Quantitative profiling of cochlear synaptosomal proteins in cisplatin-induced synaptic dysfunction.

The disruption of ribbon synapses in the cochlea impairs the transmission of auditory signals from the cochlear sensory receptor cells to the auditory cortex. Although cisplatin-induced loss of ribbon synapses is well-documented, and studies have reported nitration of cochlear proteins after cisplatin treatment, yet the underlying mechanism of cochlear synaptopathy is not fully understood. This study tests the hypothesis that cisplatin treatment alters the abundance of cochlear synaptosomal proteins, and selective targeting of nitrative stress prevents the associated synaptic dysfunction. Auditory brainstem responses of mice treated with cisplatin showed a reduction in amplitude and an increase in latency of wave I, indicating cisplatin-induced synaptic dysfunction. The mass spectrometry analysis of cochlear synaptosomal proteins identified 102 proteins that decreased in abundance and 249 that increased in abundance after cisplatin treatment. Pathway analysis suggested that the dysregulated proteins were involved in calcium binding, calcium ion regulation, synapses, and endocytosis pathways. Inhibition of nitrative stress by co-treatment with MnTBAP, a peroxynitrite scavenger, attenuated cisplatin-induced changes in the abundance of 27 proteins. Furthermore, MnTBAP co-treatment prevented the cisplatin-induced decrease in the amplitude and increase in the latency of wave I. Together, these findings suggest a potential role of oxidative/nitrative stress in cisplatin-induced cochlear synaptic dysfunction.

Computational design of non-porous pH-responsive antibody nanoparticles.

Programming protein nanomaterials to respond to changes in environmental conditions is a current challenge for protein design and is important for targeted delivery of biologics. Here we describe the design of octahedral non-porous nanoparticles with a targeting antibody on the two-fold symmetry axis, a designed trimer programmed to disassemble below a tunable pH transition point on the three-fold axis, and a designed tetramer on the four-fold symmetry axis. Designed non-covalent interfaces guide cooperative nanoparticle assembly from independently purified components, and a cryo-EM density map closely matches the computational design model. The designed nanoparticles can package protein and nucleic acid payloads, are endocytosed following antibody-mediated targeting of cell surface receptors, and undergo tunable pH-dependent disassembly at pH values ranging between 5.9 and 6.7. The ability to incorporate almost any antibody into a non-porous pH-dependent nanoparticle opens up new routes to antibody-directed targeted delivery.

A dynamic neural resource model bridges sensory and working memory.

Probing memory of a complex visual image within a few hundred milliseconds after its disappearance reveals significantly greater fidelity of recall than if the probe is delayed by as little as a second. Classically interpreted, the former taps into a detailed but rapidly decaying visual sensory or 'iconic' memory (IM), while the latter relies on capacity-limited but comparatively stable visual working memory (VWM). While iconic decay and VWM capacity have been extensively studied independently, currently no single framework quantitatively accounts for the dynamics of memory fidelity over these time scales. Here, we extend a stationary neural population model of VWM with a temporal dimension, incorporating rapid sensory-driven accumulation of activity encoding each visual feature in memory, and a slower accumulation of internal error that causes memorized features to randomly drift over time. Instead of facilitating read-out from an independent sensory store, an early cue benefits recall by lifting the effective limit on VWM signal strength imposed when multiple items compete for representation, allowing memory for the cued item to be supplemented with information from the decaying sensory trace. Empirical measurements of human recall dynamics validate these predictions while excluding alternative model architectures. A key conclusion is that differences in capacity classically thought to distinguish IM and VWM are in fact contingent upon a single resource-limited WM store.

Molecular breeding of flower load related traits in dioecious autotetraploid Actinidia arguta.

