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Biochemistry Jul 2024Munc18-1 is an SM (sec1/munc-like) family protein involved in vesicle fusion and neuronal exocytosis. Munc18-1 is known to regulate the exocytosis process by binding...
Munc18-1 is an SM (sec1/munc-like) family protein involved in vesicle fusion and neuronal exocytosis. Munc18-1 is known to regulate the exocytosis process by binding with closed- and open-state conformations of Syntaxin1, a protein belonging to the SNARE family established to be central to the exocytosis process. Our previous work studied peptide p5 as a promising drug candidate for CDK5-p25 complex, an Alzheimer's disease (AD) pathological target. Experimental and studies suggest that Munc18-1 promotes p5 to selectively inhibit the CDK5-p25 complex without affecting the endogenous CDK5 activity, a characteristic of remarkable therapeutic implications. In this paper, we identify several binding modes of p5 with Munc18-1 that could potentially affect the Munc18-1 binding with SNARE proteins and lead to off-target effects on neuronal communication using molecular dynamics simulations. Recent studies indicate that disruption of Munc18-1 function not only disrupts neurotransmitter release but also results in neurodegeneration, exhibiting clinical resemblance to other neurodegenerative conditions such as AD, causing diagnostic and treatment challenges. We characterize such interactions between p5 and Munc18-1, define the corresponding pharmacophores, and provide guidance for the validation of our findings to improve therapeutic efficacy and safety of p5.
PubMed: 38953497
DOI: 10.1021/acs.biochem.4c00148 -
European Journal of Neurology Jul 2024Cognitive complaints are common in functional neurological disorder (FND), but it is unclear whether objective neurocognitive deficits are present. This systematic... (Review)
Review
BACKGROUND AND PURPOSE
Cognitive complaints are common in functional neurological disorder (FND), but it is unclear whether objective neurocognitive deficits are present. This systematic review summarized validated/standardized cognitive test performance in FND samples across cognitive domains.
METHODS
Embase, PsycInfo and MEDLINE were searched from inception to 15 May 2023, combining terms for FND and cognitive domains (e.g., attention, memory, executive functioning). Studies included a range of FND phenotypes (seizures, motor, cognitive disorder, mixed), compared to healthy or clinical controls. Risk of bias was assessed with the modified Newcastle-Ottawa Scale and a qualitative synthesis/narrative review of cognitive performance in FND was conducted. Test performance scores were extracted, and random effects meta-analyses were run where appropriate. This review was registered on PROSPERO, CRD42023423139.
RESULTS
Fifty-six studies including 2260 individuals with FND were eligible. Although evidence for some impairments emerged across domains of executive functioning, attention, memory and psychomotor/processing speed, this was inconsistent across studies and FND phenotypes. Common confounds included group differences in demographics, medication and intellectual functioning. Only 24% of studies objectively assessed performance validity. Meta-analyses revealed higher scores on tests of naming (g = 0.67, 95% confidence interval [CI] 0.50, 0.84) and long-term memory (g = 0.43, 95% CI 0.13, 0.74) in functional seizures versus epilepsy, but no significant differences in working (g = -0.08, 95% CI -0.44, 0.29) or immediate (g = 0.25, 95% CI -0.02, 0.53) memory and cognitive flexibility (g = -0.01, 95% CI -0.29, 0.28).
CONCLUSIONS
There is mixed evidence for objective cognitive deficits in FND. Future research should control for confounds, include tests of performance validity, and assess relationships between objective and subjective neurocognitive functioning.
PubMed: 38953473
DOI: 10.1111/ene.16386 -
International Nursing Review Jul 2024To investigate how nursing students' professional identity, clinical learning environment, financial incentives, and career opportunities influence their intention to...
Linking nursing students' professional identity, clinical learning environment, financial incentives, and career opportunities with migration intent: Structural equation modeling.
AIMS
To investigate how nursing students' professional identity, clinical learning environment, financial incentives, and career opportunities influence their intention to migrate.
BACKGROUND
There is a preponderance of studies about nurse migration and its impact on the global nursing workforce. However, a critical gap remains about nursing students' intentions to migrate, particularly among developing countries like the Philippines.
METHODS
Using a cross-sectional design, third- and fourth-year nursing students (n = 316) from the largest comprehensive university in Manila were conveniently recruited. Data were collected from November to December 2023 using five validated self-report scales. Descriptive (e.g., mean, standard deviation) and inferential statistics (e.g., Spearman rho, covariance-based structural equation modeling) were used to analyze data.
RESULTS
The emerging model demonstrated acceptable model fit indices. Nursing students' professional identity (β = 0.18, p = 0.043) and financial incentives (β = 0.10, p = 0.046) significantly and positively influence the intention to migrate. The satisfaction with future career opportunities (β = -0.12, p = 0.038) and clinical learning environment perception (β = -0.15, p = 0.048) negatively influence the intention to migrate. These four predictors accounted for 4.60% of the total variance of intention to migrate.
