bluuebunny/crossref_metadata_2025 huggingface dataset:
Paternal, Maternal, and Familial Factors as Predictors of Sturge–Weber Syndrome Neurological Outcome
Authors: McKenney Kieran D. , Zabel Andrew T. , Harris Jayda M. , Comi Anne M.
Published: November 2024

Objectives:

To identify potential risk factors influencing Sturge–Weber Syndrome (SWS) and neurological outcomes in individuals with SWS and port-wine birthmarks from paternal, maternal, and familial factors.

Methods:

This study follows a retrospective cross-sectional design. Clinical visits took place at the Kennedy Krieger Institute, a tertiary care center. Participants were individuals with SWS or port-wine birthmarks.

Results:

Higher paternal age at conception was associated with a range of cognitive dysfunctions in offspring with SWS brain involvement. Indeed, paternal age was associated with low intelligence quotient (n = 25, P = .004), strokes or stroke-like episodes (n = 34, P = .030), gross and/or fine motor delay (n = 34, P = .036), delays in ability to perform activities of daily living (n = 30, P = .012), and delayed learning compared to peers (n = 31, P = .027). Furthermore, paternal age was correlated with worse cognitive outcomes, as measured by cognitive Neuroscore (r
s = 0.575, P < .001, n = 32). When maternal thyroid disease and hypertension were present during pregnancy, offspring were more likely to experience low intelligence quotient (n = 30, P = .041) and regression of any abilities (n = 37, P = .045), respectively. Logistic regression confirmed the association between paternal age and severe cognitive Neuroscore (β = .580, P = .033, odds ratio: 1.79, 95% confidence interval: 1.05–3.04), even when controlling for the effects of seizures and strokes or stroke-like episodes.

Conclusions:

Prenatal factors were associated with neurological symptoms in subjects with SWS. Older paternal age, in particular, may predict worse neurocognitive outcomes. Further research is needed in larger cohorts to determine the value of the identified prenatal factors as prognostic tools. Likewise, animal models may be used to determine the impact of prenatal factors on the severity of outcome.
Mammalian colonic contribution of amino acids to whole-body homeostasis
Authors: Kashyap Sindhu , Kurpad Anura V.
Published: November 2024

Purpose of review

The colon is an effective bioreactor with auxotrophic microbiota that can serve by hydrolyzing dietary and endogenous protein, as well as by synthesizing essential amino acids through nitrogen salvage. Due to assumed negligible amino acid absorption, this colonic contribution was thought to be minimal, but this may not be true.

Recent findings

Several studies that examined the colonic environment in health and disease, show the presence of proteases in the colonic lumen, which are of both host and microbial origin, along with indirect evidence of amino acid transporters in the colonic epithelium. There are also amino acid biosynthetic pathways in the microflora, and the contribution of colonic amino acid to host amino acid nutrition has been shown in wild animals. Yet, current direct and quantitative evidence on amino acid absorption in human colon is minimal.

Although amino acid absorption in colon is not very well established, current studies show that substantial amounts of amino acid could possibly be contributed to the host by the colon. There is a need for assessing this contribution quantitatively using direct isotopic methods under different nutritional conditions, dietary intakes, and clinical conditions.
Single-center analysis of cardiac amyloidosis using 99mTc-HMDP imaging for diagnosis and evaluation after tafamidis treatment
Authors: Egi Ryuta , Matsusaka Yohji , Watanabe Kaho , Seto Akira , Matsunari Ichiro , Arai Takahide , Nakano Shintaro , Kuji Ichiei
Published: November 2024

Objective

This study aimed to evaluate the diagnostic performance of 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) imaging for cardiac amyloidosis and to demonstrate changes in cardiac uptake of 99mTc-HMDP after tafamidis treatment.

Methods

Seventy-five patients with suspected cardiac amyloidosis who underwent 99mTc-HMDP imaging were included. We compared visual Perugini grades and semiquantitative heart-to-contralateral (H/CL) area ratios, myocardial maximum standardized uptake value (SUVmax), and peak of SUV (SUVpeak) between cardiac transthyretin amyloidosis (ATTR) and amyloid light-chain amyloidosis (AL). Comparison of interobserver reproducibility between H/CL ratios and myocardial SUVmax/SUVpeak was performed. H/CL ratio of 99mTc-HMDP and myocardial SUVmax/SUVpeak were compared before and after tafamidis administration for cardiac wild-type ATTR.

