Clinical Sample Of Patients Research Articles

13 Investigating the Influence of Educational Attainment and Crystalized Verbal Skills on Verbal Fluency Performance Among Patients from a Community-Based Outpatient Neurology Clinic

Objective:Neuropsychological measures of verbal fluency help detect cognitive decline and neuropathology. The discrepancy between semantic verbal fluency and phonemic verbal fluency is commonly utilized to differentiate between cortical and subcortical processes. Understanding how other factors influence a patient’s verbal fluency scores is vital in informing clinical interpretation of neuropsychological test data. This study aimed to investigate how educational attainment and crystalized verbal skills (i.e., word reading and vocabulary) influence verbal fluency performance among a clinical sample of patients seen for neuropsychological evaluation services at a community-based outpatient neurology clinic.Participants and Methods:We utilized data from N=26 patients [mean age = 50.5 (SD = 22.0), 31% female, mean education = 13.5 (SD = 2.3)] who completed neuropsychological evaluations as part of their clinical care at an outpatient neurology clinic. Participants were included in this study if they had complete data for all variables of interest. We used Pearson correlation analyses to investigate associations between each predictor variable of interest (years of education, WRAT-5 Reading, WASI-2 Vocabulary) and age-norm corrected D-KEFS Verbal Fluency scores. Prior to analysis, all variables were converted to z-scores.Results:We found that years of education (r = 0.49, p = 0.01) and vocabulary (r = 0.41, p = 0.04) were significantly positively correlated with category fluency performance. Reading was also positively correlated with category fluency at trend level, but this association was not statistically significant (r = 0.36, p = 0.07). We found that vocabulary (r = 0.47, p = 0.02) and reading (r = 0.51, p = 0.007) were significantly positively correlated with phonemic fluency performance, while the association between education and phonemic verbal fluency performance was not significant (r = 0.27, p = 0.18).Conclusions:Our results suggest that educational attainment and crystalized verbal skills are positively associated with verbal fluency performance, though the degree of influence of these individual factors may differ for category fluency vs phonemic fluency performance. Our results have implications for the clinical practice of neuropsychology. Namely, appreciating a patient’s educational attainment and crystalized verbal skills can help guide clinical interpretation of whether or not a patient’s verbal fluency test scores reflect a decline from their baseline. This may be particularly important to consider among patients with high educational attainment or high premorbid verbal skills, as a subtle decline in their verbal fluency abilities may not be appreciated if relying only on age-based norms for interpretation. This is clinically relevant including when assessing for the early stages of neurodegenerative disorders (e.g., Alzheimer’s disease, Primary Progressive Aphasia) or for subtle changes associated with stroke or brain injury.

Opioid use disorder in two samples of the Lebanese population: scale validation and correlation with sleep and mood disorders.

The revised Opioid Risk Tool (ORT-OUD) is a brief, self-report scale designed to provide clinicians with a simple, validated method to screen for the risk of developing an Opioid Use Disorder (OUD) in patients without a prior history of substance abuse. This study aimed to translate and validate the Arabic version of ORT-OUD in the Lebanese population and assess its clinical validity in a sample of patients with OUD. This cross-sectional study in the Lebanese population used several validated scales to assess the risk of OUD, including the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). Other tools evaluated chronotype and sleep and mood disturbances. Principal component analysis with Varimax rotation was applied to assess ORT-OUD construct validity. Convergent validity with the Arabic version of ASSIST was evaluated. The ORT-OUD criterion validity was then assessed in a clinical sample of patients with OUD. This study included 581 participants. The prevalence of the OUD risk in the Lebanese population using the ORT-OUD scale and the ASSIST-opioids scale was estimated at 14.5% and 6.54%, respectively. No items of the ORT-OUD were removed; all items converged over a solution of four factors with an eigenvalue > 1, explaining a total of 68.2% of the variance (Cronbach's alpha = 0.648). The correlation coefficients between the ORT-OUD total score and ASSIST subscales were as follows: ASSIST-opioids (r = 0.174; p = < 0.001), ASSIST-sedatives (r = 0.249; p < 0.001), and ASSIST-alcohol (r = 0.161; p = < 0.001). ORT-OUD clinical validation showed a correlation with ASSIST-opioids (r = 0.251; p = 0.093) and ASSIST-sedatives (r = 0.598; p < 0.001). Higher ORT-OUD scores were associated with a family and personal history of alcohol and substance consumption and higher insomnia and anxiety scores. This study is the first to validate the Arabic version of ORT-OUD in the Lebanese population, an essential step towards improving the detection and management of OUD in this population.

