bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormal hippocampal neurogenesis and impaired social recognition memory in two neurodevelopmental models of schizophrenia
Authors: Dong Yibei , Fu Chuxian , Zhang Ting , Dong Feiyuan , Zhu Xinyi , Jiang Yingke , Hu Linbo , Pan Luhui , Li Jiawen , Zhang Xiaoqin
Published: November 2024

Schizophrenia is a mental disorder characterized by cognitive impairments, specifically deficits in social recognition memory (SRM). Abnormal hippocampal neurogenesis has been implicated in these deficits. Due to the pathogenetic heterogeneity of schizophrenia, studying the hippocampal neurogenesis and SRM in two models with prenatal and postnatal defects could enhance our understanding of the developmental aspects of the biological susceptibility to schizophrenia. Here, we examined SRM and hippocampal neurogenesis in two developmental models of schizophrenia: gestational exposure to methylazoxymethanol acetate (MAM) and postweaning social isolation (SI). Our findings revealed that gestational MAM exposure induced a decay of social memory while postweaning SI led to impaired social memory formation and decay. In both models, we observed a correlation between impaired SRM and reduced number, and abnormal differentiation and less complex morphology of hippocampal neurons. These results indicate that aberrant hippocampal neurogenesis may contribute to the deficits of SRM in both models, and these abnormalities may be a shared underlying pathogenic factor in developmental models of schizophrenia, regardless of prenatal and postnatal pathogenesis.
Effects of the Affordable Care Act on Contraception, Pregnancy, and Pregnancy Termination Rates
Authors: Solomon Matthew D. , Zaritsky Eve F. , Warton Margaret , Millman Andrea , Huynh Ashley , Chinnakotla Bharathi , Reed Mary E.
Published: October 2024

OBJECTIVE:

To investigate the effects of the Affordable Care Act (ACA) and its elimination of cost sharing on contraception utilization, pregnancy rates, and abortion rates.

METHODS:

We conducted a retrospective cohort study within a health care system serving more than 4.5 million insured members across 21 medical centers and 250 clinics. The study included women aged 18–45 years with continuous health plan membership for at least 2 years in the pre-ACA (2007–2012) and post-ACA (2013–2018) periods. We analyzed out-of-pocket (OOP) costs for contraception, including oral contraceptives and long-acting reversible contraception (LARC), before and after the ACA's implementation. We then examined how the elimination of OOP costs affected contraception use, pregnancy rates, and abortion rates.

RESULTS:

The study identified 1,523,962 women of childbearing age. In 2013, cost sharing for contraception sharply declined, with average annual OOP costs dropping from $88–94 pre-ACA to nearly zero post-ACA. Contraceptive use increased overall, rising from 30.2% pre-ACA to 31.9% by the study's end, with a notable rise in LARC use. In interrupted time-series analyses, contraception use continued to increase post-ACA, new pregnancy rates declined at a faster rate than pre-ACA, and abortion rates continued to fall, though at a slightly slower pace than pre-ACA (P<.05 for all trends).

CONCLUSION:

The ACA's elimination of contraception cost sharing led to increased contraception use, particularly LARC methods, and contributed to declines in both pregnancy and abortion rates. This suggests that improving access to effective contraception is a key strategy in reducing unintended pregnancies.
Body Mass Index is Related to Femoral Anteversion, Hip Rotation During Gait, and Passive Hip Range of Motion in Children and Adolescents
Authors: Dobler Florian , Engler Laura , Lengnick Harald , Cip Johannes , Alexander Nathalie
Published: November 2024

Background:

Overweight and obesity are major global health issues, often linked to orthopaedic problems, skeletal malalignments, and altered gait biomechanics. However, skeletal and biomechanical adaptions in the transverse plane remain underexplored. Therefore, this study aimed to investigate the relationship between body mass index (BMI) and variables describing lower extremity torsional profiles, hip rotation mobility, and transverse plane gait characteristics in children and adolescents.

Methods:

Acetabular and femoral anteversion, tibial torsion (measured through computed tomography), hip and knee rotation, and foot progression angles during the stance phase of gait (measured by 3D gait analysis), as well as passive hip rotation range of motion (evaluated as the midpoint of hip rotation in clinical examination), were retrospectively analyzed in 122 children and adolescents. Correlations between all variables and logit-transformed BMI percentiles were calculated.

Results:

Moderate correlations were found between BMI percentile and hip rotation during the stance phase (r=-0.68, P<0.001), the passive midpoint of hip rotation (r=-0.51, P<0.001), and femoral anteversion (r=-0.50, P<0.001). Small correlations were observed for acetabular anteversion (r=-0.36, P<0.001), knee rotation during stance phase (r=0.34, P<0.001), and foot progression angle during stance phase (r=-0.31, P<0.001). Tibial torsion showed a nonsignificant negligible relationship with BMI percentile (r=-0.26, P=0.004).

Conclusion:

BMI percentile was positively correlated with external hip rotation during the stance phase of gait and passive external hip rotation, and negatively correlated with femoral anteversion. These findings suggest abnormal body weight is associated with static and dynamic biomechanical alterations. Therefore, weight management should be considered in orthopaedic assessments and treatment planning for children and adolescents.
Cervical Laminoplasty is Associated With Lower Health Care Costs as Compared With Cervical Fusion Procedures
Authors: Baumann Anthony N. , Anaspure Omkar , Patel Shiv , Kermanshahi Nazanin , Yoder R. Garrett , Conry Keegan T. , Preston Gordon , Hoffmann Jacob C.
Published: November 2024

Study Design:

Systematic review and meta-analysis.