Flowering plants exhibit a wide range of sexual reproduction systems, with the majority being hermaphroditic. However, some plants, such as Actinidia arguta (kiwiberry), have evolved into dioecious species with distinct female and male vines. In this study, we investigated the flower load and growth habits of female kiwiberry genotypes to identify the genetic basis of high yield with low maintenance requirements. Owing to the different selection approaches between female and male genotypes, we further extended our study to male kiwiberry genotypes. By combining both investigations, we present a novel breeding tool for dioecious crops. A population of A. arguta seedlings was phenotyped for flower load traits, in particular the proportion of non-floral shoots, proportion of floral shoots, and average number of flowers per floral shoot. Quantitative trait locus (QTL) mapping was used to analyse the genetic basis of these traits. We identified putative QTLs on chromosome 3 associated with flower-load traits. A pleiotropic effect of the male-specific region of the Y chromosome (MSY) on chromosome 3 affecting flower load-related traits between female and male vines was observed in an A. arguta breeding population. Furthermore, we utilized Genomic Best Linear Unbiased Prediction (GBLUP) to predict breeding values for the quantitative traits by leveraging genomic data. This approach allowed us to identify and select superior genotypes. Our findings contribute to the understanding of flowering and fruiting dynamics in Actinidia species, providing insights for kiwiberry breeding programs aiming to improve yield through the utilization of genomic methods and trait mapping. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01476-7.

The CTLH Ubiquitin Ligase Substrates ZMYND19 and MKLN1 Negatively Regulate mTORC1 at the Lysosomal Membrane.

Most Epstein-Barr virus-associated gastric carcinoma (EBVaGC) harbor non-silent mutations that activate phosphoinositide 3 kinase (PI3K) to drive downstream metabolic signaling. To gain insights into PI3K/mTOR pathway dysregulation in this context, we performed a human genome-wide CRISPR/Cas9 screen for hits that synergistically blocked EBVaGC proliferation together with the PI3K antagonist alpelisib. Multiple subunits of carboxy terminal to LisH (CTLH) E3 ligase, including the catalytic MAEA subunit, were among top screen hits. CTLH negatively regulates gluconeogenesis in yeast, but not in higher organisms. Instead, we identified that the CTLH substrates MKLN1 and ZMYND19, which highly accumulated upon MAEA knockout, associated with one another and with lysosomes to inhibit mTORC1. ZMYND19/MKLN1 bound Raptor and RagA/C, but rather than perturbing mTORC1 lysosomal recruitment, instead blocked a late stage of its activation, independently of the tuberous sclerosis complex. Thus, CTLH enables cells to rapidly tune mTORC1 activity at the lysosomal membrane via the ubiquitin/proteasome pathway.

Commentary: Is Polyethylene Glycol Toxicity From Intravenous Methocarbamol Fact or Fiction?

Methocarbamol is an antispasmodic muscle relaxant and was the fourth most-prescribed muscle relaxant by volume in the United States in 2021. Intravenous (IV) methocarbamol contains the excipient, polyethylene glycol (PEG), which has been implicated in metabolic acidosis and nephrotoxicity. Intravenous methocarbamol was first approved by the US Food and Drug Administration in 1959 and at that time the IV methocarbamol prescribing information warned of PEG-associated adverse drug events in patients living with renal impairment; however, the manufacturer acknowledged data were lacking to objectively support this claim. Clinicians prescribing and dispensing IV methocarbamol may encounter the warning for PEG-associated metabolic acidosis and nephrotoxicity without knowing the potential risks, or lack thereof, supporting or disavowing this phenomenon. This commentary debates the merits supporting and arguments refuting PEG-associated metabolic acidosis and nephrotoxicity in patients treated with IV methocarbamol.

Validation of a Natural Language Processing Algorithm using National Reporting Data to Improve Identification of Anesthesia-related ADVerse evENTs: The "ADVENTURE" Study.

