PCfun: a hybrid computational framework for systematic characterization of protein complex function.

In molecular biology, it is a general assumption that the ensemble of expressed molecules, their activities and interactions determine biological function, cellular states and phenotypes. Stable protein complexes-or macromolecular machines-are, in turn, the key functional entities mediating and modulating most biological processes. Although identifying protein complexes and their subunit composition can now be done inexpensively and at scale, determining their function remains challenging and labor intensive. This study describes Protein Complex Function predictor (PCfun), the first computational framework for the systematic annotation of protein complex functions using Gene Ontology (GO) terms. PCfun is built upon a word embedding using natural language processing techniques based on 1 million open access PubMed Central articles. Specifically, PCfun leverages two approaches for accurately identifying protein complex function, including: (i) an unsupervised approach that obtains the nearest neighbor (NN) GO term word vectors for a protein complex query vector and (ii) a supervised approach using Random Forest (RF) models trained specifically for recovering the GO terms of protein complex queries described in the CORUM protein complex database. PCfun consolidates both approaches by performing a hypergeometric statistical test to enrich the top NN GO terms within the child terms of the GO terms predicted by the RF models. The documentation and implementation of the PCfun package are available at https://github.com/sharmavaruns/PCfun. We anticipate that PCfun will serve as a useful tool and novel paradigm for the large-scale characterization of protein complex function.

The controversy about interference of photons.

In the 1960s, the demonstration of interference effects using two laser-beams raised the question: can two photons interfere? Its plausibility contested Dirac's dictum, "Interference between two different photons never occurs". Disagreements about this conflict led to a controversy. This paper will chart the controversy's contour and show that it evolved over two phases. Subsequently, I investigate the reasons for its perpetuation. The controversy was initiated and fuelled by several misinterpretations of the dictum. I also argue that Dirac's dictum is not applicable to two photon interference as they belong to different contexts of interference. Recognising this resolves the controversy.

Serum Metabolomic Markers of Dairy Consumption: Results from the Atherosclerosis Risk in Communities Study and the Bogalusa Heart Study.

BACKGROUND: Dairy consumption is related to chronic disease risk; however, the measurement of dairy consumption has largely relied upon self-report. Untargeted metabolomics allows for the identification of objective markers of dietary intake. OBJECTIVES: We aimed to identify associations between dietary dairy intake (total dairy, low-fat dairy, and high-fat dairy) and serum metabolites in 2 independent study populations of United States adults. METHODS: Dietary intake was assessed with food frequency questionnaires. Multivariable linear regression models were used to estimate cross-sectional associations between dietary intake of dairy and 360 serum metabolites analyzed in 2 subgroups of the Atherosclerosis Risk in Communities study (ARIC; n = 3776). Results from the 2 subgroups were meta-analyzed using fixed effects meta-analysis. Significant meta-analyzed associations in the ARIC study were then tested in the Bogalusa Heart Study (BHS; n = 785). RESULTS: In the ARIC study and BHS, the mean age was 54 and 48 years, 61% and 29% were Black, and the mean dairy intake was 1.7 and 1.3 servings/day, respectively. Twenty-nine significant associations between dietary intake of dairy and serum metabolites were identified in the ARIC study (total dairy, n = 14; low-fat dairy, n = 10; high-fat dairy, n = 5). Three associations were also significant in BHS: myristate (14:0) was associated with high-fat dairy, and pantothenate was associated with total dairy and low-fat dairy, but 23 of the 27 associations significant in the ARIC study and tested in BHS were not associated with dairy in BHS. CONCLUSIONS: We identified metabolomic associations with dietary intake of dairy, including 3 associations found in 2 independent cohort studies. These results suggest that myristate (14:0) and pantothenate (vitamin B5) are candidate biomarkers of dairy consumption.

The Utility of Preclinical Models in Understanding the Bone Health of Transgender Individuals Undergoing Gender-Affirming Hormone Therapy.