Objective:

The purpose of this study is to examine the cost of CLP versus CF stratified by approach to guide decision-making.

Summary of Background Data:

Cervical laminoplasty (CLP) and cervical fusion (CF) are viable alternatives for surgical management of cervical spine myelopathy, with no clear consensus on clinical superiority. However, despite clinical equivalence in patient outcomes, there is limited data on the relative costs between CLP and CF.

Methods:

This study searched PubMed, CINAHL, MEDLINE, and Web of Science databases. Inclusion criteria were articles that examined the cost between CLP and any type of CF (stratified by anterior, posterior, or combined approach). A random-effects continuous model for meta-analysis was performed using standardized mean difference (SMD).

Results:

Eleven articles were included. Patients (n = 21,033) had an average age of 56.0 ± 3.6 years and underwent either CLP (n = 4364), posterior CF (n = 3529), anterior CF (n = 13,084), or combined CF (n = 56). The mean reported cost among patients who underwent CLP (n=3742) was significantly lower compared with patients who underwent CF (n = 6329), irrespective of the approach for CF (P = 0.028; SMD = −2.965). For subgroup analysis by surgical approach, the mean reported cost among patients treated with CLP was significantly lower as compared with patients treated with posterior CF (P = 0.013; SMD = −1.861) and anterior CF (P < 0.001; SMD = −0.344). Patients who underwent CLP had a significantly lower mean hardware cost than patients who underwent posterior CF (P < 0.001; SMD = −3.275).

Conclusions:

CLP appears to be associated with statistically significant and clinically relevant lower reported costs than CF, irrespective of the approach based on meta-analysis of low or moderate-quality retrospective studies. CLP may also have lower reported costs than both posterior CF and anterior CF.

Level of Evidence:

IV.
The Obesity Paradox in Pulmonary Rehabilitation
Authors: Yohannes Abebaw M. , Dransfield Mark T. , Morris Peter E.
Published: November 2024

Pulmonary rehabilitation (PR) increases exercise capacity, reduces dyspnea, and improves quality of life (QoL) in patients with chronic obstructive pulmonary disease (COPD). Patients requiring PR can present with multiple comorbidities. One of the most common comorbidities is obesity. The prevalence of obesity in patients with COPD is increasing at an alarming rate. To date the efficacy of PR to ameliorate obesity in patients with COPD is unclear. Obesity in patients with COPD is associated with increased morbidity and mortality compared to patients without obesity. However, the benefits of obesity paradox in lower mortality rate health-related QoL and health care utilization remain unclear. This review discusses the challenges of prescribing PR to patients with obesity and COPD. In addition, the definition of and the potential challenges and benefits of the obesity paradox in patients with COPD will be discussed. Treatment strategies that include combining PR with lifestyle management, individually tailored nutritional advice, pharmacotherapy, and surgery need to be tested in prospective, randomized controlled trials. The challenges of providing complex care, prioritizing patient needs, and future directions will also be discussed for patients with obesity and COPD.
Research Priorities in Pulmonary Rehabilitation
Authors: Benzo Roberto , Benzo Maria
Published: November 2024

Pulmonary rehabilitation (PR) plays a crucial role in improving outcomes for individuals with chronic respiratory diseases. The most outstanding challenge in PR is the low referral, uptake, and adherence that is dramatically low in the post-hospitalization period in rural, minority, and low-income populations. Research efforts to increase the portfolio of PR through the testing and implementation of new and effective options for home-based and community-based programs are potential research targets. Other potential foci of research efforts are the pursuit of behavior-change techniques to achieve a lifestyle change during PR and the referral process to increase uptake and adherence rates. Creating new rehabilitation options for chronic lung disease that can reach more people may require expanding the definition of PR for chronic lung disease to one more flexible and perhaps concordant with the World Health Organization’s definition of rehabilitation as “a set of interventions designed to optimize functioning and reduce disability in individuals with health conditions in interaction with their environment.” While efforts to augment access to conventional PR are warranted, it is time to devote research efforts to reach many more individuals with chronic lung disease, particularly minorities, rural, and low-income individuals that currently have no access to any rehabilitation, a social injustice that requires action. This manuscript outlines suggested future directions in rehabilitation research with the pursuit of evidence to support feasible and effective programs that may increase the rehabilitation portfolio to accommodate most individuals with chronic lung disease.
SYMPTOMATIC MIGRATION OF SILICONE OIL TO THE VENTRICULAR SYSTEM
Authors: Nery Breno , Vieira Da Silva Rayssa Rocha , Fontes Costa Araújo Rafael Emanuel , De Souza Faria Giovana , Cestari Isabela Grozza , Souto Fernandes Thayná Dantas , Brandão Paganini Ana Carolina , Alves De Oliveira Souza Laura Maria , Ferreira Braga João Pedro , De Sousa Filho Leonardo Braz , De Sousa Segundo José Alencar , Vasconcelos Júnior Huber Martins
Published: November 2024

Purpose:

The objective of this article is to report a case of silicone oil migration into intraocular packing in cases of retinal detachment, while reviewing the existing literature on the various mechanisms and locations of this migration. However, it is important to highlight that the use of this material is not free from complications.

