Tag: pubmed

Methods Mol Biol. 2025;2873:145-165. doi: 10.1007/978-1-0716-4228-3_9.

ABSTRACT

The nuclear envelope (NE) defines the eukaryotic cell and functions in a myriad of fundamental cellular processes including but not limited to signal transduction, lipid metabolism, chromatin organization, and nucleocytoplasmic transportation. Although the general structure of the NE is well-conserved across eukaryotic kingdoms, its composition and functions vary substantially between species and remain largely unknown in plants. In this chapter, we describe a proximity-labeling-based proteomic approach to profile novel NE components in the model organism Arabidopsis. This method is generally suitable for the identification of protein components in subcellular compartments or protein complexes that are poorly accessible to traditional mass spectrometry approaches and can be easily applied to other plant species. In addition to giving a step-by-step detailed description of the proximity labeling proteomics procedure in plant samples, we also provide guidelines on the appropriate use of controls and statistical analysis to achieve a highly specific selection of probed candidates.

PMID:39576601 | DOI:10.1007/978-1-0716-4228-3_9

Methods Mol Biol. 2025;2867:201-218. doi: 10.1007/978-1-0716-4196-5_12.

ABSTRACT

Intrinsically disordered proteins (IDPs) that include one or more intrinsically disordered regions (IDRs) are abundant across all domains of life and viruses and play numerous functional roles in various cellular processes. Due to a relatively low throughput and high cost of experimental techniques for identifying IDRs, there is a growing need for fast and accurate computational algorithms that accurately predict IDRs/IDPs from protein sequences. We describe one of the leading disorder predictors, flDPnn. Results from a recent community-organized Critical Assessment of Intrinsic Disorder (CAID) experiment show that flDPnn provides fast and state-of-the-art predictions of disorder, which are supplemented with the predictions of several major disorder functions. This chapter provides a practical guide to flDPnn, which includes a brief explanation of its predictive model, descriptions of its web server and standalone versions, and a case study that showcases how to read and understand flDPnn’s predictions.

PMID:39576583 | DOI:10.1007/978-1-0716-4196-5_12

Methods Mol Biol. 2025;2867:43-53. doi: 10.1007/978-1-0716-4196-5_3.

ABSTRACT

Protein secondary structure prediction is useful for many applications. It can be considered a language translation problem, that is, translating a sequence of 20 different amino acids into a sequence of secondary structure symbols (e.g., alpha helix, beta strand, and coil). Here, we develop a novel protein secondary structure predictor called TransPross based on the transformer network and attention mechanism widely used in natural language processing to directly extract the evolutionary information from the protein language (i.e., raw multiple sequence alignment [MSA] of a protein) to predict the secondary structure. The method is different from traditional methods that first generate a MSA and then calculate expert-curated statistical profiles from the MSA as input. The attention mechanism used by TransPross can effectively capture long-range residue-residue interactions in protein sequences to predict secondary structures. Benchmarked on several datasets, TransPross outperforms the state-of-art methods. Moreover, our experiment shows that the prediction accuracy of TransPross positively correlates with the depth of MSAs, and it is able to achieve the average prediction accuracy (i.e., Q3 score) above 80% for hard targets with few homologous sequences in their MSAs. TransPross is freely available at https://github.com/BioinfoMachineLearning/TransPro .

PMID:39576574 | DOI:10.1007/978-1-0716-4196-5_3

Ann Biomed Eng. 2024 Nov 22. doi: 10.1007/s10439-024-03636-4. Online ahead of print.