From viral democratic genomes to viral wild bunch of quasispecies.

The tremendous majority of RNA genomes from pathogenic viruses analyzed and deposited in databases are consensus or "democratic" genomes. They represent the genomes most frequently found in the clinical samples of patients but do not account for the huge genetic diversity of coexisting genomes, which is better described as quasispecies. A viral quasispecies is defined as the dynamic distribution of nonidentical but closely related mutants, variants, recombinant,or reassortant viral genomes. Viral quasispecies have collective behavior and dynamics and are the subject of internal interactions that comprise interference, complementation, or cooperation. In the setting of SARS-CoV-2 infection, intrahost SARS-CoV-2 genetic diversity was recently notably reported for immunocompromised, chronically infected patients, for patients treated with monoclonal antibodies targeting the viral spike protein, and for different body compartments of a single patient. A question that deserves attention is whether such diversity is generated postinfection from a clonal genome in response to selection pressure or is already present at the time of infection as a quasispecies. In the present review, we summarize the data supporting that hosts are infected by a "wild bunch" of viruses rather than by multiple virions sharing the same genome. Each virion in the "wild bunch" may have different virulence and tissue tropisms. As the number of viruses replicated during host infections is huge, a viral quasispecies at any time of infection is wide and is also influenced by host-specific selection pressure after infection, which accounts for the difficulty in deciphering and predicting the appearance of more fit variants and the evolution of epidemics of novel RNA viruses.

3 Validity of the tele-administered Montreal Cognitive Assessment for identifying geriatric neurocognitive disorders

Objective:With the emergence of the coronavirus 2019 pandemic, investigating the validity of tele-screenings for neuropsychological status has become increasingly necessary. While the telephone version of the Montreal Cognitive Assessment (MoCA-T) has been validated for use in patients with Parkinson’s and stroke/cerebrovascular disease, the clinical utility of this instrument in geriatric patients with other suspected cognitive disorders has yet to be determined. Thus, the present study aimed to examine the classification accuracy of the MoCA-T in a mixed clinical sample of patients with mild cognitive impairment (MCI) or dementia.Participants and Methods:Ninety-one older adults were administered the MoCA-T via videoconferencing technology as part of a comprehensive neurocognitive evaluation performed by a multidisciplinary treatment team within a dementia specialty clinic. Based on this evaluation, 51 (56.0%) patients were diagnosed with dementia, 27 (29.7%) with MCI, and 13 (14.3%) with no neurocognitive diagnosis (i.e., subjective cognitive complaints). In addition to MoCA-T total and item scores, we also computed subscale scores for between-group comparisons as the sum of items assessing orientation, language, attention/executive function, and memory. ANOVA/ANCOVA and ROC curve analyses were used to examine between-group differences on the MoCA-T and its psychometric properties in discriminating patients with MCI or dementia, respectively.Results:Participants had a mean age of 74.3 ± 8.7 and education of 16 ± 2.9 years. Patients with dementia were significantly older than those with MCI and no diagnosis, but there were no other significant between-group differences in clinical characteristics. MoCA-T total [F(2,86)=28.5, p&lt;0.001] and all subscale scores (p&lt;0.01) differed significantly between groups and in the expected direction (dementia&lt;MCI&lt;no diagnosis) even after controlling for age. The only exception was language for which there was initially a statistical trend (p=0.06) that reached significance (p&lt;0.05) after controlling for age. In terms of individual items, abstraction, fluency, orientation to place/city, and category cued recall were the only items that did not differ significantly between groups. ROC curve analyses revealed -5 points to be the optimum cut-off for distinguishing between cognitively normal individuals from patients with MCI (Sensitivity=0.67; Specificity=0.77; AUC=0.78), and a cut-off of -8 points optimally distinguished between patients with MCI and dementia (Sensitivity=0.77; Specificity=0.74; AUC=0.81).Conclusions:The current study provides further evidence for the clinical utility of the MoCA-T as a screening instrument for neurocognitive disorders in older adults and extends prior work to include administration via videoconferencing technology. While previous studies have focused on the use of MoCA-T in specific patient populations, here, we demonstrate the validity of this screening tool in a mixed-clinical sample, which suggests its broader use in clinical settings for distinguishing between neurocognitive disorders, regardless of the underlying etiology.