CONCLUSION
Nursing students' professional identity and financial incentives directly impact intent to migrate, whereas future career opportunities satisfaction and clinical learning environment inversely affect intent to migrate.
IMPLICATIONS FOR NURSING PRACTICE AND POLICY
This study underscores the imperative for nursing colleges and faculty to promote positive professional identity and provide a conducive clinical learning environment to develop sustainable nurses' migration policies.
PubMed: 38953437
DOI: 10.1111/inr.13009 -
Journal of Ultrasound in Medicine :... Jul 2024This study aimed to validate the diagnostic accuracy of the International Ovarian Tumor Analysis (IOTA) Assessment of Different NEoplasias in the adneXa (ADNEX) model in...
OBJECTIVES
This study aimed to validate the diagnostic accuracy of the International Ovarian Tumor Analysis (IOTA) Assessment of Different NEoplasias in the adneXa (ADNEX) model in Japanese women, population with a distinct adnexal mass distribution compared with European women, and to evaluate the model's utility by gynecology trainees and ultrasound specialists.
METHODS
This single-center, retrospective study analyzed ultrasound data from January 2017 to March 2020 of 206 women with adnexal masses. Patients who underwent ultrasonography and serum CA-125 measurement and received postsurgery histological diagnosis were included. The ADNEX model's diagnostic performance was evaluated by two trainees and two specialists using the area under the receiver operating characteristic curve (AUC) and measures of accuracy, sensitivity, specificity, and predictive values for overall performance and each examiner.
RESULTS
Of the 206 included Japanese women, the prevalence of malignancy was 30.1%, including borderline cases. The overall AUC for distinguishing malignancy was 0.848 (95% confidence interval [CI]: 0.817-0.880). The AUC for each examiner ranged from 0.791 to 0.898, with Specialist 2 showing the highest accuracy and sensitivity varying between 0.677 and 0.839. A moderate degree of agreement was noted among the four examiners (Fleiss' kappa was 0.586). The performance of trainees and specialists differed significantly in evaluating the solid tissue and the papillary projections in both malignant and benign groups (P < .001).
CONCLUSIONS
The IOTA ADNEX model effectively differentiates benign and malignant adnexal masses in Japanese women. Although the accuracy matched up moderately among the four examiners, better accuracy is expected with training in evaluating solid tissue and papillary projections.
PubMed: 38953408
DOI: 10.1002/jum.16517 -
MBio Jul 2024pneumonia (PjP) poses a serious risk to individuals with compromised immune systems, such as individuals with HIV/AIDS or undergoing immunosuppressive therapies for...
pneumonia (PjP) poses a serious risk to individuals with compromised immune systems, such as individuals with HIV/AIDS or undergoing immunosuppressive therapies for cancer or solid organ transplants. Severe PjP triggers excessive lung inflammation, resulting in lung function decline and consequential alveolar damage, potentially culminating in acute respiratory distress syndrome. Non-HIV patients face a 30%-60% mortality rate, emphasizing the need for a deeper understanding of inflammatory responses in PjP. Prior research emphasized macrophages in infections, neglecting neutrophils' role in tissue damage. Consequently, the overemphasis on macrophages led to an incomplete understanding of the role of neutrophils and inflammatory responses. In the current investigation, our RNAseq studies on a murine surrogate model of PjP revealed heightened activation of the NLRP3 inflammasome and NETosis cell death pathways in their lungs. Immunofluorescence staining confirmed neutrophil extracellular trap (NET) presence in the lungs of the -infected mice, validating our findings. Moreover, isolated neutrophils exhibited NETosis when directly stimulated with . Isolated NETs compromised viability , highlighting the potential role of neutrophils in controlling fungal growth and promoting inflammation during pneumonia through NLRP3 inflammasome assembly and NETosis. These pathways, essential for inflammation and pathogen elimination, bear the risk of uncontrolled activation leading to excessive tissue damage and persistent inflammation. This pioneering study is the first to identify the formation of NETs and inflammasomes during infection, paving the way for comprehensive investigations into treatments aimed at mitigating lung damage and augmenting survival rates for individuals with .IMPORTANCE pneumonia (PjP) affects individuals with weakened immunity, such as HIV/AIDS, cancer, and organ transplant patients. Severe PjP triggers lung inflammation, impairing function and potentially causing acute respiratory distress syndrome. Non-HIV individuals face a 30%-60% mortality rate, underscoring the need for deeper insight into PjP's inflammatory responses. Past research focused on macrophages in managing infection and its inflammation, while the role of neutrophils was generally overlooked. In contrast, our findings in -infected mouse lungs showed neutrophil involvement during inflammation and increased expression of NLRP3 inflammasome and NETosis pathways. Detection of neutrophil extracellular traps further indicated their involvement in the inflammatory process. Although beneficial in combating infection, unregulated neutrophil activation poses a potential threat to lung tissues. Understanding the behavior of neutrophils in infections is crucial for controlling detrimental reactions and formulating treatments to reduce lung damage, ultimately improving the survival rates of individuals with PjP.