Method:

This article is a case report with a literature review. The information was obtained through a review of the medical record, interview and photographic record of the patient's diagnostic methods. PubMed was used as a database to perform the search for selected articles and literature review, selecting articles published from the year 2016.

Results/discussion:

The exact mechanism of migration of intraocular silicone oil to the central nervous system is still unclear, being a rare complication that may be related to several factors. We report a case in which the patient underwent vitrectomy surgery and, after several years, presented a complication related to the migration of intraocular silicone oil to the right frontal horn and third ventricle, causing headache. Conclusion: Knowledge about migration of intraocular silicone oil into the central nervous system (CNS) is extremely important, since it manifests itself in several clinical and radiological findings, which can lead to incorrect diagnoses. Thus, it is suggested the follow- up of the patient after introduction of silicone oil to avoid complications that threaten results.
Case report: A Unique Case of Brainstem Anesthesia and Contralateral Amaurosis Following a Sub-Tenon Block
Authors: Lu Melissa , Al Kaabi Mohammed , Xin-Ya Qian Cynthia
Published: November 2024

Purpose:

To report and discuss a case of brainstem anesthesia and contralateral amaurosis following a sub-Tenon block.

Methods:

Single surgical case report of a patient who underwent an uncomplicated pars plana vitrectomy for an epiretinal membrane peel in the left eye following a sub-Tenon anesthesia technique.

Results:

Post-operatively, the patient experienced symptoms of brainstem anesthesia as well as akinesia, a non-reactive pupil, and reduced visual acuity in the contralateral eye which gradually resolved within 24 hours. Imaging was within normal limits and did not reveal any anatomic abnormalities.

Conclusion:

Despite the use of a blunt-ended cannula in a sub-Tenon block, there is a non-negligible risk of it penetrating surrounding structures such as the optic nerve sheath. This case emphasizes the importance of monitoring for brainstem anesthesia and contralateral eye affections in patients both intra- and post-operatively.
Nontyphoidal Salmonella Osteomyelitis in Immunocompetent Children: Report of Two Cases and Literature Review
Authors: Lee Hyun A. , Jung Hyun Joo
Published: November 2024

Salmonella is a rare causative pathogen of osteomyelitis and is commonly detected in patients with sickle cell disease. We described 2 consecutive cases of nontyphoidal Salmonella osteomyelitis identified in immunocompetent children. It is evident that even children without apparent risk factors for immune dysfunctions can be affected, so maintaining clinical suspicion is crucial for early diagnosis and prompt treatment.
The use of artificial intelligence in colonoscopic evaluations
Authors: Khalaf Kareem , Rizkala Tommy , Repici Alessandro
Published: October 2024

Purpose of review

This review aims to highlight the transformative impact of artificial intelligence in the field of gastrointestinal endoscopy, particularly in the detection and characterization of colorectal polyps.

Recent findings

Over the past decade, artificial intelligence has significantly advanced the medical industry, including gastrointestinal endoscopy. Computer aided diagnosis - detection (CADe) systems have shown notable success in increasing ADR. Recent meta-analyses of RCTs have demonstrated that patients undergoing colonoscopy with CADe assistance had a higher ADR compared with conventional methods. Similarly, computer aided diagnosis - characterization (CADx) systems have proven effective in distinguishing between adenomatous and nonadenomatous polyps, enhancing diagnostic confidence and supporting cost-saving measures like the resect-and-discard strategy. Despite the high performance of these systems, the variability in real-world adoption highlights the importance of integrating artificial intelligence as an assistive tool rather than a replacement for human expertise.

Artificial intelligence integration in colonoscopy, through CADe and CADx systems, marks a significant advancement in gastroenterology. These systems enhance lesion detection and characterization, leading to improved diagnostic accuracy, training outcomes, and clinical workflow efficiency. While artificial intelligence offers substantial benefits, the optimal approach involves using artificial intelligence to augment the expertise of endoscopists, ensuring that clinical decisions remain under human oversight.
Upper tract urothelial carcinoma: conservative management - intraluminal adjuvant therapy, and surveillance
Authors: Lasmanovich Rinat , Shvero Asaf , Kleinmann Nir
Published: November 2024

Purpose of review

In recent years, intraluminal therapies have become a valid alternative for low grade upper tract urothelial carcinoma (UTUC) patients, as overall survival and cancer-specific survival rates were shown to be comparable to those achieved with radical nephroureterectomy for selected cases. Nonetheless, endoscopic treatment has its limitations. As technology progresses and the demand for endoscopic treatments increases, intraluminal chemotherapy and immunotherapy instillations within the upper tract have increasingly become the subject areas of research.

Recent findings

The main intraluminal therapies and relevant instillation approaches are reviewed in this study, including recent publications and their main outcomes. The recurrence rates demonstrated in the literature strengthen the notion that patients with UTUC following current intraluminal treatments have a better prognosis than in the past. Updated relevant guidelines regarding surveillance among this population are also reviewed and summarized.