PURPOSE OF REVIEW: To summarise the evidence regarding the effects of gender-affirming hormone therapy (GAHT) on bone health in transgender people, to identify key knowledge gaps and how these gaps can be addressed using preclinical rodent models. RECENT FINDINGS: Sex hormones play a critical role in bone physiology, yet there is a paucity of research regarding the effects of GAHT on bone microstructure and fracture risk in transgender individuals. The controlled clinical studies required to yield fracture data are unethical to conduct making clinically translatable preclinical research of the utmost importance. Novel genetic and surgical preclinical models have yielded significant mechanistic insight into the roles of sex steroids on skeletal integrity. Preclinical models of GAHT have the potential inform clinical approaches to preserve skeletal integrity and prevent fractures in transgender people undergoing GAHT. This review highlights the key considerations required to ensure the information gained from preclinical models of GAHT are informative.

Diagnostics and correction of batch effects in large-scale proteomic studies: a tutorial.

Advancements in mass spectrometry-based proteomics have enabled experiments encompassing hundreds of samples. While these large sample sets deliver much-needed statistical power, handling them introduces technical variability known as batch effects. Here, we present a step-by-step protocol for the assessment, normalization, and batch correction of proteomic data. We review established methodologies from related fields and describe solutions specific to proteomic challenges, such as ion intensity drift and missing values in quantitative feature matrices. Finally, we compile a set of techniques that enable control of batch effect adjustment quality. We provide an R package, "proBatch", containing functions required for each step of the protocol. We demonstrate the utility of this methodology on five proteomic datasets each encompassing hundreds of samples and consisting of multiple experimental designs. In conclusion, we provide guidelines and tools to make the extraction of true biological signal from large proteomic studies more robust and transparent, ultimately facilitating reliable and reproducible research in clinical proteomics and systems biology.

Main title - Socio-economic effects on informal caregivers of long-term hospitalized adult patients: A cross-sectional study.

Introduction: A significant proportion of patients are being treated at hospitals in the government sector in Sri Lanka. Informal caregivers play a major role in taking care of hospitalized surgical patients while facing physical, social, and psychological challenges. Objective: To describe the socio-economic effects on informal caregivers of long-term hospitalized adult patients. Methods: A cross-sectional descriptive study was conducted among 202 informal caregivers of long-term hospitalized patients in a tertiary care hospital in Sri Lanka, using an interviewer-administered questionnaire. Sociodemographic assessment of both caregiver and care recipient, the health status of the care recipient, effects on social life, and economic aspect of informal caregiver were assessed. Results: Most of the caregivers were married (n=164, 81.2%), first degree relative of the care receiver (n=139, 68.8%), employed (n=115, 56.9%) and sole caregivers (n=130, 64.4%). Four out of 5 caregivers (n=181, 89.6%) showed moderate to severe socio-economic maladaptation. Increasing age (p=0.00), marital status (p=0.00) and sole caregiving (p=0.01) are significantly associated with the level of maladaptation. Conclusion: Moderate to severe levels of maladaptation is present among a substantial number of informal caregivers of long-term hospitalized patients. Sole caregiving is one of the contributing factors and can be addressed by adequate formal caregivers appointed by health care authorities or from voluntary services to minimize informal caregiver burnout.

Anatomic feasibility of endoscopic endonasal intracranial aneurysm clipping: a systematic review of anatomical studies.

Clinical studies have suggested the endoscopic endonasal approach (EEA) for aneurysm clipping as a feasible way to treat select intracranial aneurysms. Among neurosurgery, there is not a consensus on the utility of EEA aneurysm clipping. This review aims to define the anatomic feasibility of EEA for aneurysm clipping. Two databases (PubMed, Cochrane) were searched for anatomical studies assessing EEA for intracranial aneurysm clipping. Literature review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Quantitative anatomical studies were included. Eleven studies met inclusion criteria. Vascular exposure and clip placement on vessels of interest were possible, although only one study assessed these parameters with physical aneurysm models. Anterior circulation vessels, although accessible in over 90% of specimens, had low successful clipping rates in a small and large aneurysm models. Small and large model posterior circulation aneurysms were more readily clipped. Proximal and distal controls were readily attainable in posterior circulation aneurysms, but not anterior. This current literature review highlights the relevance of anatomical studies in assessing the feasibility of the EEA for clipping intracranial aneurysms. As such, anterior circulation aneurysms are poor candidates for EEA given difficulties in clip placement and obtaining proximal control and distal control in small and large aneurysms. While our results suggest that clipping of posterior circulation aneurysms is feasible from a technical stand of view, further clinical experience is required to assess its feasibility in terms of safety and efficacy, balancing the indications with endovascular treatment options.