Synthesis of Au-decorated boron nitride nanotubes and its application to pretreatment-free electrochemical biosensor for matrix metalloproteinase9 in clinical sample

As matrix metalloproteinase-9 (MMP-9) is a biomarker for several diseases such as inflammatory, cardiovascular, and lung diseases, determining its level in human serum is vital for the detection of such diseases. However, accurately detecting MMP-9 in serum requires a time-consuming and expensive pre-treatment process with filters. To minimize the diagnosis process, the authors constructed a pre-treatment-free electrochemical biosensor for determining MMP-9 in clinical sample. To fabricate the biosensor, Au-decorated boron nitride nanotubes (Au@BNNTs) were synthesized to improve the sensor's performance. The synthesis of Au@BNNTs was confirmed through transmission electron microscopy (TEM), energy dispersive spectrometer (EDS), and Fourier-transform infrared spectroscopy (FT-IR) experiments. Then, the MMP-9 aptamer was immobilized on the Au@BNNTs-modified round Au micro-gap integrated printed circuit board (PCB) chip. The electrochemical biosensor's performance was validated by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Based on this, the electrochemical signal amplification ability of Au@BNNTs is confirmed, and its potential is demonstrated. In addition, the fabricated biosensor can detect the MMP-9 in 100% human serum. The linear detection range test yielded a wider concentration range (0.1–10,000 ng∙mL−1) and a lower limit of detection (0.0218 ng∙mL−1) for MMP-9 compared to previous research. Finally, through a selectivity test and clinical patient sample test, it is confirmed that the proposed biosensor specifically detects only MMP-9 well. The proposed Au@BNNT biosensor with aptamer has potential applications in MMP-9 detection and diagnosis of various diseases without the need for pretreatment.

A golgi-targeting and polarity-specific fluorescent probe for the diagnosis of cancer and fatty liver in living cells and tissues

Elucidating the intrinsic relationship between diseases and Golgi apparatus polarity remains a great challenge owing to the lack of the Golgi-specific fluorescent probe for polarity. Until now, the visualization of abnormal Golgi apparatus polarity in clinical cancer patient samples has not been achieved. To meet this urgent challenge, we facilely synthesized a robust Golgi-targeting and polarity-specific fluorescent probe (GCSP), which consists of an electron-acceptor solvatochromic coumarin 343 and an electron-donor Golgi-targeting group phenylsulfonamide. Owing to the typical D-π-A molecular configuration with unique intramolecular charge transfer effect, GCSP exhibits high sensitivity to polarity change in different solvents. Moreover, we revealed that GCSP possessed a satisfactory ability to sensitively monitor Golgi apparatus polarity changes in living cells. Using GCSP, we have successfully shown that Golgi apparatus polarity may serve as an ubiquitous marker for cancer and fatty liver detection. Surprisingly, the visualization of Golgi polarity has been achieved not only at the cellular levels, but also in clinical tissue samples from cancer patients, thus holding great potential in the clinical diagnosis of human cancer. All these features render GCSP an effective tool for the accurate diagnosis of Golgi apparatus related diseases.

Is the road to burnout paved with perfectionism? The prevalence of obsessive-compulsive personality disorder in a clinical longitudinal sample of female patients with stress-related exhaustion.