PubMed: 38953359
DOI: 10.1128/mbio.01409-24 -
MSystems Jul 2024The erythromycin resistance RNA methyltransferase () confers cross-resistance to all therapeutically important macrolides, lincosamides, and streptogramins (MLS...
UNLABELLED
The erythromycin resistance RNA methyltransferase () confers cross-resistance to all therapeutically important macrolides, lincosamides, and streptogramins (MLS phenotype). The expression of is often induced by the macrolide-mediated ribosome stalling in the upstream co-transcribed leader sequence, thereby triggering a conformational switch of the intergenic RNA hairpins to allow the translational initiation of . We investigated the evolutionary emergence of the upstream regulatory elements and the impact of allelic variation on erm expression and the MLS phenotype. Through systematic profiling of the upstream regulatory sequences across all known operons, we observed that specific subfamilies, such as and , have independently evolved distinct configurations of small upstream ORFs and palindromic repeats. A population-wide genomic analysis of the upstream regions revealed substantial non-random allelic variation at numerous positions. Utilizing machine learning-based classification coupled with RNA structure modeling, we found that many alleles cooperatively influence the stability of alternative RNA hairpin structures formed by the palindromic repeats, which, in turn, affects the inducibility of expression and MLS phenotypes. Subsequent experimental validation of 11 randomly selected variants demonstrated an impressive 91% accuracy in predicting MLS phenotypes. Furthermore, we uncovered a mixed distribution of MLS-sensitive and MLS-resistant loci within the evolutionary tree, indicating repeated and independent evolution of MLS resistance. Taken together, this study not only elucidates the evolutionary processes driving the emergence and development of MLS resistance but also highlights the potential of using non-coding genomic allele data to predict antibiotic resistance phenotypes.
IMPORTANCE
Antibiotic resistance (AR) poses a global health threat as the efficacy of available antibiotics has rapidly eroded due to the widespread transmission of AR genes. Using Erm-dependent MLS resistance as a model, this study highlights the significance of non-coding genomic allelic variations. Through a comprehensive analysis of upstream regulatory elements within the family, we elucidated the evolutionary emergence and development of AR mechanisms. Leveraging population-wide machine learning (ML)-based genomic analysis, we transformed substantial non-random allelic variations into discernible clusters of elements, enabling precise prediction of MLS phenotypes from non-coding regions. These findings offer deeper insight into AR evolution and demonstrate the potential of harnessing non-coding genomic allele data for accurately predicting AR phenotypes.
PubMed: 38953319
DOI: 10.1128/msystems.00430-24 -
Chronobiology International Jul 2024This study examined the psychometric properties and longitudinal changes of the self-reporting Traditional Chinese version of Biological Rhythms Interview for Assessment...
Chinese self-report version of biological rhythms interview for assessment in neuropsychiatry (C-BRIAN-SR) - psychometric properties and prospective follow-up in patients with non-seasonal depression.
This study examined the psychometric properties and longitudinal changes of the self-reporting Traditional Chinese version of Biological Rhythms Interview for Assessment in Neuropsychiatry (C-BRIAN-SR) among healthy controls (HC) and patients with major depressive episode (MDE). Eighty patients with a current MDE and 80 HC were recruited. Assessments were repeated after two weeks in HC, and upon the discharge of MDE patients to examine the prospective changes upon remission of depression. The C-BRIAN-SR score was significantly higher in the MDE than HC group. The concurrent validity was supported by a positive correlation between scores of C-BRIAN-SR, Insomnia Severity Index and the Hospital Anxiety Depression Scale. C-BRIAN-SR negatively correlated MEQ in the MDE group ( = .30, = 0.009), suggesting higher rhythm disturbances were associated with a tendency toward eveningness. A moderate test-retest reliability was found ( = .61, < 0.001). A cut-off of 38.5 distinguished MDE subjects from HC with 82.9% of sensitivity and 81.0% of specificity. C-BRIAN-SR score normalized in remitted MDE patients but remained higher in the non-remitted. The C-BRIAN-SR is a valid and reliable scale for measuring the biological rhythms and may assist in the screening of patients with MDE.
PubMed: 38953315
DOI: 10.1080/07420528.2024.2373215 -
Analytical Methods : Advancing Methods... Jul 2024Peroxide-mediated oxidation of drug molecules is a known challenge faced throughout the pharmaceutical development pathway-from early-stage stability studies to...