Ultrasound's Impact on Preclinical Medical Student Neurology Unit Grades: Findings After 2 Years.

OBJECTIVES: Ultrasound is a valuable tool for anatomy education, but limited evidence exists for using ultrasound to teach neuroanatomy and neurophysiology. Previous work demonstrated a potential increase in medical knowledge in preclinical medical students participating in a neurology ultrasound workshop, however, without comparison to a control group. After 2 years, we assessed how a neurology ultrasound workshop affected the medical knowledge of participating preclinical medical students compared to a traditional curriculum control group. METHODS: This quasiexperimental study compared academic performance of ultrasound workshop participants to nonparticipant classmates. The primary outcome was the overall neurologic disorders unit total score. An analysis of covariance was conducted to test for statistically significant differences while controlling for the average quiz score. RESULTS: A total of 360 medical students were included in the study. The intervention group (n = 57) showed no significant difference in the total unit score (F = 3.206; P = .074), with averages for the control and experimental groups being 87.3% ± 5.0% and 88.4% ± 4.8%, respectively. Additionally, anatomy practical scores and written final examination scores were not significantly different between groups (F = 1.035; P = .310; F = 2.035; P = .155). CONCLUSIONS: Participation in a neurologic disorders ultrasound workshop did not appear to be correlated with improved curricular performance in our cohort. Further research should continue to assess ultrasound workshops in other organ systems to elucidate the relationship between learning ultrasound and the impact on medical school academic performance.

Neuromodulatory hacking: a review of the technology and security risks of spinal cord stimulation.

BACKGROUND: Spinal cord stimulation (SCS) is a neuromodulatory technique used to relieve chronic pain. Previous instances of malicious remote control of implantable medical devices, including insulin delivery pumps and implantable cardiac defibrillators, have been documented. Though no cases of neuromodulatory hacking have been recorded outside of the academic setting, an understanding of SCS technology and the possible consequences of manipulation is important in promoting safety. METHODS: We review the components and implantation protocol of a SCS system, the functionality and technological specifications for SCS systems in the global market based on their device manuals, and patient- and clinician-specific adjustable factors. Furthermore, we assess documented instances of implantable medical device hacking and speculate on the potential harms of targeting SCS systems. RESULTS: SCS systems from Abbott Laboratories, Boston Scientific, Medtronic, and Nevro have unique functionality and technological specifications. Six parameters in device control can potentially be targeted and elicit various harms, including loss of therapeutic effect, accelerated battery drainage, paresthesia in unintended locations, muscle weakness or dysfunction, tissue burn, and electrical shock. CONCLUSIONS: Based on the history of implantable medical device hacking, SCS systems may also be susceptible to manipulation. As the prevalence of SCS use increases and SCS systems continuously evolve in the direction of wireless control and compatibility with mobile devices, appropriate measures should be taken by manufacturers and governmental agencies to ensure safety.

SIMLIN: a bioinformatics tool for prediction of S-sulphenylation in the human proteome based on multi-stage ensemble-learning models.