Few studies have investigated the relationship between stress-related mental health problems and obsessive-compulsive personality disorder (OCPD). Similarly, little research has focused on the moderating effect of OCPD on recovery in clinical patients with stress-related mental health problems. The general aim of this study was to investigate the prevalence of OCPD and the associations between OCPD and level of burnout, anxiety, and depression symptoms, during a 7-years follow-up in a clinical longitudinal sample of female patients with stress-related exhaustion. The included patients (n = 84) were referred to a specialist outpatient clinic for patients with stress-related exhaustion between 2006 and 2011. Data was collected at the initial examination and during a 7-year treatment follow-up. OCPD was the most common personality disorder in the present clinical sample, with 40% of patients fulfilling the criteria. There was a significant association between OCPD and the degree of burnout symptoms as well as the degree of depression, both at baseline and during the 7-year follow-up. No significant association between OCPD and levels of anxiety was observed. The results support the hypothesis that there might be an association between OCPD and stress-related exhaustion, including preservation of symptoms over time. OCPD and its related traits, such as perfectionism, may be important factors to consider when constructing effective treatment and rehabilitation plans for these patients.

Highly sensitive voltammetric sensor comprising CuSn(OH)6–multi-walled carbon nanotubes–β-cyclodextrin composites and poly(L-arginine) for indole-3-lactic acid analyses in alcohol use disorder serum samples

A highly sensitive voltammetric sensing platform configured via the drop-casting of composites of CuSn(OH)6–multi-walled carbon nanotubes–β-cyclodextrin (CuSn(OH)6–MWCNT–βCD) on an arginine-electropolymerized screen-printed carbon electrode (CuSn(OH)6–MWCNT–βCD/p-Arg/SPCE) was demonstrated to determine the concentrations of indole-3-lactic acid (ILA) in buffer and serum solutions. Prior to the analysis, the successful assembly of the composites and polymer layers was confirmed using field emission scanning electron microscopy, atomic force microscopy, and X-ray photoelectron spectroscopy. The changes in the current due to the direct oxidation of ILA on the modified electrode were used to quantify the ILA. A dynamic range of 0.05–20 μM with a limit of detection of 9 nM for ILA under optimal conditions was achieved primarily with the combined use of CuSn(OH)6, MWCNT, and βCD, resulting in a large electrochemical active surface area (0.185 cm2), low charge transfer resistance (∼2 Ω), and fast electron transfer. Furthermore, the sensing performance, including selectivity, sensitivity, reproducibility, repeatability, and stability, for ILA detection was evaluated. Finally, the ILA concentrations in the pooled clinical serum samples of healthy control and alcohol use disorder patients were measured using our method, the results of which exhibited a notable resemblance to those obtained using liquid chromatography with tandem mass spectrometry.

Complete genome sequences of eight Auritidibacter ignavus strains isolated from ear infections in Germany.

Here, we present the complete genome sequences of eight Auritidibacter ignavus strains isolated from clinical samples of patients with ear infections in Bochum, Germany. The sequence information will give assistance to greater knowledge about the virulence potential of this unfamiliar putative pathogen.

Transdiagnostic analysis of adverse childhood experiences and their association with psychopathology–A TRANS-D conform study

Transdiagnostic approaches challenge traditional psychiatric classification systems. Adverse childhood experiences (ACE) represent a transdiagnostic risk factor for psychopathology with dose dependency. As different qualities of ACE typically co-occur, we identified ACE patterns to assess their power for predicting psychopathology compared to traditional diagnoses. Following TRANS-D guidelines, we categorized participants (N=360) with persistent depressive disorder (PDD), borderline personality disorder (BPD), or healthy control status (HC) into subcategories defined by ACE pattern, using the Childhood Trauma Questionnaire (CTQ). Improvement of the transdiagnostic vs. diagnostic approach in predicting psychopathology was evaluated in a cross-validated predictive modeling framework focusing on the clinical sample of PDD and BPD patients. Results were externally validated in another transdiagnostic sample (N=138). Seven pattern-based subcategories with distinct ACE profiles were identified in the primary sample and replicated in the validation sample. Patterns cut across diagnostic groups. Predictive modeling showed that diagnoses could not predict depressive symptoms and loneliness. Transdiagnostic constructs systematically predicted all measures. This study showcases ACE as a promising construct for transdiagnostic research. Our data-driven framework identified robust ACE subcategories mapping onto general and interpersonal psychopathology. Patterns of CTQ-based information may provide an approach to integrating information on co-occurring ACE to inform diagnostics and treatment.