ABSTRACT

Osteoporosis represents a major healthcare concern. The development of novel treatments presents challenges due to the limited cost-effectiveness of clinical trials and ethical concerns associated with placebo-controlled trials. Computational models for the design and assessment of biomedical products (In Silico Trials) are emerging as a promising alternative. In this study, a novel In Silico Trial technology (BoneStrength) was applied to replicate the placebo arms of two concluded clinical trials and its accuracy in predicting hip fracture incidence was evaluated. Two virtual cohorts (N = 1238 and 1226, respectively) were generated by sampling a statistical anatomy atlas based on CT scans of proximal femurs. Baseline characteristics were equivalent to those reported for the clinical cohorts. Fall events were sampled from a Poisson distribution. A multiscale stochastic model was implemented to estimate the impact force associated to each fall. Finite Element models were used to predict femur strength. Fracture incidence in 3 years follow-up was computed with a Markov chain approach; a patient was considered fractured if the impact force associated with a fall exceeded femur strength. Ten realizations of the stochastic process were run to reach convergence. Each realization required approximately 2500 FE simulations, solved using High-Performance Computing infrastructures. Predicted number of fractures was 12 ± 2 and 18 ± 4 for the two cohorts, respectively. The predicted incidence range consistently included the reported clinical data, although on average fracture incidence was overestimated. These findings highlight the potential of BoneStrength for future applications in drug development and assessment.

PMID:39576502 | DOI:10.1007/s10439-024-03636-4

Ir J Med Sci. 2024 Nov 22. doi: 10.1007/s11845-024-03842-y. Online ahead of print.

ABSTRACT

BACKGROUND: Dermatological conditions are the fourth most common of all diseases affecting humans, and affect almost one third of the world’s population, necessitating effective undergraduate dermatology education.

AIMS: 1. To enquire about the self-perceived confidence of newly qualified junior doctors in recognising and diagnosing dermatological conditions. 2. To ascertain information pertaining to newly qualified junior doctors’ undergraduate dermatology education.

METHODS: A mixed-methods survey on undergraduate dermatology education and self-perceived confidence levels of interns in relation to dermatological conditions was distributed to interns working within two Irish intern networks. Mann-Whitney U testing was used to test for differences between those who had a dermatology placement versus those who did not. Qualitative thematic analysis was used to analyse reflections and comments.

RESULTS: Fifty-seven interns completed our survey. A total of 60% of respondents were female (n = 34). The median age range of respondents was 25-29 years. Fifty-eight percent of interns had a clinical dermatology undergraduate placement (n = 33). Forty-nine percent of interns were dissatisfied with their undergraduate dermatology education (n = 28), while 26% (n = 15) were satisfied and 25% (n = 14) indicated neutral feelings. Confidence levels reported were reasonable where inflammatory and malignant dermatoses were concerned. Statistical significance was established across several areas in dermatology between those who had a dermatology placement versus those who did not. Thematic analysis revealed themes of ineffective dermatology education, of a basic knowledge of dermatology, and of dermatology knowledge via other specialties.

CONCLUSION: This study demonstrates that undergraduate dermatology education is not standardised across various universities in Ireland. It also revealed several areas within dermatology within which there was a statistically significant difference in confidence levels between those who had a clinical undergraduate dermatology placement versus those who did not. This raises the question: “Would mandating a dermatology clerkship may be beneficial to interns?”.

PMID:39576470 | DOI:10.1007/s11845-024-03842-y

Clin Pharmacokinet. 2024 Nov 22. doi: 10.1007/s40262-024-01443-7. Online ahead of print.

ABSTRACT

AIMS: This study aimed to quantify the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a therapeutic approach for heart failure.

METHODS: A systematic literature review was conducted to collect pharmacokinetics (PK) and pharmacodynamics (PD) data on empagliflozin, dapagliflozin, and canagliflozin. Population pharmacokinetic models were developed separately for each drug, along with PK/PD turnover models for SGLT2 inhibitors, to describe the time course of NT-proBNP and simulate its changes over 52 weeks.

RESULTS: A total of 42 publications were included in this study. The results showed that baseline NT-proBNP levels, estimated glomerular filtration rate levels, and body weight significantly influenced the therapeutic effects of SGLT2 inhibitors. Among the studied drugs, canagliflozin demonstrated a greater reduction in NT-proBNP at comparable baseline levels.

CONCLUSIONS: Baseline NT-proBNP concentration, renal function, and body weight were covariates affecting the efficacy of SGLT2 inhibitors in reducing NT-proBNP. Canagliflozin showed the most favorable treatment outcomes at similar baseline levels. This model-based meta-analysis approach may support further drug development for SGLT2 inhibitors.