Results

Among 75 patients, 20 patients (26.7%) were visually positive based on Perugini grade. Fifteen and three patients were pathologically identified as cardiac ATTR and AL, respectively. ATTR group (n = 15) had significantly higher H/CL ratios of 99mTc-HMDP than AL group (n = 3) (P = 0.003). ATTR group (n = 15) had significantly higher myocardial SUVmax/SUVpeak of 99mTc-HMDP than AL group (n = 2) (P = 0.015). Myocardial SUVmax/SUVpeak had better interobserver reproducibility than H/CL ratios. After tafamidis treatment for cardiac wild-type ATTR, the decrease in myocardial SUVpeak was significant but not in H/CL ratios and myocardial SUVmax.

Conclusion

H/CL ratio and SUVmax/SUVpeak in 99mTc-HMDP imaging were useful for diagnosing cardiac ATTR. Myocardial SUVpeak may be useful for monitoring changes in cardiac uptake after tafamidis treatment for cardiac ATTR.
Long-term complications of extracranial pericranial flaps in skull base reconstruction
Authors: Daniels Kelly E. , Mocharnuk Joseph , Balogun Zainab , Zenonos Georgios A. , Gardner Paul A. , Snyderman Carl H. , Wang Eric W.
Published: November 2024

Purpose of review

Nasoseptal flaps are a frequently used and well characterized means of reconstruction following endoscopic endonasal approach surgery (EEA). However, there are alternative means of reconstruction, including the extracranial pericranial flap (ePCF), that while used infrequently fulfill a specialized need in larger or salvage reconstructions. This review aims to better characterize long-term outcomes using ePCF where there is currently a paucity of objective data on use and outcomes.

Recent findings

A traditional pericranial flap involves elevating and rotating the flap through a craniotomy defect to reconstruct defects of the ventral skull base. The ePCF is implemented without performing a craniotomy, and instead tunnels the flap through a bony opening created at the level of the nasion. This review presents outcomes in a large single-center cohort of patients with ePCFs to better characterize the short- and long-term success, risks, and complications of this reconstructive method.

Long-term follow-up demonstrates that obstruction of the frontal sinus outflow may occur but rarely requires surgical intervention. ePCF are a reasonable alternative to consider in cases where local tissue would be insufficient, is not available, or has already failed. There is a low risk of flap complications.
Neurofibroma-like Desmoplastic Melanoma
Authors: Baraban Ezra G. , Gru Alejandro , Guo Ruifeng , Elias Roy , Pallavajjala Aparna , Dudley Jonathan C. , Gross John M.
Published: November 2024

A subset of desmoplastic melanomas (DMs) can show extensive morphologic and immunohistochemical overlap with cutaneous diffuse-type neurofibroma. Neurofibroma-like desmoplastic melanoma (NFLDM) thus poses a significant diagnostic pitfall because the clinical implications of these 2 entities differ dramatically. A series of 17 DMs, including 5 cases of NFLDM, were compared with a cohort of 53 cutaneous diffuse-type neurofibromas to explore the utility of molecular testing in the differential diagnosis between NFLDM and neurofibroma and to determine potentially useful morphologic features in this differential diagnosis. Unlike NFLDM, cutaneous diffuse-type neurofibromas: (1) rarely feature intratumoral or peritumoral lymphoid aggregates, (2) consistently harbor an intrinsic stromal support vasculature composed of evenly spaced capillary-sized vessels, and (3) infiltrate adjacent adipose tissue in a dermatofibrosarcoma protuberans–like manner with a complete lack of chronic inflammation or fat necrosis at the leading edge of the tumor. Conversely, DMs, including NFLDM: (1) do not contain Wagner-Meissner bodies, (2) often induce fat necrosis and/or chronic inflammation at the interface with adjacent fibroadipose tissue, (3) lack the intrinsic capillary-sized stromal vasculature observed in most neurofibromas, and (4) may harbor foci of perineuriomatous differentiation, mimicking a hybrid nerve sheath tumor. Any deviation from the expected clinical or morphologic features of cutaneous diffuse-type neurofibroma should raise suspicion for NFLDM. Although not entirely sensitive or specific, molecular testing can help to support the diagnosis of NFLDM by demonstrating genetic abnormalities associated with melanoma, including a UV-light–induced mutational signature, high tumor mutational burden, and/or chromosomal copy number alterations typical of melanoma.
FDG PET/CT Image of Extragastrointestinal Stromal Tumor in the Posterior Mediastinum
Authors: Xiao Liu , Li Lin , Zhang Wenjie
Published: November 2024