Sensitive, rapid detection of NCOA4-m6A towards precisely quantifying radiation dosage on a Cas13a-Microdroplet platform

Precise quantification of low-dose ionizing radiation is of great significance in protecting people from damage caused by clinical radiotherapy or environmental radiation. Traditional techniques for detecting radiation, however, remain extreme challenges to achieve high sensitivity and speed in quantifying radiation dosage. In this work, we report a Cas13a-Microdroplet platform that enables sensitive detection of ultra-low doses of radiation (0.5 Gy vs. 1 Gy traditional) within 1 h. The micro-platform adopts an ideal, specific radiation-sensitive marker, m6A on NCOA4 gene (NCOA4-m6A) that was first reported in our recent work. Microfluidics of the platform generate uniform microdroplets that encapsulate a CRISPR/Cas13a detection system and NCOA4-m6A target from the whole RNA extraction, achieving 10-fold enhancement in sensitivity and significantly reduced limit of detection (LOD). Systematic mouse models and clinical patient samples demonstrated its superior sensitivity and LOD (0.5 Gy) than traditional qPCR, which show wide potentials in radiation tracking and damage protection.

A - 183 Novel Performance Validity Indicators for Frequently Used Memory Tests Using Infrequent Patterns of Memory Performance.

Determining performance validity is an imperative part of neuropsychological assessment in concussion management. Several existing embedded performance validity tests (PVTs) have been developed for popular measures of memory, Hopkins Verbal Learning Test Revised (HVLT-R) and Brief Visuospatial Memory Test Revised (BVMT-R). However, many PVTs utilize cognitive performance measures to classify performance invalidity, which increases the likelihood of false positives, especially in clinical populations. To reduce this possibility, a novel embedded PVT was developed utilizing infrequent patterns of performance in a primarily amnestic, dementia population. Neuropsychological data for 50 adult outpatients (Mean Age = 73, Range = 50-97) who met criteria for Major Neurocognitive Disorder (MND) were reviewed. Infrequent patterns of performance (IPOP) were identified on the HVLT-R and BVMT-R, including inconsistency between recall and recognition, unusually high intrusions, exceedingly poor learning, and lack of primary effect. Scaled scores were developed from the IPOP scores (0 = 0-74%, 1 = 75-94%, 2 = 95-99%). Total IPOP scaled scores were compared to existing embedded PVTs, which utilized recognition discrimination and percent retention scores, to examine classification rates. Failure rates on the embedded PVTs for the HVLT-R were 16-42% and BVMT-R 38-58% whereas elevated IPOP scaled scores were identified in less than 15% of the sample. High frequencies of embedded PVT failures were found in a clinical sample of patients with MND, which is concerning for false positive misclassification. Infrequent patterns of memory performances identified in a dementia population were less frequent and could potentially be utilized to examine performance validity in persons suspected of producing invalid memory performances.

Phenotypic detection of extended-spectrum beta-lactamase produced by Klebsiella pneumoniae isolated from different clinical samples from intensive care unit, Khamis Military Hospital, Abha, Kingdom of Saudi Arabia

Background: Klebsiella pneumoniae is an opportunistic pathogen that is one of the commonest causes of infection in intensive care units. K. pneumoniae infection have contributed considerably to morbidity and mortality in patients with chronic illnesses. The coexistence of virulence factors and the genetic determinant of antibiotic resistance complicates treatment outcomes. The emergence of pathogenic multi-drug resistant K. pneumoniae poses a great threat to the healthcare system. Thus, the aim of this study was to isolate and to phenotypically detect the extended-spectrum beta-lactamase produced by K. pneumoniae that are isolated from different clinical samples from ICU in Khamis Military Hospital. Methods: A retrospective observational study was conducted at Khamis Military Hospital from December 2021 to April 2022. Clinical samples collected within the ICU underwent microbiological identification phase to confirm the presence of K. pneumoniae. This was followed by antibiotic susceptibility testing to various antimicrobial agents to detect the production of carbapenemases (KPC, NDM-1, OXA-48) and extended spectrum beta lactamase (ESBL). The collected data were subjected to statistical analysis using appropriate tools. Descriptive statistics were used to summarize the demographic and clinical characteristics of the patient population from whom the samples were obtained. Results: A total of 114 isolates of K. pneumoniae were identified from different clinical samples of ICU patients. The percentage of ESBL production constituted 28.94% (33 isolates). Regarding the distribution of carbapenemases production, 43 isolates (37.7%) had the KPC and NDM carbapenemases, while 34 isolates (29.8%) had the OXA-48 carbapenemases. Conclusions: The high prevalence of K. pneumoniae represents a threat to ICU patients, thus, this issue should be treated with urgent attention. Our data informs the need for regular surveillance of antibiotic resistance in pathogenic bacteria in clinical settings for meaningful control of emergence and spreading of multi-drug-resistant K. pneumoniae.