PMID:39576469 | DOI:10.1007/s40262-024-01443-7

Breast Cancer Res Treat. 2024 Nov 22. doi: 10.1007/s10549-024-07552-y. Online ahead of print.

ABSTRACT

PURPOSE: Chemotherapy in combination with trastuzumab is the standard neoadjuvant and adjuvant therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). Assessing the regimens administered to patients with HER2-positive BC in the real world is lacking. We evaluated neoadjuvant and adjuvant regimen patterns among HER2-positive BC patients (2007 to 2021) identified in a health insurance claims database.

METHODS: Female BC patients ≥ 18 years who received chemotherapy, surgery, and trastuzumab were chosen from Optum’s de-identified Clinformatics® Data Mart database. Summary statistics, Joinpoint models, Kaplan-Meier survival curves, and Cox regression models were used to analyze the data.

RESULTS: We identified 6474 patients (median age 60 years), 71.7% were White, 10.9% were Black, 8.6% were Hispanic, 4.1% were Asian, and 4.7% had unknown race/ethnicity. About 33.8% received neoadjuvant therapy and neoadjuvant therapy use increased with an annual percent change of 10.24% (P < .001). The three most common regimens were adjuvant docetaxel, carboplatin, and trastuzumab (TCH; 29.0%); adjuvant paclitaxel and trastuzumab (17.7%); and neoadjuvant TCH with pertuzumab followed by adjuvant trastuzumab (17.7%). The 5-year overall survival (OS) was 96% (95% CI, 95-96%). Patients had an increased risk of death if they were ≥ 59 years at diagnosis, had a health maintenance organization or other insurance plan, had dual Medicare/Medicaid eligibility, had a mastectomy, did not receive 18 cycles of trastuzumab, or received regimens not recommended by the National Comprehensive Cancer Network.

CONCLUSION: Treatment regimen patterns for HER2-positive BC evolved in correspondence with the U.S. Food and Drug Administration’s approval of new drugs for this cancer and National Comprehensive Cancer Network treatment guidelines.

PMID:39576449 | DOI:10.1007/s10549-024-07552-y

Hormones (Athens). 2024 Nov 22. doi: 10.1007/s42000-024-00617-z. Online ahead of print.

ABSTRACT

AIM: Neuropathy, a common complication of diabetes associated with metabolic issues, lacks clarity regarding its prevalence in metabolically healthy obese versus non-obese individuals. Our study aims to compare neuropathy rates between those with and those without obesity and who are metabolically healthy.

METHODS: We included individuals aged 20-50, one group with a body mass index (BMI) ≥ 30 kg/m² (metabolically healthy and obese) and another with a BMI < 30 kg/m² (metabolically healthy and non-obese). Exclusion criteria encompassed diabetes, hypertension, chronic renal disease, vitamin B12 deficiency, anemia, primary amyloidosis, immune system disorders, malignancy, active infection, and paraneoplastic syndromes. Patients underwent assessments using the Neuropathy Symptom Score (NSS) and modified Neuropathy Disability Score (mNDS).

RESULTS: The median scores for NSS and mNDS were higher among metabolically healthy obese individuals than non-obese participants (2 (1-4) vs. 0 (0-1) for NSS; p < 0.001 and 4 (2-5) vs. 2 (1-4) for mNDS; p < 0.001). Individuals with obesity had a 110.09 times higher likelihood of experiencing neuropathy compared to those without obesity. The severity of neuropathy was significantly greater in the metabolically healthy group with obesity. There were no statistically significant differences in anthropometric and laboratory values between participants with and without neuropathy, except for triglyceride levels. Patients with neuropathy exhibited higher triglyceride levels compared to those without neuropathy.

CONCLUSION: Our study demonstrated a higher prevalence of neuropathy among metabolically healthy obese individuals in comparison to those who were metabolically healthy and non-obese.