The treatment of upper tract urothelial carcinoma is clinically challenging. Developments in recent years show promising results in this field and ongoing research with new developments is emerging. Further studies are required to better understand the contribution of intraluminal therapies to the management of this disease.
Detection of Small Brain Metastases by 18F-Thretide PET/CT in Clear Cell Renal Cell Carcinoma
Authors: Cheng Xin , Hou Guozhu , Zheng Rong , Zhang Jingjing , Wang Xuejuan
Published: October 2024

A 46-year-old woman with a history of radical nephrectomy for clear cell renal cell carcinoma underwent 18F-FDG and 18F-Thretid (also known as Al18F-PSMA-BCH) PET/CT. Although the 18F-FDG PET/CT failed to detect any brain metastases, the 18F-Thretide PET/CT revealed 2 small metastases: one measuring 1.0 × 0.7 cm in the right cerebellum and the other measuring 0.4 cm in the right frontal lobe. These metastatic lesions were subsequently confirmed by brain MRI.
Hepatic Recurrence of Neuroendocrine Tumor Component in Gallbladder Cancer
Authors: Ikejiri Tatsuki , Yoh Tomoaki , Kasai Yosuke , Nagai Kazuyuki , Hatano Etsuro
Published: October 2024

A 60-year-old man underwent an extended cholecystectomy with regional lymphadenectomy for T2N0M0 gallbladder cancer (GBC), which showed significant FDG uptake (SUVmax = 6.5). However, CT scan at 24 months postsurgery revealed multiple hepatic masses. Unlike the primary GBC, the hepatic masses showed limited FDG uptake (SUVmax = 3.7). A tumor biopsy revealed the diagnosis of a grade 3 neuroendocrine tumor. Furthermore, the hepatic masses showed significant uptake on somatostatin receptor scintigraphy. Upon reevaluation, the primary resected specimen was found to include approximately 10% of neuroendocrine tumor components. This case suggests that different FDG uptake between primary and metastatic cancer may necessitate differential diagnosis.
Cleft Lip Scar Appearance is Associated With Speech Outcomes After Primary Palatoplasty
Authors: Prezelski Kayla , Carter Lillian , Peters Victoria , Rizvi Imran , Furtado Kailee , Kane Alex A. , Seaward James R.
Published: November 2024

Objective:

This study aims to investigate the correlation between the quality of cleft lip scar and velopharyngeal insufficiency (VPI).

Methods:

Clinical photographs from 56 patients with repaired cleft lip and palate (CLP) were collected and anonymized by cropping the image to the region of interest around the lip and nose. A survey displaying each cleft lip scar image with five associated scar quality features, including scar color, thickness, width, lip shortening, and overall appearance, was distributed. Surveys were distributed using Amazon Mechanical Turk (MTurk), an online crowdsourcing platform, to obtain ratings from 330 laypeople. The same surveys were also distributed to 45 medical students.

Main Outcome Measure:

Hypernasality was used as the primary speech outcome measure. Ordinal logistic regression was used to compare the ratings for each of the five scar quality categories with the patients’ CAPS-A-AM hypernasality rating for both MTurk and medical student raters. Significance was set at α = 0.05.

Results:

For medical student ratings’, ordinal logistic regression showed a statistically significant relationship between lip shortening (P=0.019) and overall appearance (P=0.044) with CAPS-A-AM hypernasality score, whereas the other scar categories showed no significant association. There was no statistically significant relationship between MTurk ratings and hypernasality for any of the scar categories.

Conclusions:

The association found between lip shortening and overall scar appearance, thought by the authors to indicate scar contracture, and hypernasality, an indicator of VPI severity, provides an interesting insight into how to potentially identify patients who may be at increased risk for developing VPI.
Membrane staining and phospholipid tracking in Pseudomonas aeruginosa PAO1 using the phosphatidylcholine mimic propargyl-choline
Authors: Graham Chris LB , Bryant Jack , Roper David I , Banzhaf Manuel
Published: October 2024

The use of membrane-specific dyes for in vivo fluorescent microscopy is commonplace. However, most of these reagents are non-specific and cannot track specific lipid species movement, instead often acting as non-covalent lipid associated probes or requiring uptake of whole lipids and acyl tails into the membrane. This issue has been solved in eukaryotic cell biology by use of click-chemistry liable phospholipid headgroup pulse-labels. Here we describe a method for in vivo phospholipid labelling by fluorescent imaging in Pseudomonas aeruginosa using a phosphatidylcholine (PC) mimic, “propargyl-choline”(PCho). This click-chemistry liable headgroup mimic is visible by microscopy and allows the covalent labelling of lipids. Fluorescence of the cell membranes, visible in heterogenous patches, is dependent on PCho concentration and is localised in the membrane fraction of cells, demonstrating that it is suitable for membrane labelling and cell imaging.
Mechanical stretch induced collective cell alignment
Authors: Shi Xuechen , Zhang Sulin
Published: October 2024