BACKGROUND: Reporting and analysis of adverse events (AE) is associated with improved healthcare learning, quality outcomes, and patient safety. Manual text analysis is time-consuming, costly, and prone to human errors. We aimed to demonstrate the feasibility of machine learning and natural language processing (NLP) approaches for early predictions of adverse events and provide input to direct quality improvement and patient safety initiatives. METHODS: We used machine learning to analyze 9,559 continuously reported AE by clinicians and healthcare systems to the French National Health accreditor (HAS) between January 1, 2009, and December 31, 2020, for a total of 135,000 unique de-identified AE reports. We validated the labeling and determined the associations between different root causes and patient consequences. The model was validated by independent expert anesthesiologists. RESULTS: The machine learning and Artificial Intelligence (AI) model trained on 9,559 AE datasets accurately categorized 8800 (88%) of reported AE. The three most frequent AE types were "difficult orotracheal intubation" (16.9% of AE reports), "medication error" (10.5%), and "post-induction hypotension" (6.9%). The accuracy of the AI model reached 70.9% sensitivity, 96.6% specificity for "difficult intubation", 43.2% sensitivity, and 98.9% specificity for "medication error." CONCLUSIONS: This unsupervised method provides an accurate, automated, AI-supported search algorithm that ranks and helps to understand complex patterns of risky patient situations and has greater speed, precision, and clarity when compared to manual human data extraction. Machine learning (ML) and natural language processing models can effectively be used to process natural language AE reports and augment expert clinician input. This model can support clinical applications and methodological standards of implementations and be used to better inform and enhance decision-making for improved risk management and patient safety. TRIAL REGISTRATION: The study was approved by the ethics committee of the French Society of Anesthesiology (IRB 00010254-2020-20) and the CNIL (CNIL: 118 58 95) and the study was registered with ClinicalTrials.gov (NCT: NCT05185479).

Impact of coronary artery disease and revascularization on outcomes of transcatheter aortic valve replacement for severe aortic stenosis.

BACKGROUND/PURPOSE: To evaluate the impact of coronary artery disease (CAD), percutaneous coronary intervention (PCI), and coronary lesion complexity on outcomes of transcatheter aortic valve replacement (TAVR) for aortic stenosis. METHODS/MATERIALS: This retrospective study included 1042 patients divided into two groups by the presence or absence of CAD (SYNTAX score 0, no history of revascularization). Propensity score matching was used to compare the two groups. The effect of PCI, SYNTAX score, and residual SYNTAX score was also analyzed. RESULTS: The median age of the cohort was 82 years, and 641 patients had CAD. After propensity score matching, 346 pairs were analyzed. During 5 years of follow-up (median: 25, range 0-72 months), the rate of coronary intervention was significantly higher in CAD patients (p = 0.018). However, all-cause mortality, composite of all-cause mortality, stroke, and coronary intervention, and overt bleeding defined by VARC-3 were comparable. After stratification, in patients with creatinine ≥1.5 mg/dl, CAD was associated with a worse composite outcome (p = 0.016). Neither PCI nor SYNTAX score was associated with all-cause mortality in CAD patients. Similarly, residual SYNTAX score showed no association with mortality in patients undergoing PCI (all p values >0.7). PCI did not reach a significant difference in overt bleeding in CAD patients (adjusted p = 0.06). CONCLUSIONS: Despite a higher incidence of coronary interventions, major clinical outcomes were similar between patients with and without CAD after TAVR. In patients with chronic kidney disease, CAD may be associated with an adverse composite outcome. Neither PCI nor SYNTAX/residual SYNTAX score influenced all-cause mortality.

Microstructural Mapping of Neural Pathways in Alzheimer's Disease using Macrostructure-Informed Normative Tractometry.