PMID:39576448 | DOI:10.1007/s42000-024-00617-z

Clin Rheumatol. 2024 Nov 22. doi: 10.1007/s10067-024-07241-7. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to assess the potential impact of primary Sjögren’s syndrome (pSS) on fertility and ovarian reserve by evaluating the number of antral ovarian follicles (AFC) through ultrasound and analysing serum levels of anti-müllerian hormone (AMH) and follicle-stimulating hormone (FSH), which are currently the most reliable indicators of fertility potential.

METHOD: A total of 52 premenopausal women were recruited from the Maternal, Infantile, and Urological Sciences Department at Umberto I Hospital, Sapienza University of Rome. Among them, 26 had pSS, and 26 served as healthy controls. All participants underwent a gynaecological examination, a transvaginal ultrasound, and serum testing for AMH and FSH levels.

RESULTS: The study found that serum AMH levels were significantly lower (p = 0.002) in pSS patients compared to the controls, indicating a potential reduction in ovarian reserve in these patients. However, no statistically significant differences were observed in FSH levels between the two groups.

CONCLUSIONS: The findings suggest that pSS may have a negative impact on ovarian reserve, as evidenced by lower AMH levels in comparison to age-matched controls. AFC and FSH levels, however, were similar to those of healthy women. These results provide new insights that could be beneficial for this patient population, though further, larger-scale studies are necessary to more comprehensively understand the relationship between pSS and female fertility. Key Points • The study assesses the possible impact of pSS on fertility and ovarian reserve by evaluation of AMH, FSH, and AFC. • Family planning and fertility are important issues for patients with rheumatic disorders and must be considered and discussed with the patient already at the time of diagnosis, and appropriate counselling must be performed.

PMID:39576415 | DOI:10.1007/s10067-024-07241-7

Insights Imaging. 2024 Nov 22;15(1):283. doi: 10.1186/s13244-024-01857-8.

ABSTRACT

OBJECTIVES: To explore the impact of hepatic steatosis measured by MRI-proton density fat fraction (MRI-PDFF) on liver stiffness measurement (LSM) value and its diagnostic performance for staging liver fibrosis in patients with chronic hepatitis B (CHB).

METHODS: A total of 914 patients with CHB who underwent liver biopsy and MRI-PDFF were retrospectively reviewed. The influence of MRI-PDFF on LSM value was assessed using univariate and multivariate linear analyses. To assess the influence of liver steatosis on the diagnostic performance of LSM, a series of ROC analyses were performed and compared by stratifying patients into non-steatosis (PDFF < 5%) and steatosis (PDFF ≥ 5%) groups according to MRI-PDFF values. The effects of different LSM cut-off values on the false-positive rate in the steatosis cohort were compared using McNemar’s test.

RESULTS: LSM values were significantly affected by MRI-PDFF in the entire cohort (B-coefficient: 0.003, p < 0.001), F1 cohort (B-coefficient: 0.005, p < 0.001), and F2 cohort (B-coefficient: 0.003, p = 0.002). Hepatic steatosis was not observed to have a significant influence on the ROC curve of LSM for staging liver fibrosis. Compared with using the cut-off values for the CHB cohort, using relatively higher cut-off values for hepatic steatosis significantly improved the false-positive rate of LSM in the steatosis cohort.

CONCLUSION: Steatosis significantly influenced LSM, with a higher value in the early stage of liver fibrosis but did not affect the diagnostic efficiency of LSM for staging liver fibrosis. Moreover, using relatively high cut-off values significantly improved the false-positive rate of LSM in CHB patients with steatosis.

CLINICAL RELEVANCE STATEMENT: The identified correlation between MRI-PDFF and VCTE-measured LSM is not clinically relevant since the diagnostic performance of LSM in staging liver fibrosis is not affected by steatosis. A higher cut-off should be applied in CHB patients with steatosis to improve the false-positive rate.

KEY POINTS: Steatosis can affect liver stiff measurement (LSM) values in the early stage of liver fibrosis. The diagnostic performance of LSM in staging liver fibrosis is not affected by steatosis. LSM’s cutoffs should be increased in patients with steatosis to improve the false-positive rate.

PMID:39576387 | DOI:10.1186/s13244-024-01857-8