Cell alignment is a fundamental process in development and plays an essential role in tissue function. Although it has been found that cell alignment exhibits a density-dependent collective behavior, the collective mechanisms within this process remain elusive. In this study, we present a model of collective cell alignment induced by uniaxial mechanical stretch and explore the mechanisms driving this phenomenon. We demonstrate that alignment occurs in a density-dependent manner, with dense cell populations aligning while sparse populations do not. Contrary to previous findings, our results show that this alignment is initiated by substrate deformation upon stretch, which biases cell orientations towards the stretched direction. This deformation-induced alignment occurs passively and simultaneously, allowing us to isolate and identify the factors contributing to the collective behavior. Importantly, we find that once stretched, cells in low-density cultures lose alignment over time, while cells in high-density cultures are able to maintain the alignment level, exhibiting positional adaptation. Furthermore, we observe a self-organization process in high-density cultures, where cells actively reorient towards the stretched direction through cell-cell interactions, enhancing the overall alignment level over time. The emergence of the alignment response has implications for how cell alignment is achieved and sheds light on the cooperative mechanisms underlying collective cell behaviors. Additionally, our findings introduce a novel methodology for aligning cells that could be used for biomedical and tissue engineering applications.
Automated Extraction of Mortality Information from Publicly Available Sources Using Language Models
Authors: Al-Garadi Mohammed , LeNoue-Newton Michele , Matheny Michael E. , McPheeters Melissa , Whitaker Jill M. , Deere Jessica A. , McLemore Michael F. , Westerman Dax , Khan Mirza S. , Hernández-Muñoz José J. , Wang Xi , Kuzucan Aida , Desai Rishi J. , Reeves Ruth
Published: November 2024

Background

Mortality is a critical variable in healthcare research, but inconsistencies in the availability of death date and cause of death (CoD) information limit the ability to monitor medical product safety and effectiveness.

Objective

To develop scalable approaches using natural language processing (NLP) and large language models (LLM) for the extraction of mortality information from publicly available online data sources, including social media platforms, crowdfunding websites, and online obituaries.

Methods

Data were collected from public posts on X (formerly Twitter), GoFundMe campaigns, memorial websites (EverLoved.comandTributeArchive.com), and online obituaries from 2015 to 2022. We developed a natural language processing (NLP) pipeline using transformer-based models to extract key mortality information such as decedent names, dates of birth, and dates of death. We then employed a few-shot learning (FSL) approach with large language models (LLMs) to identify primary and secondary causes of death. Model performance was assessed using precision, recall, F1-score, and accuracy metrics, with human-annotated labels serving as the reference standard for the transformer-based model and a human adjudicator blinded to labeling source for the FSL model reference standard.

Results

The best-performing model obtained a micro-averaged F1-score of 0.88 (95% CI, 0.86-0.90) in extracting mortality information. The FSL-LLM approach demonstrated high accuracy in identifying primary CoD across various online sources. For GoFundMe, the FSL-LLM achieved 95.9% accuracy for primary cause identification, compared to 97.9% for human annotators. In obituaries, FSL-LLM accuracy was 96.5% for primary causes, while human accuracy was 99.0%. For memorial websites, FSL-LLM achieved 98.0% accuracy for primary causes, with human accuracy at 99.5%.

Conclusions

These findings highlight the potential of leveraging advanced NLP techniques and publicly available data to enhance the timeliness, comprehensiveness, and granularity of mortality surveillance.

Funding statement

This project was supported by Task Order 75F40123F19010 under Master Agreement 75F40119D10037 from the US Food and Drug Administration (FDA). FDA coauthors reviewed the study protocol, statistical analysis plan, and the manuscript for scientific accuracy and clarity of presentation. Representatives of the FDA reviewed a draft of the manuscript for the presence of confidential information and accuracy regarding the statement of any FDA policy. The views expressed are those of the authors and not necessarily those of the US FDA.
Age-Related Changes in the Cholinergic System in Adults with Down Syndrome Assessed Using [18F]-Fluoroethoxybenzovesamicol Positron Emission Tomography Imaging
Authors: Russell Jason K , Conley Alexander C. , Boyd Brian D. , Begnoche J. Patrick , Schlossberg Rachel , Stranick Allison , Rosenberg Adam J. , Acosta Lealani Mae Y , Martin Dann , Neal Yasmeen , Kanel Prabesh , Albin Roger L. , Rafii Michael S. , Dumas Julie , Newhouse Paul A.
Published: November 2024

Adults with Down syndrome are genetically predisposed to developing Alzheimer’s disease after the age of 40. The cholinergic system, which is critical for cognitive functioning, is known to decline in Alzheimer’s disease and although first investigated in individuals with Down syndrome 40 years ago, remains relatively understudied. Existing studies suggest individuals with Down syndrome have an intact cholinergic system at birth that declines through adulthood alongside the development of Alzheimer’s disease pathology. The present study provides the first description of cholinergic terminals in vivo in non-demented adults with Down syndrome utilizing [18F]-fluoroethoxybenzovesamicol PET imaging. In addition, we investigated age-associated decline in cholinergic terminal density. Sixteen non-demented adults with Down syndrome and 20 neurotypically developed individuals were studied, comparing radiotracer uptake groupwise and associations with age utilizing a voxel-based approach. Adults with Down syndrome displayed significantly increased [18F]-fluoroethoxybenzovesamicol uptake in the cerebellum, brainstem, thalamus, and numerous cortical regions compared to age-matched controls. Cholinergic terminal density in numerous cortical regions showed a steeper decline associated with increasing age in adults with Down syndrome than observed in neurotypically developed adults in the age range tested. These data suggest increased cholinergic terminal density in early adulthood in individuals with Down syndrome with a more rapid or earlier age-associated decline than is observed in neurotypically developed individuals.
Computational design of Bax-inhibiting peptides
Authors: Vlaar Tom , Mayer Bernadette , van der Heide Lars , Ilie Ioana M.
Published: October 2024