BACKGROUND: S-sulphenylation is a ubiquitous protein post-translational modification (PTM) where an S-hydroxyl (-SOH) bond is formed via the reversible oxidation on the Sulfhydryl group of cysteine (C). Recent experimental studies have revealed that S-sulphenylation plays critical roles in many biological functions, such as protein regulation and cell signaling. State-of-the-art bioinformatic advances have facilitated high-throughput in silico screening of protein S-sulphenylation sites, thereby significantly reducing the time and labour costs traditionally required for the experimental investigation of S-sulphenylation. RESULTS: In this study, we have proposed a novel hybrid computational framework, termed SIMLIN, for accurate prediction of protein S-sulphenylation sites using a multi-stage neural-network based ensemble-learning model integrating both protein sequence derived and protein structural features. Benchmarking experiments against the current state-of-the-art predictors for S-sulphenylation demonstrated that SIMLIN delivered competitive prediction performance. The empirical studies on the independent testing dataset demonstrated that SIMLIN achieved 88.0% prediction accuracy and an AUC score of 0.82, which outperforms currently existing methods. CONCLUSIONS: In summary, SIMLIN predicts human S-sulphenylation sites with high accuracy thereby facilitating biological hypothesis generation and experimental validation. The web server, datasets, and online instructions are freely available at http://simlin.erc.monash.edu/ for academic purposes.

Does Time-in-Range Matter? Perspectives From People With Diabetes on the Success of Current Therapies and the Drivers of Improved Outcomes.

IN BRIEF After assessing patient perspectives on the success of current diabetes therapies and the factors that have the greatest impact on daily life, we show that time-in-range is a crucial outcome for people with diabetes and that current therapies are falling short on this metric. We also show that patients feel significant stress and worry, and they believe they are falling short in diet, exercise, and weight maintenance. In addition, they believe diet and exercise and in-range blood glucose are the biggest drivers of improved diabetes management and mindset. Together, these findings support the need for therapies that improve outcomes including and beyond A1C.

Surgical Scar Site Recurrence in Patients With Cervical Cancer on 18F-FDG PET-CT: A Case-Control Study.

PURPOSE: The purpose of this study was to assess the role of fluorine 18 ((18)F)-fluorodeoxyglucose positron emission tomography-computed tomography ((18)F-FDG PET-CT) in evaluating various parameters in patients with surgical scar site recurrence in cervical carcinoma. METHODS: Data of all patients with cervical cancer (n = 329) who underwent PET-CT at our institute between 2005 and 2013 was reviewed. Of these 329 patients, 132 patients who were surgically treated and underwent restaging/follow-up PET-CT were included in the present study for final analysis. Tumor recurrence at the abdominal surgical scar site was looked for. Abnormal uptakes suggestive of active disease at other sites were also noted. Maximum standardized uptake value was measured for all the lesions. Patients with scar site recurrence were taken as cases (n = 6), whereas the remaining patients served as controls (n = 126). Comparison with conventional imaging modalities was made wherever available. Histopathological examination was always sought for. RESULTS: The incidence of scar site recurrence after surgery was found to be 4.5% (6/117). A total of 56 of 132 patients had recurrent disease, including 6 patients with scar site recurrence. All of the patients with scar site recurrence also had recurrent disease at other sites (local, nodal, or distant). Conventional imaging modalities were available in 4 of these 6 patients and detected scar site recurrence in 3 of those 4 patients. In patients with scar site recurrence, the mean ± SD time to scar site recurrence was 14.0 ± 10.9 months (median, 10 months; range, 7-36 months). Significant difference was seen between cases and control for International Federation of Genecology and Oncology stage (P = 0.001) and nodal recurrence (P = 0.007). Additionally, age, nodal recurrence, distant recurrence, and scar site recurrence were significantly associated with death. CONCLUSIONS: Scar site recurrence carries a poor prognosis, and the incidence is much higher than previously known when PET-CT is used as a modality for its detection.

Effect of Ivabradine on Heart Rate and Duration of Exercise in Patients With Mild-to-Moderate Mitral Stenosis: A Randomized Comparison With Metoprolol.