INTRODUCTION: Diffusion MRI is sensitive to the microstructural properties of brain tissues and shows great promise in detecting the effects of degenerative diseases. However, many approaches analyze single measures averaged over regions of interest, without considering the underlying fiber geometry. METHODS: Here, we propose a novel Macrostructure-Informed Normative Tractometry (MINT) framework, to investigate how white matter microstructure and macrostructure are jointly altered in mild cognitive impairment (MCI) and dementia. We compare MINT-derived metrics with univariate metrics from diffusion tensor imaging (DTI), to examine how fiber geometry may impact interpretation of microstructure. RESULTS: In two multi-site cohorts from North America and India, we find consistent patterns of microstructural and macrostructural anomalies implicated in MCI and dementia; we also rank diffusion metrics' sensitivity to dementia. DISCUSSION: We show that MINT, by jointly modeling tract shape and microstructure, has potential to disentangle and better interpret the effects of degenerative disease on the brain's neural pathways.

Computational Design of Cyclic Peptide Inhibitors of a Bacterial Membrane Lipoprotein Peptidase.

There remains a critical need for new antibiotics against multi-drug-resistant Gram-negative bacteria, a major global threat that continues to impact mortality rates. Lipoprotein signal peptidase II is an essential enzyme in the lipoprotein biosynthetic pathway of Gram-negative bacteria, making it an attractive target for antibacterial drug discovery. Although natural inhibitors of LspA have been identified, such as the cyclic depsipeptide globomycin, poor stability and production difficulties limit their use in a clinical setting. We harness computational design to generate stable de novo cyclic peptide analogues of globomycin. Only 12 peptides needed to be synthesized and tested to yield potent inhibitors, avoiding costly preparation of large libraries and screening campaigns. The most potent analogues showed comparable or better antimicrobial activity than globomycin in microdilution assays against ESKAPE-E pathogens. This work highlights computational design as a general strategy to combat antibiotic resistance.

Airway and Systemic Immunoglobulin Profiling and Immune Response in Adult Asthma.

INTRODUCTION: Immunoglobulins play a vital role in host immune response and in the pathogenesis of conditions like asthma. Therapeutic agents such as monoclonal antibodies target specific elements of the asthmatic inflammatory cascade. Decisions to utilize these medications are often based on systemic inflammatory profiling without direct insight into the airway inflammatory profile. We sought to investigate the relationship between immunoglobulin and cytokine profiles in the airway and systemic immune compartments of adult asthmatics. METHODS: Blood sampling and bronchoscopy with bronchoalveolar lavage (BAL) were performed in 76 well-defined adult asthmatics. Antibody and cytokine profiles were measured in both BAL and serum using ELISA and quantibody arrays. RESULTS: There was no relationship between BAL and serum levels of IgE. This is of significance in an asthma population. For some analytes, correlation analysis was significant (P < 0.05) indicating representativeness of our cohort and experimental setup in those cases. Nevertheless, the predictive power (r2) of the BAL-to-serum comparisons was mostly low except for TNF-α (r2 = 0.73) when assuming a simple (linear) relationship. CONCLUSION: This study highlights the importance of sample site when investigating the roles of immunoglobulins and cytokines in disease pathogenesis and suggests that both localized and systemic immune responses are at play. The prescription of asthma monoclonal therapy is generally based on systemic evaluation of cytokine and immunoglobulin levels. Our research suggests that this approach may not fully reflect the pathophysiology of the disease and may provide insight into why some patients respond to these targeted therapies while others do not.

Reliability of beat-to-beat blood pressure variability in older adults.

Blood pressure variability (BPV) is emerging as an important risk factor across numerous disease states, including cerebrovascular and neurodegenerative disease in older adults. However, there is no current consensus regarding specific use cases for the numerous available BPV metrics. There is also little published data supporting the ability to reliably measure BPV across metrics in older adults. BPV metrics were derived from continuous beat-to-beat blood pressure monitoring data. Two sequential 7-minute waveforms were analyzed. Absolute and relative reliability testing was performed. Differences between antihypertensive medication users and non-users on BPV metric reliability was also assessed. All sequence and dispersion based BPV metrics displayed good test-retest reliability. A measure of BP instability displayed only moderate reliability. Systolic and diastolic average real variability displayed the highest levels of reliability at ICC= .87 and .82 respectively. Additionally, systolic average real variability was the most reliable metric in both the antihypertensive use group, and the no antihypertensive use group. Beat-to-beat dispersion and sequence-based metrics of BPV can be reliably obtained from older adults using noninvasive continuous blood pressure monitoring. Average real variability may be the most reliable and specific beat-to-beat blood pressure variability metric due to its decreased susceptibility to outliers and low frequency blood pressure oscillations.