High frequency of carbapenemase in extensively drug-resistant Acinetobacter baumannii isolates in central Iran.

We assessed the frequency of occurrence for infections caused by wild-type A. baumannii, multidrug-resistant (MDR) or XDR A. baumannii, and CRAB. We detected different antibiotic resistance genes in the genomes of infectious A. baumannii strains from central Iran. This study investigated 546 clinical patient samples for the presence of A. baumannii by using conventional culture methods and PCR. Antibiotic resistance profiles, and the phenotypic and genotypic characteristics of various antibiotic genes were analyzed. Out of 546 samples, 87 (15.9%) A. baumannii isolates were obtained using culture and all culture positive samples were also positive by PCR. The most effective antibiotics were polymyxin B (n = 84 strains) (96.6% susceptibility), colistin (n = 81) (93.1%), and ampicillin/sulbactam (n = 18) (20.7%). All clinical A. baumannii isolates were ESBL-positive. The number of CRAB was 84 (96.5%). All CRAB isolates were both MDR and XDR. Of all CRAB isolates, 78 out of 84 (92.4%) produced metallo-β-lactamase (MBL) by phenotypic diagnosis. The most abundant genes were blaPER (32/87; 36.7%), blaTEM (29/87; 33.3%), blaVEB (26/87; 29.8%) for ESBL and Ambler class D β -lactamases included blaOXA-23 (69/84; 82.1%), blaOXA-24 (46/84; 54.7%), MBLs included blaVIM (51/84; 60.7%), and blaIMP (28/84; 33.3%) for carbapenemase. High frequencies of XDR A. baumannii and CRAB (96.5%) were detected in central Iran. Quick and accurate diagnosis, appropriate isolation of patients colonized or infected by CRAB isolates, application of accurate and effective infection control policies and programs, and appropriate preventive measures are deemed helpful in preventing the further spread of these resistant and clinically highly relevant strains.

Polish adaptation of the Dimensional Anhedonia Rating Scale (DARS) - validation in the clinical sample.

Anhedonia is the core symptom of depression. Its presence has been linked to worsened prognosis. The Dimensional Anhedonia Rating Scale (DARS) is a scale measuring desire, motivation, effort and consummatory pleasure across different domains. The aim of this paper was to confirm factor structure, assess reliability and validity of the Polish adaptation of the DARS in a clinical sample of patients with mood disorders and healthy controls (HC). The study sample included 161 participants aged 18-65 years - 34 HC, 72 patients with bipolar disorder and 55 with major depressive disorder (in depressive episode or remission). Reliability of the Polish adaptation of the DARS was assessed using Cronbach's α and the average inter-item correlation (AIC). Convergent and divergent validity was established by Pearson's correlations between the DARS and the Snaith-Hamilton Pleasure Scale (SHAPS), the Quick Inventory of Depressive Symptomatology- self-report (QIDS-SR), the Hospital Anxiety and Depression Scale (HADS). The structure of the scale was examined by factor analysis. The factor structure was consistent with the original scale. Strong internal consistency for the DARS total score (Cronbach's α = 0.95) and all subscales (0.86-0.93) was observed. The DARS demonstrated good convergent (moderate to strong correlations with measures of anhedonia and depression) and divergent validity (weak correlations with anxiety level). The Polish DARS demonstrated excellent internal consistency and very good validity. The scale is a valuable contribution to the psychometrics of anhedonia measures in patients with mood disorders.

Genome-wide DNA methylation sequencing reveals epigenetic features and potential biomarkers of Sjögren syndrome.