The proteins of the Bcl-2 family play crucial roles in regulating apoptosis. It is divided into pro-survival and pro-apoptotic proteins that determine cellular fate. In particular, Bax is a crucial executor of apoptosis as its activation initiates the apoptotic phenotype. Hence, targeting this protein represents an attractive therapeutic approach, which can aid in regulating apoptotic signalling and potentially contribute to the development of novel therapies against cancer and neurodegenerative diseases. Here, we introduce a digital paradigm, which relies on rational design and computer simulations to develop and validate peptide-based agents that bind to Bax, thereby inhibiting its apoptotic properties. The peptides are rationally designed and optimized to bind to Bax starting from the crystal structures of affimers in complex with Bcl-2 proteins. Next, molecular dynamics simulations (MD) are employed to probe the stability of the Bax-peptide complexes and to estimate the binding free energies. The results show that the designed peptides bind with high affinity to Bax. Two of the designed peptides bind in the canonical hydrophobic groove (BH1 domain) of Bax and one peptide binds to the outside of the BH3 domain (α2-helix). Notably, the peptides restrict the flexibility of theα1-α2loop, modulating the bottom trigger site associated with toxicity. All in all, the results highlight the potential of these peptides as valuable tools for further exploration in modulating apoptotic pathways and set the structural foundation for a machine learning powered engine for peptide design.
Co-evolution of host dispersal and parasite virulence in complex landscapes
Authors: Deshpande Jhelam N. , Pallagatti Ruthvik S. , Dakos Vasilis , Kaltz Oliver , Fronhofer Emanuel A.
Published: October 2024

Spatial network structure impacts the ecological and evolutionary dynamics of species interactions. Previous work on host-parasite systems has shown that parasite virulence is driven by dispersal rates and spatial structure, assuming that dispersal is an ecologically fixed parameter. However, dispersal is also a trait under selection and can evolve. In this context, we develop an individual-based eco-evolutionary model, in which both parasite virulence and host dispersal can evolve in representative terrestrial (random-geometric graphs; RGGs) and riverine aquatic (optimal channel networks; OCNs) landscapes. We find that in riverine aquatic landscapes, evolutionarily stable (ES) dispersal rates are lower and ES virulence is greater relative to terrestrial landscapes when dispersal mortality is low. When dispersal mortality is high, both dispersal and virulence evolve to lower values in both landscape types. Diverging co-evolutionary patterns between landscapes are explained by differences in network topology. Specifically, the highly heterogeneous degree distribution in riverine aquatic landscapes 1) leads to low parasite relatedness allowing for the evolution of greater virulence and 2) leads to spatial heterogeneity in host densities that constrains the evolution of dispersal to lower values. Our work highlights the importance of considering the concurrent and co-evolution of dispersal when studying trait evolution in complex landscapes.
Crystal structure of a Photosystem II-related, Manganese-binding, TPM-domain protein at a 1.6 Å resolution
Authors: Vidal-Meireles André , Malesinski Soazig , Horrenberger Yann , Monteil Caroline , Alric Jean , Siponen Marina , Johnson Xenie
Published: October 2024

Conserved proteins across oxygenic phototrophic organisms are important players in photosynthetic acclimation, yet many remain poorly or completely uncharacterized. In the green algaChlamydomonas reinhardtiiwe identified Cre15.g636050, previously annotated asCPLD31, that encodes such an uncharacterized, conserved, thylakoid lumenal protein belonging to the “TPM” domain family (PF04536). TPM refers to a protein fold named after the three founding proteins of this family, TLP18.3, Psb32, and MOLO-1, with the first two being Photosystem II-related proteins. We also found a paralogue ofCPLD31, Cre03.g154600, previously annotated asTLP15.2. In this work, we generated knock-out mutants of these genes in Chlamydomonas and produced the recombinant proteins. We showed both proteins are regulated by light and phototrophy, and while the former binds manganese in a TPM-domain metal binding site, the latter does not. Therefore, we reannotated them asLumenalMn-bindingTPM-domainProtein1(LMTP1) andThylakoidLumenalProtein26kDa (TLP26), respectively.
Interactions of N- and C-terminal parts of Ana1 permitting centriole duplication but not elongation
Authors: Nagy Agota , Kovacs Levente , Rangone Helene , Fu Jingyan , Ladinsky Mark , Glover David M.
Published: October 2024

The conserved process of centriole duplication requires establishment of a Sas6-centred cartwheel initiated by Plk4’s phosphorylation of Ana1/STIL. Subsequently the centriole undergoes conversion to a centrosome requiring its radial expansion and elongation, mediated by a network requiring interactions between Cep135, Ana1/Cep295, and Asterless/Cep152. Here we show that mutant alleles encoding overlapping N- and C-terminal parts of Ana1 are capable of intragenic complementation to rescue radial expansion. This permits recruitment of Asl and thereby centriole duplication and mechanosensory cilia formation to restore the coordination defects of these mutants. This genetic combination also rescues centriole duplication in the male germ line but does not rescue the elongation of the triplet microtubule-containing centrioles of primary spermatocytes and consequently these males are coordinated but sterile. Such centriole elongation is rescued by the continuous, full-length Ana1 sequence. We define a region that when deleted within otherwise intact Ana1 does not permit primary spermatocyte centrioles to elongate but still allows recruitment of Asl. Our findings point to differing demands upon the physical organization of Ana1 for the distinct processes of radial expansion and elongation of centrioles.