A population health approach to workplace mental health: rationale, implementation and engagement.

Objectives: To describe a population health-based program to support employee and dependent mental health and learn from engagement trends. Methods: Retrospective analysis of a program utilizing an assessment of mental health risk. For scoring "at risk," a Care Concierge is offered to connect users with resources. Results: Participation was offered to 56,442 employees and dependents. Eight thousand seven hundred thirty-one completed the assessment (15%). Of those, 4,644 (53%) scored moderate or higher. A total of 418 (9%) engaged the Care Concierge. Factors that negatively influenced the decision to engage care included bodily pain, financial concerns. Positive influences were younger age, high stress, anxiety, PTSD and low social support. Conclusion: Proactive assessment plus access to a Care Concierge facilitates mental healthcare utilization. Several factors influence likelihood to engage in care. A better understanding of these factors may allow for more targeted outreach and improved engagement.

Dataset for computational and experimental buckling analysis of constant-stiffness and variable-stiffness composite cylinders.

This dataset encapsulates comprehensive information and experimental outcomes derived from the buckling test of variable-stiffness composite cylinders subjected to axial compression. It is the first dataset about the correlation between experimental and computational analysis for a Rapid-Tow Sheared composite cylinder, a recently developed advanced composite manufacturing technique. The data gathered during the test contains: raw test data for force, end-compression and strain gauges; and digital image correlation. The data for finite element validation is for a quasi-isotropic shell and variable-stiffness rapid tow-sheared shell. The data also contain imperfection signatures from a coordinate-measurement machine (CMM) of both cylinders. This compilation of documented data stands as a robust resource for future investigations, enabling comparative analyses, validation of theoretical models, and advancements in the domain of designing and testing composite structures, particularly those employing variable-stiffness manufacturing techniques.

Age-specific reference scores for the PISQ-12 on female sexual functioning in the Netherlands: a retrospective population-based survey.

BACKGROUND: Female sexual dysfunction is common in the general population, with age emerging as a significant determinant of sexual activity and functioning. AIM: To establish age-specific reference scores for the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12) in the general Dutch female population. METHODS: A retrospective, cross-sectional, questionnaire-based study was conducted in the Netherlands. The study population comprised 2518 Dutch-speaking women aged ≥18 years, representing a cross section of the general Dutch population. The PISQ-12 was used to assess sexual functioning in heterosexual women. The Groningen Defecation and Fecal Continence questionnaire was utilized to demonstrate demographic factors. OUTCOMES: We established age-specific reference scores for the PISQ-12 in the general Dutch population. RESULTS: Of the 2518 women, 1592 (63.2%) were sexually active and 926 (36.8%) were not. Further analysis focused on the sexually active group: we found a decrease in mean total PISQ scores, ranging from 38.34 among 18- to 34-year-olds to 36.98 among ≥65-year-olds. Older women scored lower in the behavior domain, specifically pertaining to sexual desire (P < .001) and sexual excitement (P < .001). They also had lower scores in the partner-related domain regarding partner problems of erection (P < .001) and orgasm perception (P < .001). With increasing age, negative emotional reaction scores were higher (P < .001). In the physical domain, we observed significantly different scores for pain during sexual intercourse (P < .001) and restrictions in sexual activity due to fear of urinary leakage (P < .001), with the lowest scores in the youngest group. CLINICAL IMPLICATIONS: These age-specific references scores of the PISQ-12 provide an overview of sexual functioning of a general population, which enables caregivers to assess and interpret patients' individual scores more accurately. STRENGTHS AND LIMITATIONS: We included only sexually active women in our subanalyses, potentially introducing selection bias for older women with better physical conditions. The study's strength lies in its extensive sample size, representing a cross section of the general Dutch population. Furthermore, the self-administered questionnaire approach helped minimize embarrassment and obtain realistic responses. CONCLUSION: Our study demonstrated age-specific PISQ-12 reference scores and highlighted associations between aging and diminishing scores of sexual desire, sexual excitement, erection problems, and orgasm perception, while women aged 18 to 34 years reported the lowest scores for pain during intercourse and limited sexual activity due to fear of urinary leakage.

