bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of long-term rapamycin treatment on age-related osteoarthritis in common marmoset
Authors: Minton Dennis M. , Ailiani Aditya R. , Focht Michael D.K. , Kersh Mariana E. , Marolf Angela J. , Santangelo Kelly S , Salmon Adam B. , Konopka Adam R.
Published: May 2024

Objective

Pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) can attenuate experimental osteoarthritis (OA) in young, male preclinical models. However, the potential of mTOR inhibition as a therapeutic mechanism for OA remains unknown. The goal of this study was to determine if mTOR-inhibition by oral rapamycin can modify OA pathology in the common marmoset, a translational model of age-associated OA.

Methods

microCT and histopathologic assessments of the knee were performed on formalin-fixed hindlimbs obtained from common marmosets treated with oral rapamycin (n=24; 1mg/kg/day) or parallel control group (n=41). Rapamycin started at 9.2±3.0 years old and lasted until death (2.1±1.5 years). In a subset of marmosets, contralateral hind limbs were collected to determine mTOR signaling in several joint tissues.

Results

Rapamycin decreased P-RPS6Ser235/36and increased P-Akt2Ser473in cartilage, meniscus, and infrapatellar fat pad, suggesting inhibition of mTORC1 but not mTORC2 signaling. Rapamycin-treated marmosets had lower lateral synovium score versus control but there was no difference in the age-related increase in microCT or cartilage OA scores. Subchondral bone thickness and thickness variability were not different with age but were lower in rapamycin-treated geriatric marmosets, which was largely driven by females. Rapamycin also tended to worsen age-related meniscus calcification in female marmosets.

Conclusion

Oral rapamycin attenuated mTORC1 signaling and may have caused feedback activation of mTORC2 signaling in joint tissues. Despite modifying site-specific aspects of synovitis, rapamycin did not modify the age-associated increase in OA in geriatric marmosets. Conversely, rapamycin may have had deleterious effects on meniscus calcification and lateral tibia subchondral bone, primarily in geriatric female marmosets.
TGFβ1 plasma levels and clot lysis assay to better characterize patients after a first unprovoked episode of pulmonary embolism
Authors: des Deserts Marc Danguy , de Moreuil Claire , Elhasnaoui Jamal , Gourhant Lenaïck , Gourdou-Latyszenok Virginie , Espinasse Benjamin , Menguy Juliette , Tromeur Cécile , Le Corre Rozenn , Le Mao Raphael , Kraemmer Daniel , Sanchez Olivier ,   PADIS-PE investigators, Couturaud Francis , Lemarié Catherine A.
Published: May 2024

Introduction

The pathophysiology of residual pulmonary vascular obstruction (RPVO) and recurrent venous thromboembolism (VTE) after unprovoked pulmonary embolism (PE) remains poorly understood. The purpose was to evaluate fibrinolytic and tissue remodeling markers as indicators of RPVO and recurrence after a first unprovoked PE.

Methods

Analyses were conducted in the 18 to 70-year-old patients included in the PADIS-PE trial, with a pulmonary vascular obstruction (PVO) index ≥30% at PE diagnosis. After an initial six-month vitamin K antagonist treatment, patients were randomised to receive placebo or warfarin for 18 months, assessed for the absence or presence of residual pulmonary vascular obstruction (RPVO < or ≥5%, respectively) and followed during two years. Quantitative assessment of fibrinolytic (D-dimer, tPA, uPA, TFPI) and tissue remodeling (TGFß1) markers, and a tissue-factor-based turbidimetric clot lysis assay (CLA) were performed one month after warfarin discontinuation.

Results

Among the 371 patients included in PADIS-PE, 23 were eligible. Six (26%) patients presented RPVO ≥ 5%, symptomatic recurrent VTE occurred in nine (39%) patients. Clot formation and lysis parameters were not associated with RPVO. TGFß1 plasma levels were higher in patients with RPVO. Clot formation potential measured with CLA was higher in patients with recurrent VTE. No association between recurrent VTE and TGFß1 was observed. In multivariable analysis, time to peak was associated with VTE recurrence.

Conclusion

In adult patients with a first unprovoked PE and a PVO index ≥30%, TGFß1 plasma level was associated with RPVO, whereas clot formation parameters measured with CLA were associated with VTE recurrence.
Bias in the estimated reporting fraction due to vaccination in the time-series SIR model
Authors: Leung Tiffany , Ferrari Matthew
Published: May 2024

The time-series Susceptible-Infectious-Recovered (TSIR) model has been a standard tool for studying the non-linear dynamics of acute, immunizing infectious diseases. The standard assumption of the TSIR model, that vaccination is equivalent to a reduction in the recruitment of susceptible individuals, or the birth rate, can lead to a bias in the estimate of the reporting fraction and of the total incidence. We show that this bias increases with the level of vaccination due to a double-counting of individuals who are infected prior to the age of vaccination. We present a simple correction for this bias by discounting the observed number of cases by the product of the number that occur prior to the average age of vaccination and the vaccination coverage during the initial susceptible reconstruction step of the TSIR model fitting. We generate a time series of measles cases using an age-structured SIR transmission model with vaccination after birth (at 9 months of age) and illustrate the bias with the standard TSIR fitting method. We then illustrate that our proposed correction eliminates the bias in the estimated reporting fraction and total incidence. We note further that this bias does not impact the estimates of the seasonality of transmission.
Association between BMI and cause-specific long-term mortality in acute myocardial infarction patients
Authors: Schmitz Timo , Freuer Dennis , Raake Philip , Linseisen Jakob , Meisinger Christa
Published: May 2024

Background

To investigate the association between body mass index (BMI) at acute myocardial infarction (AMI) and all-cause as well as cause-specific long-term mortality.