IMPACT STATEMENT

The centriole can undergo radial development and duplication using separated parts of the conserved Ana1 protein whereas elongation of centriolar microtubule triplets requires the continuous Ana1 primary sequence.
GBRAP: A Comprehensive Database and Tool for Exploring Genomic Diversity Across All Domains of Life
Authors: Yaddehige Sachithra Kalhari , Vischioni Chiara , Alberghini Leonardo , Berselli Michele , Taccioli Cristian
Published: October 2024

Evolutionary studies require extensive examination of genomic information across all domains of life. Despite the availability of a large number of genomes through GenBank, the effective visualisation or comparison of the information they contain is challenging due to many reasons including their size. We introduce GBRAP, a comprehensive software tool to analyse GenBank files, and an online database housing an extensive collection of carefully curated, high-quality genome statistics for all the organisms available in the RefSeq database of NCBI. Users can either directly search, or select from pre-categorized groups, the organisms of their choice and retrieve data, which eventually output as tables containing more than 200 columns of useful genomic information (Base counts, GC content, Shannon Entropy, Codon Usage etc.) separately calculated for different genomic elements (eg. CDS, Introns, tRNA, rRNA, ncRNA, etc.). The data are independently displayed (if applicable) for each chromosomal, mitochondrial, plastid, or plasmid sequence. All the data can be visualised on the database or downloaded as CSV or Excel files. The GBRAP database is free to access without any registration and is publicly available at .
A Bayesian Framework for Genome-wide Circadian Rhythmicity Biomarker Detection
Authors: Ding Haocheng , Meng Lingsong , Zhang Yutao , Bryant Andrew J. , Xing Chengguo , Esser Karyn A. , Chen Li , Huo Zhiguang
Published: November 2024

Circadian rhythms are endogenous ∼24-hour cycles that significantly influence physiological and behavioral processes. These rhythms are governed by a transcriptional-translational feedback loop of core circadian genes and are essential for maintaining overall health. The study of circadian rhythms has expanded into various omics datasets, necessitating accurate analytical methodology for circadian biomarker detection. Here, we introduce a novel Bayesian framework for the genome-wide detection of circadian rhythms that is capable of incorporating prior biological knowledge and adjusting for multiple testing issue via a false discovery rate approach. Our framework leverages a Bayesian hierarchical model and employs a reverse jump Markov chain Monte Carlo (rjMCMC) technique for model selection. Through extensive simulations, our method, BayesCircRhy, demonstrated superior false discovery rate control over competing methods, robustness against heavier-tailed error distributions, and better performance compared to existing approaches. The method’s efficacy was further validated in two RNA-Sequencing data, including a human resitrcted feeding data and a mouse aging data, where it successfully identified known and novel circadian genes. R package “BayesianCircadian” for the method is publicly available on GitHubhttps://github.com/jxncdhc/BayesianCircadian.
Role of Complexin 2 in the regulation of hormone secretion from the islet of Langerhans
Authors: Ng Xue Wen , DiGruccio Michael R. , Kong Chen , Lee Jeongmin , Piston David W.
Published: October 2024

Regulated secretion of insulin from β-cells, glucagon from α-cells, and somatostatin from δ-cells is necessary for the maintenance of glucose homeostasis. The release of these hormones from pancreatic islet cells requires the assembly and disassembly of the SNARE protein complex to control vesicle fusion and exocytosis. Complexin 2 (Cplx 2) is a small soluble synaptic protein that participates in the priming and release steps of vesicle fusion. It plays a dual role as a molecular switch that first clamps and prevents fusion pore opening, and subsequently undergoes a conformational change upon Ca2+binding to synaptotagmin to facilitate exocytosis. Using a Cplx 2 knockout (KO) mouse model, we show a direct inhibitory role of Cplx 2 for glucagon and somatostatin secretion, along with an indirect role in the paracrine inhibition of insulin secretion by somatostatin. Deletion of Cplx 2 increases glucagon and somatostatin secretion from intact mouse islets, while there is no difference in insulin secretion between WT and Cplx 2 KO islets. The normal paracrine inhibition of insulin secretion by somatostatin is disrupted in Cplx 2 KO islets. On the contrary, deletion of Cplx 2 did not affect the known role of somatostatin in the paracrine inhibition of glucagon at elevated glucose levels, since the paracrine inhibition of glucagon secretion by somatostatin is similar for both WT and Cplx 2 KO islets. In both β- and α-cells, the secretion profiles are parallel to Ca2+activity changes following somatostatin treatment of WT and Cplx 2 KO islets. The loss of paracrine inhibition of insulin secretion is substantiated by direct measurements of insulin vesicle fusion events in Cplx 2 KO islets. Together, these data show a differential role for Cplx 2 in regulating hormone secretion from pancreatic islets.
An assessment of evidence to inform best practice for the communication of acute venous thromboembolism diagnosis: a scoping review
Authors: Mishra Samarth , Klok Frederikus A. , Gal Grégoire Le , de Wit Kerstin , Schwartz Aviva , Luijten Dieuwke , Sadeghipour Parham , Bayley Julie , Woller Scott C.
Published: October 2024

Background

Physician communication with patients is a key aspect of excellent care. Scant evidence exists to inform best practice for physician communication in patients diagnosed with pulmonary embolism and deep vein thrombosis, collectively referred to as venous thromboembolism (VTE). The aim of this study was to summarize the existing literature on best practices for communication between healthcare providers and patients newly diagnosed with VTE.