Extragastrointestinal stromal tumor (EGIST) in the posterior mediastinum is very rare. Herein, we report FDG PET/CT findings of posterior mediastinum EGIST in a 77-year-old man. On FDG PET/CT, it manifested as a solitary posterior mediastinum mass with heterogeneous necrosis and intense FDG uptake. The final pathology supported a diagnosis of EGIST. This case hints us when we encounter a soft tissue mass with intense FDG uptake in the posterior mediastinum; EGIST should be regarded as a differential diagnosis.
Rare Findings of Multiple Bone Metastases From Duodenal Gangliocytic Paraganglioma on 68Ga-DOTATATE PET/CT Imaging
Authors: Xin Tong , Chen Xiaoliang , Li Yanxia
Published: November 2024

We present the imaging findings of a 48-year-old woman that metastasized to multiple bones with a history of duodenal gangliocytic paraganglioma. 68Ga-DOTATATE PET/CT showed multiple osteolytic bone destruction with intense uptake. Multiple bone metastases originating from duodenal gangliocytic paraganglioma confirmed histopathological results of a biopsy on the chest-back bone.
Innovative Use of Limberg Flap for MRONJ Reconstruction
Authors: Gedik Betül
Published: November 2024

Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication associated with bisphosphonate therapy, characterized by necrotic bone exposure in the maxillofacial region. This case report details the surgical management of a 68-year-old female patient with a history of cancer and bisphosphonate-related osteonecrosis. After the initial sequestrectomy, the patient developed a purulent discharge, necessitating soft tissue reconstruction using a Limberg flap. The surgical procedure involved meticulous debridement and flap placement, resulting in successful healing and resolution of symptoms. This case highlights the importance of tailored management strategies for MRONJ and the potential benefits of the Limberg flap in reconstructive surgery, addressing a notable gap in the literature regarding its application in this context.
A Patient-Specific 3D Printed Lingual Nerve Protector in Third Molar Extraction
Authors: Kim Hye-Won , Kim Moonsoo , Kim Seok-Ho , Kim Moon-Young
Published: November 2024

We present a novel, patient-specific 3D-printed lingual nerve protector designed to minimize the risk of nerve injury during mandibular third molar extraction, a common cause of lingual nerve damage. Lingual nerve injuries, often resulting from trauma, dental procedures, or maxillofacial surgeries, lead to significant functional impairments. Using computed tomography (CT) data, the custom protector is fabricated through 3D printing with a self-retaining structure to shield the lingual mucosa and nerve. The device effectively separates the lingual nerve from the surgical field without requiring retraction of the lingual flap, thereby reducing the risk of nerve injury and enhancing the safety and ease of the procedure.
Return to Play Guidelines in Pediatric Concussion: A Systematic Review of Current Literature
Authors: Isch Emily L. , Schillinger Kristen , Monzy Judith N. , Galantini Gianfranco , Self Dwight Mitchell , Habarth-Morales Theodore E. , Caterson Edward J.
Published: November 2024

Introduction:

Pediatric concussions, particularly in youth sports, are a significant public health concern, with up to 18% of children experiencing one by age 17. Return-to-play (RTP) guidelines aim to protect athletes from the adverse effects of repeated injuries, but these protocols vary widely based on factors such as age, sport, and geography. This review synthesizes current literature on RTP guidelines for pediatric concussions to provide evidence-based recommendations.

Methods:

A systematic search of PubMed was conducted using Medical Subject Headings (MeSH) terms “return to play,” “pediatric concussion,” and “mild traumatic brain injury.” Studies published between January 2000 and December 2023 were included if they focused on RTP protocols for children aged 5 to 17. After screening 60 articles, 45 were selected for review. Study quality was assessed using the Newcastle-Ottawa Scale and Cochrane Risk of Bias Tool.

Results:

RTP protocols showed significant variability influenced by age, gender, and sport type. Common themes included initial rest followed by a gradual return to activity. Female athletes generally required longer recovery periods. Multidisciplinary care and early therapeutic interventions, such as vestibular therapy, were associated with better outcomes and faster recovery.