Methods

The analysis was based on 10,651 hospitalized AMI patients (age 25-84 years) recorded by the population-based Myocardial Infarction Registry Augsburg between 2000 and 2017. The median follow-up time was 6.7 years [IQR: 3.5-10.0)]. Cause-specific mortality was obtained by evaluating the death certificates. In multivariable-adjusted COX regression models using cubic splines for the variable BMI, the association between BMI and cause-specific mortality (all-cause, cardiovascular, ischemic heart diseases, cancer) was investigated. Additionally, a subgroup analysis in three age groups was performed for all-cause mortality.

Results

Overall, there was a statistically significant U-shaped association between BMI at AMI and long-term mortality with the lowest hazard ratios (HR) found for BMI values between 25 and 30 kg/m². For cancer mortality, higher BMI values > 30 kg/m² were not associated with higher mortality. In patients aged <60 years, there was a significant association between BMI values > 35 kg/m² and increased all-cause mortality; this association was missing in 60 to 84 years old patients. For all groups and for each specific cause of mortality, lower BMI (< 25kg/m²) values were significantly associated with higher mortality.

Conclusions

Overall, a lower BMI – and also a high BMI in patients younger than 60 years - seem to be a risk factors for increased all-cause mortality after AMI. A BMI in a mid-range between 25 and 30 kg/m² is favorable in terms of long-term survival after AMI.

What is Known?

Obesity is considered a major risk factor for cardiovascular diseases and coronary artery disease.

Nonetheless, the results of prior studies indicated lower mortality for overweight and obese individuals after acute myocardial infarction (AMI); a phenomenon often called ‘obesity paradox’.

What the Study Adds

This study analyzed the association between body mass index (BMI) and cause-specific long-term mortality after AMI in a population-based cohort of 10.000 AMI patients recorded by the Myocardial Infarction Registry Augsburg.

The obesity paradox was partially confirmed, as we found a U-shaped association between BMI and long-term mortality with the lowest risk of mortality in overweight individuals.

For cancer mortality and in elderly, obesity (BMI > 30 kg/m²) was not associated with mortality. Lower BMI < 25 kg/m² went along with significantly higher mortality in all age groups and for all causes of death (all-cause, cardiovascular, ischemic heart disease, cancer)
The dynamic impact of location and resection on the glioma CSF proteome
Authors: Riviere-Cazaux Cecile , Graser Christopher J. , Warrington Arthur E. , Hoplin Matthew D. , Andersen Katherine M. , Malik Noor , Palmer Elizabeth A. , Carlstrom Lucas P. , Dasari Surendra , Munoz-Casabella Amanda , Ikram Samar , Ghadimi Keyvan , Himes Benjamin T. , Jusue-Torres Ignacio , Sarkaria Jann N. , Meyer Fredric B. , Van Gompel Jamie J. , Kizilbash Sani H. , Sener Ugur , Michor Franziska , Campian Jian L. , Parney Ian F. , Burns Terry C.
Published: May 2024

While serial sampling of glioma tissue is rarely performed prior to recurrence, cerebrospinal fluid (CSF) is an underutilized longitudinal source of candidate glioma biomarkers for understanding therapeutic impacts. However, the impact of key variables to consider in longitudinal CSF samples, including anatomical location and post-surgical changes, remains unknown. To that end, pre- versus post-resection intracranial CSF samples were obtained at early (1-16 days; n=20) or delayed (86-153 days; n=11) timepoints for patients with glioma. Paired lumbar-versus-intracranial glioma CSF samples were also obtained (n=14). Using aptamer-based proteomics, we identify significant differences in the CSF proteome between lumbar, subarachnoid, and ventricular CSF. Our analysis of serial intracranial CSF samples suggests the early potential for disease monitoring and evaluation of pharmacodynamic impact of targeted therapies. Importantly, we found that resection had a significant, evolving longitudinal impact on the CSF proteome. Proteomic data are provided with individual clinical annotations as a resource for the field.

One Sentence Summary

Glioma cerebrospinal fluid (CSF) accessed intra-operatively and longitudinally via devices can reveal impacts of treatment and anatomical location.
The number of effectors limits the relative sleep gain: Insights from seven finger tapping experiments
Authors: Erlacher Daniel , Schmid Daniel
Published: May 2024

The role of sleep in motor memory consolidation is still a matter of ongoing debate. A classic task to investigate mechanisms of motor memory consolidation is the finger tapping task, which reliably shows small effects in performance enhancement after sleep but not after a corresponding wake interval. However, variants of the task with a varying number of effectors (e.g., one hand) failed to demonstrate this effect on motor memory consolidation. Thus, in a series of seven experiments we investigate five variants of the classic finger tapping task in which the number of effectors (1 or 2 hands combined with 1, 2 or 4 fingers) used to perform the task are systematically varied. For the groups, where sleep immediately followed learning, a beneficial effect of sleep in comparison with a corresponding wake interval was found, except for the task variant where the finger tapping task was performed with 1 hand and 1 finger. However, no clear-cut pattern could be identified for the numbers of effectors used to perform the task and the magnitude of offline motor memory consolidation. Furthermore, for groups with an intervening wake interval between learning and sleep no differences between the post-sleep and post-wake gain were observed.

