats. Eight Holtzman rats were divided into the control and experimental periodontitis groups. The PDL was isolated using laser capture microdissection, and protein extracts were analyzed by mass spectrometry. Data analysis utilized specialized software, and Gene Ontology enrichment analysis identified significant protein functions. The data are available via ProteomeXchange with identifier PXD055817. Proteins such as SerpinB1, C5, and Lgals3 were validated through immunohistochemistry, and their gene expression was examined in an in vitro human PDL cell line. This study identified 1326 proteins, with 156 unique to the control group, 294 unique to the periodontitis group, and 876 common to both groups. Enrichment analysis revealed that proteins associated with the regulation of enzyme activity and RNA binding were significantly represented in the periodontitis group. There were increased levels of SerpinB1, C5, and Lgals3 in the periodontitis group based on proteomic and immunohistochemical analyses. Furthermore, these targets showed increased gene expression in stimulated human PDL cells. This study provides insights into the periodontitis-related alterations in the protein composition of the PDL and PDL cells, identifying both novel and previously known disease-associated proteins. SIGNIFICANCE: The periodontal ligament plays a crucial role in oral functions by providing structural support to the tooth. Due to the presence of undifferentiated mesenchymal cells, research into its regenerative capacity is ongoing. Pathological conditions can affect these functions and protein composition. Currently, there is a lack of comprehensive research specifically focusing on evaluating the periodontal ligament in both healthy and diseased states. This pioneering study screened for protein alterations and the mechanisms related to periodontitis. The possibility of using proteomic analysis to evaluate the protein alterations that occur in periodontitis-a disease with a high global incidence-could provide therapeutic targets and new biomarkers for future clinical studies.

Neuropsychological test performance in mild cognitive impairment with Lewy bodies: A systematic review and meta-analysis.

We sought to characterize the cognitive profile among individuals with mild cognitive impairment with Lewy bodies (MCI-LB) to help guide future clinical criteria. Systematic review and meta-analysis included MCI-LB studies with cognitive data from PubMed, Embase, Web of Science, and PsycINFO (January 1990 to March 2023). MCI-LB scores were compared to controls, MCI due to Alzheimer's disease (MCI-AD), and dementia with Lewy bodies (DLB) groups with random-effects models. We included 26 studies and 2823 participants. Across all domains, the MCI-LB group performed worse than controls and better than DLB. Compared to MCI-AD, the MCI-LB group performed worse in attention/processing speed (g=-0.24, 95% confidence interval [CI]: -0.35, -0.12), attention/executive (g=-0.42, 95% CI: -0.56, -0.28); better in verbal immediate recall (g=0.37; 95% CI: 0.15, 0.59) and delayed memory (g=0.40; 95% CI: 0.22, 0.58). The cognitive profiles in MCI-LB and MCI-AD are consistent with established profiles in DLB and AD. Neuropsychological assessment may be helpful in differential diagnosis, even in early disease states. We performed a systematic review and meta-analysis for cognition in mild cognitive impairment with Lewy bodies (MCI-LB). Compared to MCI due to Alzheimer's disease (MCI-AD), MCI-LB had worse attention, executive function, and processing speed. Compared to MCI-AD, MCI-LB had better verbal immediate and delayed recall. The MCI-LB group was worse on all cognitive domains than controls, and better than dementia with Lewy bodies. Studies used different tests and there is a need for global efforts for harmonization.