Conclusions:

There is a need for standardized, evidence-based RTP guidelines to address inconsistencies in concussion management. Future research should focus on creating universally applicable protocols, with attention to gender, sport-specific factors, and early intervention to improve recovery outcomes for young athletes.
Genome Sequence of antibiotic resistant Klebsiella quasipneumoniae FSFC0558; a Novel Sequence Type
Authors: Robins Daniel , Goodman Richard N. , Pulmones Ralfh , Kibwana Upendo O. , Manyahi Joel , Blomberg Bjørn , Langeland Nina , Moyo Sabrina , Roberts Adam P
Published: November 2024

Klebsiella quasipneumoniae is a Gram-negative bacteria of the family Enterobacteriaceae, distinguished from other members of the Klebsiella genus through a chromosomally encoded extended spectrum β-lactamase, blaOKP. Here, we report a hybrid assembled genome of a novel sequence type of Klebsiella quasipneumoniae subspecies similipneumoniae isolated from a faecal sample of a patient with sepsis.
Emergence of highly pathogenic avian influenza viruses H5N1 and H5N5 in white-tailed eagles, 2021–2023
Authors: Bøe Cathrine Arnason , Fiskebeck Eve Marie Louise Zeyl , Reiten Malin Rokseth , Åkerstedt Johan , Saghafian Maryam , Tønnessen Ragnhild , Gjerset Britt , Sturød Kjersti , Moldal Torfinn , Rømo Grim , Helberg Morten , Halley Duncan , Rondestveit Lars-Erik Lundblad , Madslien Knut , Granstad Silje
Published: November 2024

Highly pathogenic avian influenza (HPAI) poses a substantial threat to several raptors. Between 2021 and 2023, HPAI viruses (HPAIVs) of the Goose/Guangdong lineage H5 clade 2.3.4.4b became widespread in wild birds in Norway, and H5N1 and H5N5 viruses were detected in 31 white-tailed eagles (Haliaeetus albicilla, WTEs). Post-mortem examinations of four WTEs revealed no macroscopic pathological findings. Microscopic examinations showed the presence of myocardial and splenic necroses and a few lesions in the brain.In situhybridization revealed the presence of the virus in several organs, suggesting a multisystemic infection. The detection of HPAIV H5N5 in a WTE in February 2022 marked the first recorded occurrence of this subtype in Norway. Since then, the virus has persisted, sporadically being detected in WTEs and other wild bird species. Phylogenetic analyses reveal that at least two distinct incursions of HPAIV H5N1 Eurasian (EA) genotype C affected WTEs, likely introduced by migratory birds from Eurasia and seabirds entering from Western and Central Europe. Some WTE isolates from 2021 to 2022 clustered with those from Canada and Ireland, aligning with the transatlantic spread of H5N1. Others were related to the 2021 mass mortality of great skuas in the UK or outbreaks in seabird populations, including gannets, gulls and terns, during 2022 in the North Sea region. This suggests that the WTEs were likely preying on the affected birds. Our study highlights that WTEs can act as sentinels for some HPAIV strains, but the absence of several known circulating genotypes in WTEs suggests varying pathogenic effects on this species.
A high protein meal does not change autophagy in human blood
Authors: Singh S , Fourrier C , Hattersley K , Hein LK , Gore J , Heilbronn LK , Bensalem J , Sargeant TJ
Published: November 2024

Autophagy is a catabolic quality control pathway that has been linked to neurodegenerative disease, atherosclerosis and ageing, and can be modified by nutrient availability in preclinical models. Consequently, there is immense public interest in stimulating autophagy in people. However, progress has been hampered by the lack of techniques to measure human autophagy. As a result, several key concepts in the field, including nutritional modulation of autophagy, have yet to be validated in humans. We conducted a single arm pre-post study in 42 healthy individuals, to assess whether an acute nutritional intervention could modify autophagy in humans. Two blood samples were collected per participant: after a 12 h overnight fast and 1 h post-consumption of a high protein meal. Autophagy turnover was assessed using a physiologically relevant measure of autophagic flux in peripheral blood mononuclear cells. A lysosomal inhibitor was added directly to whole blood, with the resulting build-up of autophagy marker LC3B-II designated as flux, and measured quantitatively via ELISA. Notably, consumption of a high protein meal had no impact on autophagy, with no differences between overnight fasting and postprandial autophagic flux. We observed sexual dimorphism in autophagy, with females having higher autophagic flux compared to males (p = 0.0031). Exploratory analyses revealed sex-specific correlations between autophagy, insulin and glucose signalling. Importantly, our findings show that an acute nutritional intervention (overnight fasting followed by consumption of a protein-rich meal) does not change autophagic flux in humans, highlighting the need to conduct further autophagy studies in humans.
Organ damage proteomic signature identifies patients with MASLD at-risk of systemic complications
Authors: Pirola Carlos José , Diambra Luis , Fernández Gianotti Tomas , Castaño Gustavo Osvaldo , San Martino Julio , Garaycoechea Martin , Sookoian Silvia
Published: November 2024