Sjögren syndrome (SS) is a slowly progressive, inflammatory, autoimmune disease. The aim of this study was to construct the DNA methylation profiles of whole blood of SS patients and healthy controls (HC), and to explore the role of differentially methylated genes in the pathogenesis of the disease. Whole-genome bisulfite sequencing was performed on three SS patients and four HC. The biological function of genes associated with differentially methylated regions (DMRs) was investigated using Gene Ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis, using network-based key driver analysis (KDA) to find KDA genes. In clinical samples of SS patients and controls, the expression levels of KDA genes were validated by quantitative real-time polymerase chain reaction and immunohistochemical analysis. Moreover, the diagnostic value of KDA genes for SS was confirmed using receiver operating characteristic curves. We identified 322 DMRs, annotated as 162 associated genes. Six genes were selected via the number of networks of KDA genes. Differential expression of genes such as human leukocyte antigen (HLA) class I, ADAR, and OAS2 was observed in patients' peripheral blood mononuclear cells and the minor salivary glands, which can be used as potential diagnostic biomarkers for SS. Clinical sample validation suggested that HLA class I, ADAR, and OAS2 might play a role in the development of SS. Our study shows epigenetic regulatory mechanisms and potential disease markers associated with SS, which in turn will enable us to identify new therapeutic targets.

METTL3 Regulates the m6A Modification of NEK7 to Inhibit the Formation of Osteoarthritis.

Osteoarthritis (OA) is a common degenerative joint disease. The occurrence of OA slowly destroys the soft tissue structure of the patient's joint. Severe cases could lead to disability. Current studies had shown that inhibition of chondrocytes pyroptosis could slow down the progression of OA. Our work aimed to explore the specific mechanisms and ways of regulating this process. In this work, the level of N6-methyladenosine (m6A) in clinical tissues was detected by ribonucleic acid (RNA) m6A dot blot. qRT-PCR (quantitative real-time polymerase chain reaction) was used to detect the messenger RNA (mRNA) expression level of m6A modified enzyme in clinical tissues. MTT (3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromid) and flow cytometry were used to detect the effect of sh-METTL3 (methyltransferase like 3) and NIMA-related kinase 7 (NEK7) transfection on chondrocytes pyroptosis in OA. Western blot was used to detect the protein expression levels of pyroptosis-related proteins. ELISA (enzyme-linked immunosorbent assay) was used to measure the protein concentration of inflammatory cytokines. The SRAMP online database was used to predict the m6A site of NEK7. HE staining was used to assess the progression of OA in mice. The level of m6A in clinical samples of OA patients was higher, and METTL3 was significantly higher expressed in clinical samples of OA patients. We provided evidence that low expression of METTL3 inhibited chondrocytes pyroptosis. In addition, Rescue experiments and in vivo experiments had shown that METTL3 in combination with NEK7 inhibited the progression of OA by promoting chondrocytes pyroptosis. METTL3 regulates m6A modification of NEK7 and inhibits OA progression.

Gut-derived 4-hydroxyphenylacetic acid attenuates sepsis-induced acute kidney injury by upregulating ARC to inhibit necroptosis

BackgroundStudies have found that the plasma content of gut-derived 4-hydroxyphenylacetic acid (4-HPA) was significantly increased in septic patients. However, the mechanism of 4-HPA elevation during sepsis and its relationship with sepsis-induced acute kidney injury (SAKI) remain unclear. MethodsCecal ligation and puncture (CLP) was performed in C57BL/6 mice to establish the SAKI animal model. Human renal tubular epithelial (HK-2) cells stimulated with lipopolysaccharide were used to establish the SAKI cell model. The widely targeted metabolomics was applied to analyze the renal metabolite changes after CLP. Proteomics was used to explore potential target proteins regulated by 4-HPA. The blood sample of clinical sepsis patients was collected to examine the 4-HPA content. ResultsWe found that renal gut-derived 4-HPA levels were significantly increased after CLP. The high permeability of intestinal barrier after sepsis contributed to the dramatic increase of renal 4-HPA. Intriguingly, we demonstrated that exogenous 4-HPA administration could further significantly reduce CLP-induced increases in serum creatinine, urea nitrogen, and cystatin C, inhibit renal pathological damage and apoptosis, and improve the survival of mice. Mechanistically, 4-HPA inhibited necroptosis in renal tubular epithelial cells by upregulating the protein expression of apoptosis repressor with caspase recruitment domain (ARC) and enhancing the interaction between ARC and receptor-interacting protein kinase 1 (RIPK1). ConclusionsThe increase of gut-derived 4-HPA in the kidney after sepsis could play a protective effect in SAKI by upregulating ARC to inhibit necroptosis.