Methods

We performed a scoping review of the extant literature on best practice for physician patient communication and the diagnosis and management of VTE. Manuscripts on communication between healthcare professionals and patients with acute vascular diseases, including VTE, were eligible. Two authors independently reviewed titles, and consensus determined article inclusion. The manuscripts were further categorized into two main categories: best practice in communication and unmet needs in communication. Data aggregation was achieved by a modified thematic synthesis.

Results

Among 345 initial publications, 22 manuscripts met inclusion criteria with 11 that addressed VTE, five pulmonary embolism, four deep vein thrombosis, one atrial fibrillation, and one acute coronary syndrome. Eleven manuscripts addressed communication of VTE diagnosis, while 12 focused on communication of VTE treatment. Eleven manuscripts identified unmet communication needs, and 14 addressed best practice. Our review shows that good communication surrounding the VTE diagnosis and treatment can enhance satisfaction while suboptimal communication can incur emotional, cognitive, behavioral, social, and health-systems adverse effects.

Conclusion

Scant literature guides best practices for communicating VTE diagnosis and treatment. Further research is necessary to establish practices for improving communication with VTE patients.
Spatial and temporal signatures of cell competition revealed by K-function analysis
Authors: Day Nathan , Michalowska Jasmine , Kelkar Manasi , Vallardi Giulia , Charras Guillaume , Lowe Alan R.
Published: November 2024

It is generally hypothesised that in MDCK wild-type versus ScrKDco-cultures mechanical competition leads to the physical elimination of ScrKDcells, while in MDCK wild-type versus RasV12co-cultures biochemical competition results in the non-apoptotic extrusion of RasV12cells. However, the exact spatiotemporal signatures of competitive interactions in these systems remains largely unknown. Utilising advanced single-cell image analysis, this research quantifies the spatiotemporal dynamics of these competitive interactions. Time-lapse microscopy, combined with cellular segmentation, tracking, cell-state classification, and K-function clustering analysis provide detailed insights into how wild-type cell proliferation relates to the elimination of mutant cells. We find striking differences in the underlying processes of each competition type. In the ScrKDcompetition, elimination seems driven by diffuse proliferative forces unrelated to the immediate elimination site. In contrast, RasV12cell elimination is closely linked to local increases in wild-type cell mitoses prior to the RasV12extrusion. Both competitions trigger an increase in local wild-type cell proliferation post-elimination, although the timing of these responses vary. This study not only sheds light on the diverse mechanisms of cell competition but also underscores the complexity of cellular interactions in tissue dynamics, providing new perspectives on cellular quality control and a new quantitative approach to characterise these interactions.
PAM-flexible adenine base editing rescues hearing loss in a humanizedMPZL2mouse model harboring an East Asian founder mutation
Authors: Hu Shao Wei , Jeong Sohyang , Jiang Luoying , Koo Hansol , Wang Zijing , Choi Won Hoon , Zhu Biyun , Seok Heeyoung , Zhou Yi , Kim Min Gu , Mu Dan , Guo Huixia , Zhou Ziyi , Jung Sung Ho , Zhang Yingting , Chae Ho Byung , Chen Liheng , Lee Sung-Yeon , Guo Luo , Suh Myung-Whan , Xiao Yang , Park Moo Kyun , Tang Honghai , Song Jae-Jin , Chen Xi , Chen Ai , Lee Jun Ho , Bae Sangsu , Lee Sang-Yeon , Shu Yilai
Published: November 2024

Hearing loss is one of the most prevalent sensory disorders, but no commercial biological treatments are currently available. Here, we identified an East Asia-specific founder mutation, the homozygous c.220C>T mutation inMPZL2, that contributes to a significant proportion of hereditary deafness cases in our cohort study. We found that the disease-causing mutation could be targetable by adenine base editors (ABEs) that enable A·T-to-G·C base corrections without DNA double-strand breaks. To demonstrate this, we developed a humanized mouse model (hMPZL2Q74X/Q74X) that recapitulates humanMPZL2deafness and leads to progressive hearing loss. A PAM-flexible ABE variant with reduced bystander and off-target effects (ABE8eWQ-SpRY:sgRNA3) was packaged in dual adeno-associated viruses (AAVs) and injected into the inner ear ofhMPZL2Q74X/Q74Xmice and effectively corrected the mutation. This treatment significantly restored hearing function, improved inner ear structural integrity, and reversed altered gene expression. Base editing may hold therapeutic potential for hereditary deafness, including most cases ofMPZL2deafness.