Highlights

In a variation of the classical finger tapping task with one hand and one finger, no sleep-dependent enhancement was found.

In all other variations, small to large effects of sleep-dependent offline-gains were found.

An interposed wake interval between learning and sleep substantially diminishes the post-sleep enhancement.

Motor skill complexity, with respect to the coordination of more than one effector, does partially play a role in predicting sleep-dependent motor memory enhancement.
Crystal structure determination of the antipsychotic drug of olanzapine form III
Authors: Anyfanti Goulielmina , Husanu Elena , Andrusenko Iryna , Marchetti Danilo , Gemmi Mauro
Published: May 2024

Olanzapine, an antipsychotic drug, is well known for its complex polymorphism. Although widely investigated, the crystal structure of one of its anhydrous polymorphs, form III, is still unknown. Its appearance, always in concomitance with form II and I, and the impossibility of isolating it from that mixture, has prevented its structure determination so far. The scenario has changed with the emerging field of 3D electron diffraction (3D ED) technique and its great advantages in the characterization of polyphasic mixture of nanosized crystals. In this study we show how the application of 3D ED allows the ab-initio structure determination and dynamical refinement of this elusive crystal structure unknown for more than 20 years. Olanzapine form III is monoclinic and shows a similar but shifted packing with respect to form II. It is remarkably different from the lowest energy structures predicted by the energy minimization algorithms of crystal structure prediction.
TbpB-based oral mucosal vaccine provides heterologous protection against Glässer’s disease caused by different serovars of Spanish field isolates ofGlaesserella parasuis
Authors: González-Fernández Alba , Mencía-Ares Oscar , García-Iglesias María José , Petrocchi-Rilo Máximo , Miguélez-Pérez Rubén , Perelló Jiménez Alberto , Herencia-Lagunar Elena , Acebes-Fernández Vanessa , Gutiérrez-Martín César B. , Martínez-Martínez Sonia
Published: May 2024

Background

Glaesserella parasuishas a substantial impact on the pig production as the primary agent of Glässer’s disease, particularly affecting nursery and early fattening stages. Current prophylactic measures, mainly based in serovar-specific bacterins administered parenterally to sows, face limitations due to maternal immunity, which may interfere with the active immunization of piglets. The mucosal administration of TbpB-based subunit vaccines offers a promising approach to overcome these limitations for the control of the disease in weaning piglets. This study evaluates the immunogenicity and heterologous protection of the oral mucosal TbpBY167Asubunit vaccine in colostrum-deprived piglets challenged with fourG. parasuisclinical isolates belonging to different TbpB clusters and serovars (SVs) recovered from Spanish pig farms.

Results

The mucosal administration of a two-dose TbpB-based vaccine induced a robust humoral immune response in immunized colostrum-deprived piglets, significantly increasing IgA (p <0.01) and IgM (p <0.01) concentration 15 days after the second dose. Subsequent infection challenge with fourG. parasuisclinical isolates demonstrated heterologous protection, markedly improving survival rates (OR: 8.45; CI 95%: 4.97-14.36) and significantly reducing clinical signs and lesions, regardless of theG. parasuisTbpB cluster and serovar. The vaccine not only reducedG. parasuiscolonization in the respiratory tract of immunized piglets (p< 0.0001), but also in systemic target tissues, such as the tarsus and carpus joints, liver, and brain (p< 0.05). Further immunohistochemical analysis in different lung locations revealed a significantly lower macrophage count in immunized piglets (p< 0.0001).

Conclusions

Overall, this study demonstrates that the oral mucosal administration of the TbpBY167Asubunits vaccine in piglets provides effective heterologous protection against different virulent EuropeanG. parasuisfield isolates, significantly reducing bacterial colonization and dissemination. These facts position this TbpB-based vaccine as a leading candidate for a universal vaccine against Glässer’s disease.
Gynura procumbensLeaf Extract-Loaded Self-Microemulsifying Drug Delivery System Offers Enhanced Protective Effects in the Hepatorenal Organs of the Experimental Rats
Authors: Shill Manik Chandra , Jalal Md. Faisal Bin , Shuma Madhabi Lata , Mollick Patricia Prova , Muhit Md. Abdul , Halder Shimul
Published: May 2024

Gynura procumbens, known as longevity spinach, is a plant traditionally used in tropical Asian countries for its anti-inflammatory, hepatoprotective, anti-hypertensive, anti-hyperglycemic, and anti-inflammatory properties. The current study aimed to enhance the hepatorenal protective activity ofGynura procumbensleaf extract (GLE) by developing a self-microemulsifying drug delivery system (SMEDDS). SMEDDS-GLE exhibited the formation of small micelles with a mean droplet size of 231 nm. This resulted in a significant enhancement in the dispersion of GLE in water, as evidenced by a dispersibility that was at least 4.8 times greater than that of GLE alone. In the rat model of hepatic injury induced by cisplatin (7.5 mg/kg,i.p.), the administration of SMEDDS-GLE (75 mg-GLE/kg,p.o.) significantly reduced liver damage, observed by histological examination and reduced levels of plasma biomarkers associated with hepatic injury. Furthermore, according to histological examination findings and plasma biomarkers assessment, SMEDDS-GLE enhanced nephroprotective benefits of GLE in the rat model of acute kidney injury. Based on these findings, a strategic application of the SMEDDS-based approach could be a viable choice to enhance GLE’s nutraceutical properties.
Mitochondria-targeted hydrogen sulfide donor reduces atherogenesis by reprogramming macrophages and increasing UCP1 expression in vascular smooth muscle cells
Authors: Stachowicz Aneta , Wiśniewska Anna , Czepiel Klaudia , Pomierny Bartosz , Skórkowska Alicja , Kuśnierz-Cabala Beata , Surmiak Marcin , Kuś Katarzyna , Wood Mark E. , Torregrossa Roberta , Whiteman Matthew , Olszanecki Rafał
Published: May 2024