BACKGROUND: Symptoms in mitral stenosis (MS) are heart rate (HR) dependent. Increase in HR reduces diastolic filling period with rise in transmitral gradient. By reducing HR, beta-blockers improve hemodynamics and relieve symptoms, but the use may be limited by side effects. The present randomized crossover study looked at comparative efficacy of ivabradine and metoprolol on symptoms, hemodynamics, and exercise parameters in patients with mild-to-moderate MS (mitral valve area, 1-2 cm) in normal sinus rhythm. MATERIAL AND METHODS: Baseline clinical assessment, treadmill stress testing, and an echocardiographic Doppler evaluation were performed to determine resting HR, total exercise duration, mean gradient across mitral valve, and mean pulmonary artery systolic pressure (PASP). Patients were then allocated to either metoprolol or ivabradine to maximal tolerated doses over 6 weeks (metoprolol: 100 mg twice a day, ivabradine: 10 mg twice a day). Reevaluation was done at the end of this period, and all drugs stopped for washout over 2 weeks. Thereafter, the 2 groups were crossed over to the other drug that was continued for another 6 weeks. Assessment was again performed at the end of this period. RESULTS: Thirty-three patients of 34 completed the protocol. Fifteen were male, mean age was 28.9 ± 6.6 years, all were in New York Heart Association class 2, and mean resting HR was 103.5 ± 7.2/min. Mean mitral valve area was 1.56 ± 0.16 cm, mean PASP was 38.1 ± 5.1 mm Hg, and mean gradient across mitral valve was 10.6 ± 1.6 mm Hg. Significant decrease in baseline and peak exercise HR was observed at the end of follow-up with both drugs. Reduction in mitral valve gradient after ivabradine (42%) and metoprolol (37%) and reduction in PASP after both ivabradine (23%) and metoprolol (27%) were to a similar extent. Significant reduction in total exercise duration after both ivabradine and metoprolol therapy was observed. One patient developed blurring of vision with ivabradine therapy but did not require discontinuation of drug. An improvement in dyspnea of one grade was observed in all the patients by treatment with both ivabradine and metoprolol. CONCLUSIONS: Both metoprolol and ivabradine reduced symptoms and improved hemodynamics significantly from baseline to a similar extent. Ivabradine thus can be used effectively and safely in patients with MS in normal sinus rhythm who are intolerant or contraindicated for beta-blocker therapy.

White Light Emission Through Downconversion of Terbium and Europium Doped CeF3 Nanophosphors.

CeF3 nanophosphors have been extensively investigated in recent years for lighting and numerous bio-applications. Downconversion emissions in CeF3:Eu(3+)/Tb(3+) phosphors were studied with the objective of attaining a white light emitting composition, by means of a simple co-precipitation method. The material was characterized by X-ray Diffraction (XRD), Transmission Electron Microscopy (TEM), Fourier Transform Infrared Spectroscopy (FT-IR) and Photoluminescence (PL). Uniformly distributed nanoparticles were obtained with an average particle size range of 8-10 nm. Various studies were undertook utilizing different doping concentrations and respective fluorescence studies were carried out to optimize dopant concentrations while achieving maximum luminescence intensity. From PL results, it was observed that the efficient energy transfers from the donor to the acceptor ions. Different concentrations of Tb(3+), Eu(3+) were doped in order to achieve a white light emitting phosphor for UV-based Light Emitting Diodes (LEDs). The nanoparticles showed characteristic emission of respective dopants (Eu(3+), Tb(3+)) when excited at the 4f → 5d transition of Ce(3+). The chromaticity coordinates for CeF3 doped with Eu(3+) and Tb(3+) were calculated and an emission very close to white light was observed.

Using hip measures to avoid misdiagnosing early rapid onset osteoarthritis for osteonecrosis.

In the early phases, subchondral insufficiency fractures and rapidly destructive osteoarthritis of the hip are often mistaken for osteonecrosis of the hip. Three hip measures were used comparing combined subchondral insufficiency fractures and rapidly destructive 18 osteoarthritis patients to 18 osteonecrosis patients. Due to the rarity of these conditions there was no statistical power. Initial diagnoses for the osteoarthritis patients were recorded. The osteoarthritis group had significantly higher means for Tönnis angle (P < 0.001), lateral center edge angle (P = 0.006), and acetabular extrusion index (P = 0.014). Only 7 of the 18 patients were initially diagnosed without reservation as subchondral insufficiency fracture or rapidly destructive osteoarthritis. Using hip measures will reduce the misdiagnosis of rapid onset osteoarthritis of the hip for osteonecrosis.