Peroxide-mediated oxidation of drug molecules is a known challenge faced throughout the pharmaceutical development pathway-from early-stage stability studies to manufacturing processes. During the initial development stage, the major source of peroxide is the formulation excipients, whether they are pre-loaded or generated due to slow degradation, and in the late phase, peroxides can be introduced during sanitization processes or generated cavitation. In essence, a control strategy for peroxide mitigation often becomes a critical quality attribute for successful drug development. To this end, quantitation of peroxide is essential to monitor the peroxide level to ensure product quality and proposed shelf-life. However, methods for reliable and robust quantitation to detect trace levels of peroxide in a complex drug product matrix become increasingly challenging. This article discusses three high-throughput assays based on absorbance, fluorescence and chemiluminescence measurements to detect peroxide at a low level and compares the methods through validation studies in water. Selected methods have also been tested to understand the forced degradation of model peptide drug products with spiked hydrogen peroxide. Peptide degradation profiles and residual peroxide levels are presented to provide an understanding of the suitability of the quantitation methods and their performance.
PubMed: 38953302
DOI: 10.1039/d4ay00652f -
Cancer Medicine Jul 2024Recent studies provide compelling evidence linking the gut microbiota to most cancers. Nevertheless, further research is required to establish a definitive causal...
BACKGROUND
Recent studies provide compelling evidence linking the gut microbiota to most cancers. Nevertheless, further research is required to establish a definitive causal relationship between the gut microbiota and malignant cardiac tumors.
METHODS
The genome-wide association studies (GWAS) data on the human gut Microbiota, included in the IEU Open GWAS project, was initially collected by the MiBioGen consortium. It encompasses 14,306 individuals and comprises a total of 5,665,279 SNPs. Similarly, the GWAS data on malignant cardiac tumors, also sourced from the IEU Open GWAS project, was initially stored in the finnGen database, including 16,380,303 SNPs observed within a cohort of 174,108 individuals within the European population. Utilizing a two-sample Mendelian randomization (MR) methodology, we examined whether there exists a causal association between the gut microbiota and cardiac tumors. Additionally, to bolster the credibility and robustness of the identified causal relationships, we conducted an extensive array of sensitivity analyses, encompassing Cochran's Q test, MR-PRESSO tests, MR-Egger interpret test, directionality test and leave-one-out analysis.
RESULTS
Our analysis unveiled seven distinct causal associations between genetic susceptibility in the gut microbiota and the incidence of malignant cardiac tumors. Among these, the Family Rikenellaceae, genus Eubacterium brachy group, and genus Ruminococcaceae UCG009 exhibited an elevated risk of cardiac tumors, while the phylum Verrucomicrobia, genus Lactobacillus, genus Ruminiclostridium5, and an unknown genus id.1868 were genetically linked to a reduced risk of cardiac tumors. The causal relationship between these two bacteria, belonging to the phylum Verrucomicrobia (OR = 0.178, 95% CI: 0.052-0.614, p = 0.006) and the genus Ruminococcaceae UCG009 (OR = 3.071, 95% CI: 1.236-7.627, p = 0.016), and cardiac tumors was further validated through sensitivity analyses, reinforcing the robustness and reliability of the observed associations.
CONCLUSION
Our MR analysis confirms that the phylum Verrucomicrobia displays significant protection against cardiac tumor, and the genus Ruminococcaceae UCG009 leads to an increasing risk of cardiac tumor.
Topics: Humans; Mendelian Randomization Analysis; Gastrointestinal Microbiome; Genome-Wide Association Study; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Heart Neoplasms; Risk Factors
PubMed: 38953300
DOI: 10.1002/cam4.7455 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Objective To construct a risk prediction model by integrating the molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) and immune-related genes.Methods With...
Objective To construct a risk prediction model by integrating the molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) and immune-related genes.Methods With GSE71729 data set (=145) as the training set,the differentially expressed genes and differential immune-related genes between the squamous and non-squamous subtypes of PDAC were integrated to construct a regulatory network,on the basis of which five immune marker genes regulating the squamous subtype were screened out.An integrated immune score (IIS) model was constructed based on patient survival information and immune marker genes to predict the clinical prognosis of PDAC patients,and its predictive performance was tested with 5 validation sets (=758).Results PDAC patients were assigned into high risk and low risk groups according to the IIS.In both training and validation sets,the overall survival of patients in the high risk group was shorter than that in the low risk group (both <0.001).The multivariable Cox regression showed that IIS was an independent prognostic factor for PDAC (=2.16,95%=1.50-3.10,<0.001).Conclusion IIS can be used for risk stratification of PDAC patients and may become a potential prognostic marker for PDAC.
Topics: Humans; Carcinoma, Pancreatic Ductal; Prognosis; Pancreatic Neoplasms; Female; Male; Middle Aged; Biomarkers, Tumor; Risk Assessment
PubMed: 38953259
DOI: 10.3881/j.issn.1000-503X.15736