Aims

Atherosclerosis is a leading cause of morbidity and mortality in the Western countries. A growing body of evidence points to the role of mitochondrial dysfunction in the pathogenesis of atherosclerosis. Recently, it has been shown that mitochondrial hydrogen sulfide (H2S) can complement the bioenergetic role of Krebs cycle leading to improved mitochondrial function. However, controlled, direct delivery of H2S to mitochondria was not investigated as a therapeutic strategy in atherosclerosis. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with mitochondrial H2S donor AP39 on the development of atherosclerotic lesions in apolipoprotein E knockout (apoE-/-) mice.

Results

Our results indicated that AP39 reduced atherosclerosis in apoE-/-mice and stabilized atherosclerotic lesions through decreased total macrophage content and increased collagen depositions. Moreover, AP39 reprogrammed macrophages from proinflammatory M1 to anti-inflammatory M2 in atherosclerotic lesions. It also upregulated pathways related to mitochondrial function, such as cellular respiration, fatty acid β-oxidation and thermogenesis while downregulated pathways associated with immune system, platelet aggregation and complement and coagulation cascades in the aorta. Furthermore, treatment with AP39 increased the expression of mitochondrial brown fat uncoupling protein 1 (UCP1) in vascular smooth muscle cells (VSMCs) in atherosclerotic lesions and upregulated mRNA expression of other thermogenesis-related genes in the aorta but not perivascular adipose tissue (PVAT) of apoE-/-mice. Finally, AP39 treatment decreased markers of activated endothelium and increased endothelial nitric oxide synthase (eNOS) expression and activation.

Conclusions

Taken together, mitochondrial H2S donor AP39 could provide potentially a novel therapeutic approach to the treatment/prevention of atherosclerosis.
Learning precise segmentation of neurofibrillary tangles from rapid manual point annotations
Authors: Ghandian Sina , Albarghouthi Liane , Nava Kiana , Sharma Shivam R. Rai , Minaud Lise , Beckett Laurel , Saito Naomi , DeCarli Charles , Rissman Robert A. , Teich Andrew F. , Jin Lee-Way , Dugger Brittany N. , Keiser Michael J.
Published: May 2024

Accumulation of abnormal tau protein into neurofibrillary tangles (NFTs) is a pathologic hallmark of Alzheimer disease (AD). Accurate detection of NFTs in tissue samples can reveal relationships with clinical, demographic, and genetic features through deep phenotyping. However, expert manual analysis is time-consuming, subject to observer variability, and cannot handle the data amounts generated by modern imaging. We present a scalable, open-source, deep-learning approach to quantify NFT burden in digital whole slide images (WSIs) of post-mortem human brain tissue. To achieve this, we developed a method to generate detailed NFT boundaries directly from single-point-per-NFT annotations. We then trained a semantic segmentation model on 45 annotated 2400µm by 1200µm regions of interest (ROIs) selected from 15 unique temporal cortex WSIs of AD cases from three institutions (University of California (UC)-Davis, UC-San Diego, and Columbia University). Segmenting NFTs at the single-pixel level, the model achieved an area under the receiver operating characteristic of 0.832 and an F1 of 0.527 (196-fold over random) on a held-out test set of 664 NFTs from 20 ROIs (7 WSIs). We compared this to deep object detection, which achieved comparable but coarser-grained performance that was 60% faster. The segmentation and object detection models correlated well with expert semi-quantitative scores at the whole-slide level (Spearman’s rho ρ=0.654 (p=6.50e-5) and ρ=0.513 (p=3.18e-3), respectively). We openly release this multi-institution deep-learning pipeline to provide detailed NFT spatial distribution and morphology analysis capability at a scale otherwise infeasible by manual assessment.
Variation in high-amplitude events across the human lifespan
Authors: Jo Youngheun , Tanner Jacob , Seguin Caio , Faskowitz Joshua , Betzel Richard
Published: May 2024

Edge time series decompose functional connections into their fine-scale, framewise contributions. Previous studies have demonstrated that global high-amplitude "events" in edge time series can be clustered into distinct patterns. To date, however, it is unknown whether events and their patterns change or persist throughout the human lifespan. Here, we directly address this question by clustering event frames using the Nathan Kline Institute-Rockland sample that includes subjects with ages spanning the human lifespan. We find evidence of two main clusters that appear across subjects and age groups. We also find that these patterns of clusters systematically change in magnitude and frequency with age. Our results also demonstrate that such event clusters have distinct, heterogeneous relationships with structural connectivity-derived communication measures, which change with age. Finally, event clusters were found to outperform non-events in predicting phenotypes regarding human intelligence and achievement. Collectively, our findings fill several gaps in current knowledge about co-fluctuation patterns in edge time series and human aging, setting the stage for future investigation into the causal origins of changes in functional connectivity throughout the human lifespan.
Endocardial primary cilia and blood flow are required for regulation of EndoMT during endocardial cushion development
Authors: Berg Kathryn , Gorham Joshua , Lundt Faith , Seidman Jonathan , Brueckner Martina
Published: May 2024