Untangling the loops of STAG2 mutations in myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a heterogeneous myeloid neoplasm that is hallmarked by the acquisition of genetic events that disrupt normal trilineage hematopoiesis and results in bone marrow dysfunction. Somatic genes involving transcriptional regulation, signal transduction, DNA methylation, and chromatin modification are often implicated in disease pathogenesis. The cohesin complex, composed of SMC1, SMC3, RAD21, and either STAG1 or STAG2, has been identified as a recurrent mutational target with STAG2 mutations accounting for more than half of all cohesin mutations in myeloid malignancies. In the last decade, STAG2 cohesin biology has been of great interest given its role in transcriptional activation, association with poorer prognosis, and lack of mutation-specific therapies. This review discusses the clinical landscape of cohesin mutant myeloid malignancies, particularly STAG2 mutant MDS, including molecular features of STAG2 mutations, clinical implications of cohesin mutant neoplasms, and the current understanding of the pathophysiological function of STAG2 mutations in MDS.

Comparing and Contrasting Professional Identity Formation Among Health Professional Students.

This project aims to review and compare the professional identity formation (PIF) of medical, dental, nursing, and pharmacy students while analyzing the role of interprofessional education (IPE) in this journey. Our medical research librarian conducted a literature review. Papers were selected based on the inclusion criteria developed by authors for PIF and IPE topics, which were then stratified for each health program of interest: medicine, dentistry, nursing, and pharmacy. The IPE core competencies were analyzed to understand the effect of IPE on each respective group of health professional students. Among all four major health professions, trust, collaboration, responsibility, accountability, communication, and empathy are key values within PIF. Trust, collaboration, and empathy were also regarded as core values in developing professionalism. Medical and dental students placed greater emphasis on responsibility and accountability regarding PIF. IPE played a crucial role in PIF for all students as values, teamwork, roles, and responsibilities were emphasized among each healthcare discipline of interest. This review provides significant information regarding which characteristics are emphasized for professional development across healthcare training programs. Future research to explore how certain characteristics and values influence healthcare as a whole is crucial. Investigating various influences on PIF outcomes is warranted for enhancing professional training programs and promoting interprofessional collaboration for better healthcare delivery.

Advances in Hierarchical Inorganic Nanostructures for Efficient Solar Energy Harvesting Systems.

The urgent need to address the global energy and environmental crisis necessitates the development of efficient solar-power harvesting systems. Among the promising candidates, hierarchical inorganic nanostructures stand out due to their exceptional attributes, including a high specific surface area, abundant active sites, and tunable optoelectronic properties. In this comprehensive review, we delve into the fundamental principles underlying various solar energy harvesting technologies, including dye-sensitized solar cells (DSSCs), photocatalytic, photoelectrocatalytic (water splitting), and photothermal (water purification) systems, providing a foundational understanding of their operation. Thereafter, the discussion is focused on recent advancements in the synthesis, design, and development of hierarchical nanostructures composed of diverse inorganic material combinations, tailored for each of these solar energy harvesting systems. We meticulously elaborate on the distinct synthesis methods and conditions employed to fine-tune the morphological features of these hierarchical nanostructures. Furthermore, this review offers profound insights into critical aspects such as electron transfer mechanisms, band gap engineering, the creation of hetero-hybrid structures to optimize interface chemistry through diverse synthesis approaches, and precise adjustments of structural features. Beyond elucidating the scientific fundamentals, this review explores the large-scale applications of the aforementioned solar harvesting systems. Additionally, it addresses the existing challenges and outlines the prospects for achieving heightened solar-energy conversion efficiency.