Integrative analysis of the prognostic value and immune microenvironment of mitophagy-related signature for multiple myeloma

BackgroundMultiple myeloma (MM) is a fatal malignant tumor in hematology. Mitophagy plays vital roles in the pathogenesis and drug sensitivity of MM.MethodsWe acquired transcriptomic expression data and clinical index of MM patients from NCI public database, and 36 genes involved in mitophagy from the gene set enrichment analysis (GSEA) database. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was conducted to construct a risk score prognostic model. Kaplan–Meier survival analysis and receiver operation characteristic curves (ROC) were conducted to identify the efficiency of prognosis and diagnosis. ESTIMATE algorithm and immune-related single-sample gene set enrichment analysis (ssGSEA) was performed to uncover the level of immune infiltration. QRT-PCR was performed to verify gene expression in clinical samples of MM patients. The sensitivity to chemotherapy drugs was evaluated upon the database of the genomics of drug sensitivity in cancer (GDSC).ResultsFifty mitophagy-related genes were differently expressed in two independent cohorts. Ten out of these genes were identified to be related to MM overall survival (OS) rate. A prognostic risk signature model was built upon on these genes: VDAC1, PINK1, VPS13C, ATG13, and HUWE1, which predicted the survival of MM accurately and stably both in training and validation cohorts. MM patients suffered more adverse prognosis showed more higher risk core. In addition, the risk score was considered as an independent prognostic element for OS of MM patients by multivariate cox regression analysis. Functional pathway enrichment analysis of differentially expressed genes (DEGs) based on risk score showed terms of cell cycle, immune response, mTOR pathway, and MYC targets were obviously enriched. Furthermore, MM patients with higher risk score were observed lower immune scores and lower immune infiltration levels. The results of qRT-PCR verified VDAC1, PINK1, and HUWE1 were dysregulated in new diagnosed MM patients. Finally, further analysis indicated MM patients showed more susceptive to bortezomib, lenalidomide and rapamycin in high-risk group.ConclusionOur research provided a neoteric prognostic model of MM based on mitophagy genes. The immune infiltration level based on risk score paved a better understanding of the participation of mitophagy in MM.

Dual-channel fluorescent probe for simultaneously detecting H2S and viscosity/polarity and its application in non-alcoholic fatty liver, tumor tissue, and food spoilage

Intracellular hydrogen sulfide (H2S) and micro-environments (e.g. viscosity and polarity) are tightly correlated with various physiological/pathological processes, making them potential biomarkers of many diseases. However, the simultaneously detecting H2S, viscosity, and polarity in inflammation, non-alcoholic fatty liver (NAFL) and tumor tissues containing clinical cancer patient samples has not been achieved yet due to the lack of effective tools. Herein, we presented a mitochondria-targeting near-infrared (NIR) fluorescent probe MQA-DNP) for simultaneously monitoring H2S, viscosity/polarity through dual channels. The probe could specifically recognize H2S via far-red emission (λem = 634 nm), and exhibited high sensitivity toward micro-environmental viscosity/polarity in the NIR channel (λem > 714 nm). Facilitated with the probe, we revealed for the first time that inflammation cells and NAFL tissues are accompanied by an up-regulation of H2S, as well as an increase in viscosity level (and/or decrease in polarity degree). Surprisingly, the simultaneous visualization of H2S, viscosity/polarity has also been achieved not only at the cancer cells and tumor models, but also in clinical cancer patients. Compared to detecting a single biomarker, the simultaneous tracking multi-markers through multi-channels seems to be more reliable for visual medical diagnosis of mitochondria-related diseases. Furthermore, inspired by the significant color changes and high sensitivity of MQA-DNP reaction with H2S, MQA-DNP has been successfully used to detect H2S released during food spoilage through test strips, and has great potential for application in complex environments systems.