Blood flow is critical for heart valve formation, and cellular mechanosensors are essential to translate flow into transcriptional regulation of development. Here, we identify a role for primary ciliain vivoin the spatial regulation of cushion formation, the first stage of valve development, by regionally controlling endothelial to mesenchymal transition (EndoMT) via modulation ofKruppel-like Factor 4 (Klf4). We find that high shear stress intracardiac regions decrease endocardial ciliation over cushion development, correlating with KLF4 downregulation and EndoMT progression. Mouse embryos constitutively lacking cilia exhibit a blood-flow dependent accumulation of KLF4 in these regions, independent of upstream left-right abnormalities, resulting in impaired cushion cellularization. snRNA-seq revealed that cilia KO endocardium fails to progress to late-EndoMT, retains endothelial markers and has reduced EndoMT/mesenchymal genes that KLF4 antagonizes. Together, these data identify a mechanosensory role for endocardial primary cilia in cushion development through regional regulation of KLF4.
Therapeutic dose prediction of α5-GABA receptor modulation from simulated EEG of depression severity
Authors: Guet-McCreight Alexandre , Mazza Frank , Prevot Thomas D. , Sibille Etienne , Hay Etay
Published: May 2024

Treatment for major depressive disorder (depression) often has partial efficacy and a large portion of patients are treatment resistant. Recent studies implicate reduced somatostatin (SST) interneuron inhibition in depression, and new pharmacology boosting this inhibition via positive allosteric modulators of α5-GABAAreceptors (α5-PAM) offers a promising effective treatment. However, testing the effect of α5-PAM on human brain activity is limited, meriting the use of detailed simulations. We utilized our previous detailed computational models of human depression microcircuits with reduced SST interneuron inhibition and α5-PAM effects, to simulate EEG of virtual subjects across depression severity and α5-PAM doses. We developed machine learning models that predicted optimal dose from EEG with high accuracy and recovered microcircuit activity and EEG. This study provides dose prediction models for α5-PAM administration based on EEG biomarkers of depression severity. Given limitations in doing the above in the living human brain, the results and tools we developed will facilitate translation of α5-PAM treatment to clinical use.
Genome-Wide Association Study Identifies Novel Genetic Variants Associated with Widespread Pain in the UK Biobank (N=172,230)
Authors: Pan Qi , Cai Tengda , Tao Yiwen , Compte Roger , Naeini Maryam Kazemi , Haque Mainul , Dottorini Tania , Williams Frances M.K. , Meng Weihua
Published: May 2024

Objectives

Widespread pain is a hallmark characteristic of fibromyalgia, commonly affecting older individuals. This study aimed to identify novel genetic variants associated with widespread pain by utilizing the extensive UK Biobank dataset.

Methods

We conducted a primary genome-wide association study (GWAS) using a novel definition of widespread pain, defined as pain experienced all over the body during the past month. Sex-stratified GWAS analysis approach was also performed to analyze the impact of sex on widespread pain.

Results

The primary GWAS identified one novel significant genetic locus (rs34691025,p= 1.76 × 10-8) on chromosome 5q13.2 within theARHGEF28gene and several loci that approached genome-wide significance. The sex-stratified GWAS outputs revealed biological difference widespread pain between males and females, with a novel locus identified in the female-specific analysis within theLRMDAgene on chromosome 10. Genetic Correlation analysis demonstrated significant genetic correlations between widespread pain and other phenotypes, including joint disorders and spondylosis. The PheWAS revealed associations between the significant genetic variants with hearing disorders and cardiovascular diseases.

Conclusions

Our study advances the understanding of the genetic factors contributing to widespread pain, highlighting notable differences between males and females and identifying a novel genetic locus associated with this condition.
Assessing the environmental impact of medicines in Italy using data from the Italian Medicines Agency
Authors: Giunchi Valentina , Fusaroli Michele , Cangini Agnese , Fortinguerra Filomena , Zito Simona , Pierantozzi Andrea , Lunghi Carlotta , Poluzzi Elisabetta , Trotta Francesco
Published: May 2024

Aim

This study builds upon the environmental risk analysis presented in the 2022 National Report on Medicines Use in Italy by the Italian Medicines Agency and aims to assess the environmental risk posed by medicines in Italy and in its regions.

Methods

The analysis selected 90 medicines based on three criteria: high utilization, low PNEC, and inclusion or candidacy for the European Watch List. For each medicine, the environmental risk was computed as the ratio between the Predicted Environmental Concentration (PEC) and the Predicted No Effect Concentration (PNEC). PEC was derived following the approach of the Swedish Association of Pharmaceutical Industries and Italian drug utilization data. The risk was classified high if the ratio was greater than 10, and moderate if greater than 1.

Results

Overall, 13 medicines were identified as posing a high risk, including cardiovascular agents, antibiotics, analgesics, antidepressants, and antiparasitic agents. The high risk was driven by either a very low PNEC (e.g., estradiol and lacidipine), and high utilization (e.g., amoxicillin, ibuprofen, and diclofenac). Regional analysis showed higher risk due to high consumption for azithromycin and ofloxacin in Central and Southern Italy, and for levonorgestrel in Northern Italy.

Conclusion

This study points to the need of prioritizing targeted sampling in surface waters for medicines estimated at high risk. To prevent and mitigate the risk, a more conscious clinical practice coupled with appropriate waste management are required.

What is already known about this subject

Medicines represent a growing concern as a source of contamination in water systems.