Histological analysis of laser-enabled tissue coring with a novel 2910 nm erbium-doped fluoride glass fiber laser.

OBJECTIVES: There remains an unmet need for a laser-enabled tissue coring device that can effectively improve face and neck skin laxity and rhytides. We investigate a novel 2910 nm erbium-doped fluoride glass fiber laser (2910 nm fiber laser) (UltraClear; Acclaro Medical) for laser-coring of submental tissue. METHODS: Five subjects, Glogau scale III-IV, were treated with a single pulse of the laser-coring mode of the 2910 nm fiber laser in the submentum. A 4 mm punch biopsy was immediately performed. Biopsy specimens were sectioned and stained with hematoxylin and eosin and placed on glass slides. All sections were reviewed, and sections containing the center of the transected core were analyzed for depth and diameter of the ablative microchannel and width of the surrounding zone of coagulation. RESULTS: A total of 15 intact micro-cores were analyzed. Histological analysis revealed an average ± standard deviation microchannel diameter of 242.5 ± 65.2 µm, an average ablative depth of 980 ± 318.8 µm, and an average zone of coagulation of 104 ± 32 µm. CONCLUSIONS: Laser-enabled tissue coring with a novel 2910 nm fiber laser can safely achieve a wider microchannel diameter with ablative depth extending to the mid and deep dermis, which has the potential for collagen contraction and tissue tightening. Laser-coring to this ablation diameter and depth and with the surrounding zone of coagulation was found to be safe without adverse effects of post-inflammatory erythema or scarring in our study.

Short-term blood pressure variability and brain functional network connectivity in older adults.

Background: Blood pressure variability is increasingly linked with cerebrovascular disease and Alzheimer's disease, independent of mean blood pressure levels. Elevated blood pressure variability is also associated with attenuated cerebrovascular reactivity, which may have implications for functional hyperemia underpinning brain network connectivity. It remains unclear whether blood pressure variability is related to functional network connectivity. We examined relationships between beat-to-beat blood pressure variability and functional connectivity in brain networks vulnerable to aging and Alzheimer's disease. Methods: 53 community-dwelling older adults (mean [SD] age = 69.9 [7.5] years, 62.3% female) without history of dementia or clinical stroke underwent continuous blood pressure monitoring and resting state fMRI scan. Blood pressure variability was calculated as variability independent of mean. Functional connectivity was determined by resting state fMRI for several brain networks: default, salience, dorsal attention, fronto-parietal, and language. Multiple linear regression examined relationships between short-term blood pressure variability and functional network connectivity. Results: Elevated short-term blood pressure variability was associated with lower functional connectivity in the default network (systolic: standardized ß = -0.30 [95% CI -0.59, -0.01], p = .04). There were no significant associations between blood pressure variability and connectivity in other functional networks or between mean blood pressure and functional connectivity in any network. Discussion: Older adults with elevated short-term blood pressure variability exhibit lower resting state functional connectivity in the default network. Findings support the role of blood pressure variability in neurovascular dysfunction and Alzheimer's disease. Blood pressure variability may represent an understudied early vascular risk factor for neurovascular dysfunction relevant to Alzheimer's disease, with potential therapeutic implications.