Traditional surface water samplings are resource-expensive and should be supported by estimation methods.

The Italian Medicines Agency’s National report on medicines use included, for the first time in its 2022 version, an assessment of the environmental impact.

What this study adds

90 medicines with either high utilization, low Predicted No-Effect Concentration, or present in the European Watch List were included.

13 medicines were at high environmental risk either because of their high toxicity to aquatic species or their high consumption in Italy.

Regional differences potentially reflect various social and prescribing habits.
Supporting continuous glucose monitoring for people with serious mental illness and type 2 diabetes: Protocol for a co-design study
Authors: Brown Jennifer VE , Ajjan Ramzi , Siddiqi Najma , Kellar Ian , Coventry Peter A
Published: May 2024

Introduction

Compared with the general population, people with serious mental illness (SMI) are 2-3 times more likely to develop type 2 diabetes, have poorer outcomes, and die 15 to 20 years younger, often as a result of long-term physical health conditions. Standard diabetes care does not meet the needs of people with SMI and they are frequently excluded from research, missing out on innovation. As diabetes care increasingly uses technology like continuous glucose monitoring (CGM) it is important to consider the views of people with SMI when new interventions are developed. This is a study protocol to identify candidate components of a structured CGM intervention for people with SMI, including the co-design of a logic model and programme theory.

Methods

Drawing on experience-based co-design (EBCD) methods, we propose to collaborate with service-users, carers, and healthcare professionals to undertake early-phase development work for a novel intervention that maximises the potential of CGM to facilitate behaviour change. Fifteen participants will be recruited through existing cohorts and networks in England. The co-design will be informed by existing evidence and based on links between mechanisms of action and behaviour change techniques. Through a series of events (discovery sessions, co-design workshop, celebration event), we will identify candidate components for a prototype intervention ready for further development and testing. A logic model and programme theory will be developed and refined iteratively.

Discussion

The main output of this study will be a logic model and programme theory for a novel prototype intervention, ready for further testing following best practice intervention development, such as the Medical Research Council guidance for the development and evaluation of complex interventions. An intervention that makes CGM accessible for people with SMI has the potential to make a considerable contribution to reducing the profound health inequalities experienced by this population.
MiRNA encoded PTEN’s Impact on Clinical-Pathological Features and Prognosis in Osteosarcoma: a Systematic Review and Meta-Analysis
Authors: Limijadi Edward Kurnia Setiawan , Novriansyah Robin , Respati Danendra Rakha Putra , Tjandra Kevin Christian
Published: May 2024

Background

Osteosarcoma (OSC) is considered one of the most common malignant bone tumours in adolescents. Due to OSC’s poor prognosis, a comprehensive approach to exploring these aspects is highly needed to improve the survival probability of OSC. In this study, we tried to explore the significance of miRNA-encoded PTEN for clinical-pathological features and prognostic value in OSC.

Method

We performed this systematic review and meta-analysis using articles and sources published between 2013 and 2023 from six databases (Scopus, PubMed, ProQuest, Science Direct, Sage Pub, and Cochrane). Included studies were clinical cross-sectional studies. Other study designs, articles not written in English, without full text, and not relevant—were excluded. Then, ROBINS-I is used to evaluate the distance. The results are constructed according to the PICOS criteria in a table. The expression of miRNA related to OSC is assessed in the meta-analysis as the main outcome to determine its ability as a diagnostic and prognostic agent for OSC. This systematic review followed the PRISMA guidelines.

Results

A total of 17 studies were included in the final screening. The meta-analysis showed significantly increased (p < 0.00001) miRNA expression in patients with osteosarcoma compared to healthy controlled with pooled md (2.85) (95% CI: 2.69, 3.02; I2= 22%, p= 0.20), the high inverse correlation (p < 0.001) between miRNA and PTEN expression was shown as mean effect size (−0.681) (95% CI: −0.787, −0.536; I2= 75%, p < 0.0001), and the prognostic evaluation of overall survival was significantly increased in low expression miRNA (p < 0.00001) with pooled OR.

Conclusion

Fiveteen miRNAs from 17 studies were found, and together with PTEN expression, they may serve as potential prognostic biomarkers for OSC. High-level levels of miRNA expression are correlated with low PTEN expression, leading to a bad prognosis for OSC.
Stepping it up: A Longitudinal Assessment of Stair Negotiation Among ACL Reconstruction Patients Outside the Laboratory
Authors: Yona Tomer , Peskin Bezalel , Fischer Arielle
Published: May 2024

Introduction

Anterior Cruciate Ligament Reconstruction (ACLR) is crucial for knee stability in ACL-injured individuals and for resuming pre-injury physical activities. Despite advancements, achieving symmetrical movement patterns during rehabilitation, particularly in stair negotiation, poses challenges. This study examines lower limb kinematics during stair negotiation at various rehabilitation stages post-ACLR, employing inertial measurement units (IMUs) and Statistical Parametric Mapping (SPM) for in-depth analysis outside the laboratory.

Methods

This cohort study longitudinally assessed stair ambulation kinematics in patients aged 18-40, three (n=26) and five months (n=18) post-ACLR, using IMUs to track sagittal plane movement during stair ascent and descent. The participants ambulated on a flight of 20 stairs outside the laboratory.

Results

At three months post-ACLR, the injured knee was less flexed compared to the contralateral knee during stair ascent (mean difference = -11.3°, CI [-14.4, -8.1], p<.001) and descent (mean difference = -6.3°, CI [-10.2, -2.4], p=.002). SPM analysis identified clusters where the injured knee showed decreased flexion at 0-35% and 87-99% of the stair ascent cycle (p<.005). By five months, flexion differences during ascent improved (mean difference = -4.7°, CI [-8.1, -1.4], p=.008), but significant asymmetry persisted, with decreased flexion at 10-32% of the cycle during ascent and 20-29% during descent (p<.017). Improvements between three and five months were observed in knee flexion during ascent (mean increase = 6.1°, p<.001) and descent (mean increase = 9.3°, p=.004). Ankle and hip joint movements also exhibited persistent asymmetries, with minimal improvements over time.

Conclusions

Persistent lower limb kinematic asymmetries remain five months post-ACLR during stair ascent and descent.
Patients’ perceptions of, emotional responses to, and disengagement from, physician-services for HIV: The relationship of trust and the mental and social effects of HIV to perceived service-adequacy
Authors: Whitaker R , Otis M
Published: May 2024

An exploratory, two-language, online survey assessed patients in relation to physician-services for HIV-infection. Most respondents had experienced primarily mental rather than physical illness due to HIV or its treatment, as well as a marked HIV-related impact on social networks. Mental and social factors were identified that predicted patients’ relationship to, and disengagement from, physicians’ services, including patients’ satisfaction, trust, physicians’ relational skills, time-pressure, the opportunity for clinical intimacy, physician-credibility; ‘heart-sink’ physicians, anxiety, passivity, self-efficacy, experience of HIV-related illness, experience of medication-toxicity, degree of loss in social networks, and ‘changing physician due to disagreement’, with ramifications for physicians’ concept of the ‘difficult patient’. The prevalence and significance of such issues and the related risk of distrust of, and disengagement from, physician-services confirm the still-remaining need for evidence-based treatment to be implemented for people with HIV, to include the delivery of integrated, multi-professional, and biopsychosocial health-services.

What do we know already about this topic?

Mental and social aspects of illness affect services’ ability to help patients to get well and stay well (i.e., health-effectiveness), but since the advent of HAART few clinics provide integrated, biopsychosocial services necessary to address these issues, despite the extensive evidence-base demonstrating such need.

How does this research contribute to the field?

This research: confirms the significance of biopsychosocial aspects of illness and identifies pervasive factors that intensify such challenges to the provision of health-effective services—and which can act as signal-events in quality-related service-audit—as well as analysing other factors, such as patients’ satisfaction, that have no value except to consumerism but relate to other variables, such as trust, that need to be used in service-evaluation.

What are the implications of this research for theory, practice, or policy?

The implications of this research are that each services needs a competent, multi-professional team to address the biopsychosocial factors identified, and to integrate the factors into the audit of services’ health-effectiveness, supported by specific policy such as treatment-guidelines that require the evidence-based formulation and delivery of health-services, not solely pharmaceuticals of choice.
Monomer-dimer structural comparison in quinol-dependent nitric oxide reductase reveals a functional basis for superior enzymatic activity in the dimer
Authors: Gopalasingam Chai C. , Egami Haruka , Shigematsu Hideki , Sakaue Masatora , Fukumoto Kouki , Gerle Christoph , Yamamoto Masaki , Shiro Yoshitsugu , Muramoto Kazumasa , Tosha Takehiko
Published: May 2024

The leading cause of bacterial meningitis,Neisseria meningitidis,deploys a quinol-dependent nitric oxide reductase (NmqNOR), belonging to the heme-copper oxidase superfamily. By detoxifying NO, an antimicrobial gas produced by host’s immune system, qNOR enables pathogen survival within hosts. Here, we determined cryoEM structures of the less active monomer and highly active dimer ofNmqNOR at resolutions of 2.25 and 1.89 Å, respectively, showing the structural elements responsible for effective NO reduction. Helical disorder at the dimer interface, associated with an altered conformation of the critical Glu563 near the heme/non-heme Fe active site, was observed in the monomer. These findings suggest that dimerization stabilizes the active conformation of Glu563 through the structural network between the dimerization site and the active site. Since other members of the heme-copper oxidases exhibit dimerization, the current data on qNOR helps us understand a regulatory mechanism related to the function of heme-copper oxidases upon oligomerization.

Teaser

CryoEM structures unveil a functional rationale for dimerization in nitric oxide detoxifying enzyme from a pathogen
TRIM52 is a primate-specific player in the DNA repair process under tight proteolytic control by a triad of giant E3 ligases
Authors: Shulkina Alexandra , Hacker Kathrin , Ehrmann Julian F. , Budroni Valentina , Mandlbauer Ariane , Bock Johannes , Grabarczyk Daniel B. , Cochella Luisa , Clausen Tim , Versteeg Gijs A.
Published: May 2024

Tripartite motif 52 (TRIM52) exhibits strong positive selection in humans, yet is lost in many other mammals. In contrast to what one would expect for such a non-conserved factor,TRIM52loss compromises cell fitness. We set out to determine the cellular function of TRIM52. Genetic and proteomic analyses revealed TRIM52’s involvement in resolving topoisomerase 2 (TOP2)-DNA cross-links, mitigating DNA damage and preventing cell-cycle arrest. Consistent with a fitness-promoting function, TRIM52 is upregulated in various cancers, prompting us to investigate its regulatory pathways. We found TRIM52 to be targeted for ultra-rapid proteasomal degradation by the giant E3 ubiquitin ligases BIRC6, HUWE1, and UBR4/KCMF1. BIRC6 mono-ubiquitinates TRIM52, with subsequent extension by UBR4/KCMF1. These findings underscore TRIM52’s pivotal role in DNA damage repair and regulation of its own abundance through multi-ligase degradation.
Tracing Homopolymers inOikopleura dioica’s mitogenome
Authors: Dierckxsens Nicolas , Watanabe Kosei , Tan Yongkai , Masunaga Aki , Mansfield Michael J. , Miao Jiashun , Luscombe Nicholas M. , Plessy Charles
Published: May 2024

Oikopleura dioicais a planktonic tunicate (Appendicularia class) found extensively across the marine waters of the globe. The genome of a single male individual collected from Okinawa, Japan was sequenced using the single-molecule PacBio Hi-Fi method and assembled with NOVOLoci. The mitogenome is 39,268 bp long, featuring a large control region of around 22,000 bp. We annotated the proteins atp6, cob, cox1, cox2, cox3, nad1, nad4 and nad5, and found one more open reading frame that did not match any known gene. This study marks the first complete mitogenome assembly for an appendicularian, and reveals that A and T homopolymers cumulatively account for nearly half of its length. This reference sequence will be an asset for environmental DNA and phylogenetic studies.

http://dx.doi.org/10.1364/ao.XX.XXXXXX
Cell invasive amyloid assemblies from SARS-CoV-2 peptides can form multiple polymorphs with varying neurotoxicity
Authors: Sanislav Oana , Tetaj Rina , Metali  , Ratcliffe Julian , Phillips William , Klein Annaleise , Sethi Ashish , Zhou Jiangtao , Mezzenga Raffaele , Saxer Sina , Charnley Mirren , Annesley Sarah , Reynolds Nicholas P
Published: May 2024

The neurological symptoms of COVID-19, such as memory loss, cognitive and sensory disruption (neuro-COVID) are well reported. These neurological symptoms frequently persist for months (post-acute sequalae of COVID-19 or PASC). The molecular origins of neuro-COVID and how it contributes to PASC are unknown, however a growing body of research highlights that the self-assembly of protein fragments from SARS-CoV-2 into amyloid nanofibrils may play a causative role. Previously, we identified two fragments from the proteins Open Reading Frame 6 (ORF6) and ORF10 that self-assemble into neurotoxic amyloid assemblies. Here we further our understanding of the self-assembly mechanisms and nano-architectures formed by these fragments as well as performing a more in-depth study of the biological responses of co-cultured neurons. By solubilising the peptides in a fluorinated solvent we eliminate insoluble aggregates in the starting materials (seeds) that change the polymorphic landscape of the assemblies. The resultant assemblies are dominated by structures with higher free energies (e.g. ribbons and amorphous aggregates) that are less toxic to cultured neurons. We also show the first direct evidence of cellular uptake by viral amyloids. This work highlights the importance of understanding the polymorphic behaviour of amyloids particularly in the context of neuro-COVID and PASC.

Graphical Abstract for ToC

The neurological symptoms of COVID-19 are likely to be, in part, caused by the aggregation of viral proteins into neurotoxic amyloid nanofibrils. Changes in aggregation conditions alters the balance of fibril structures formed (polymorphism), influencing their toxicity to a neuronal cell line. These findings increase our understanding of viral amyloids and highlight the importance of careful choice of experimental protocol when studying these systems.
Preclinical evaluation of the novel [18F]CHDI-650 PET ligand for non-invasive quantification of mutant huntingtin aggregates in Huntington’s disease
Authors: Zajicek Franziska , Verhaeghe Jeroen , De Lombaerde Stef , Van Eetveldt Annemie , Miranda Alan , Munoz-Sanjuan Ignacio , Dominguez Celia , Khetarpal Vinod , Bard Jonathan , Liu Longbin , Staelens Steven , Bertoglio Daniele
Published: May 2024

Purpose

Positron emission tomography (PET) imaging of mutant huntingtin (mHTT) aggregates is a potential tool to monitor disease progression as well as the efficacy of candidate therapeutic interventions for Huntington’s disease (HD). To date, the focus has been mainly on the investigation of11C radioligands; however, favourable18F radiotracers will facilitate future clinical translation. This work aimed at characterising the novel [18F]CHDI-650 PET radiotracer using a combination ofin vivoandin vitroapproaches in a mouse model of HD.

Methods

After characterising [18F]CHDI-650 usingin vitroautoradiography, we assessedin vivoplasma and brain radiotracer stability as well as kinetics through dynamic PET imaging in the heterozygous (HET) zQ175DN mouse model of HD and wild-type (WT) littermates at 9 months of age. Additionally, we performed a head-to-head comparison study at 3 months with the previously published [11C]CHDI-180R radioligand.

Results

Plasma and brain radiometabolite profiles indicated a suitable metabolic profile forin vivoimaging of [18F]CHDI-650. Bothin vitroautoradiography andin vivo[18F]CHDI-650 PET imaging at 9 months of age demonstrated a significant genotype effect (p<0.0001) despite the poor test-retest reliability. [18F]CHDI-650 PET imaging at 3 months of age displayed higher differentiation between genotypes when compared to [11C]CHDI-180R.

Conclusion

Overall, [18F]CHDI-650 allows for discrimination between HET and WT zQ175DN mice at 9 and 3 months of age. [18F]CHDI-650 represents the first suitable18F radioligand to image mHTT aggregates in mice and its clinical evaluation is underway.