Background & objectives

Metabolic steatotic liver disease (MASLD), which affects more than 30% of the world’s population, is associated with multisystemic comorbidities. We combined multidimensional OMICs approaches to explore the feasibility of using high-throughput targeted circulating proteomics to track systemic organ damage and to infer its underlying mechanisms at the molecular level.

Desing

We tested a 92-plex panel of prioritised proteins with pathophysiological relevance to organ damage in serum samples of patients with in-depth phenotyping. We included proteomics data from 60,042 people in the discovery and validation stages. The identified protein was validated across diverse study designs and cross-proteomic platforms. Deconvolution strategies were used to investigate whether the affected liver is involved in expressing biomarkers of organ damage. To assess the cell type-specific transcriptional changes of the selected target we used liver organoid data.

Results

The implicated proteins, including ADGRG1 (GPR56), are deregulated in patients with MASLD at-risk of progressive disease and significant fibrosis. ADGRG1 liver expression profile mirrors the circulation pattern. ADGRG1 levels were associated with increased risk of end-stage liver disease and a modest but clinically significant risk of death, chronic obstructive pulmonary disease, and ischaemic heart disease over 16 years of follow-up. Mechanistic insight shows that ADGRG1 shifts its transcriptional profile from low expression to upregulation in liver cells of the fibrotic niche in response to injury.

Conclusions

Our study provides a framework of potential mechanisms associated with systemic organ injury that facilitates holistic management by stratifying patients with MASLD into subclasses at-risk of extrahepatic manifestations.
Parallel transmit improves 7T MRI adult epilepsy pre-surgical evaluation
Authors: Klodowski Krzysztof , Zhang Minghao , Jen Jian P. , Scoffings Daniel J , Morris Robert , Lupson Victoria , Mauconduit Franck , Massire Aurélien , Gras Vincent , Boulant Nicolas , Rodgers Christopher T. , Cope Thomas E.
Published: November 2024

Objective

To implement parallel transmit (pTx) 7T MRI in the pre-surgical evaluation of patients with drug resistant focal epilepsy, and to compare quality and diagnostic yield to conventional single transmit (specifically, circularly polarised, CP) 7T MRI.

Methods

We implemented a comparative protocol comprising both pTx and CP 7T MRI in consecutive adult candidates for epilepsy surgery who had negative or equivocal 3T MRI imaging. Here we report the outcomes from the first 31 patients.

We acquired pTx and CP T1, T2, FLAIR and EDGE images, all in the same 3D 0.8mm isotropic space. 2D high-resolution T2and T2*-weighted sequences were acquired only in CP mode due to current technological limitations.

Two neuroradiologists, a neurologist and a neurosurgeon made independent, blinded quality and preference ratings of pTx vs CP images. Quantitative methods were used to assess signal dropout.

Results

Blinded comparison confirmed significantly better overall quality of pTx FLAIR images (F(2,184)=13.7, p=2.88×10-6), while pTx MP2RAGE images were subjectively non-inferior and had improved temporal lobe coverage with quantitatively less signal drop-out.

7T-pTx revealed previously-unseen structural lesions in 9 patients (29%), confirmed 3T-equivocal lesions in 4 patients (13%), and disproved 3T-equivocal lesions in 4 patients (13%).

Lesions were better visualised on pTx than CP in 57% of cases, and never better visualised on CP.

Clinical management was altered by pTx-7T in 18 cases (58%). 9 cases were offered surgical resection and 1 LITT. 3 cases were removed from the surgical pathway because of bilateral or extensive lesions. 5 cases were offered sEEG with better targeting (in 3 because the 7T lesion was deemed equivocal by the MDT, and in 2 because the lesion was extensive).

Significance

Parallel transmit 7T MRI is implementable in a clinical pathway, is superior to single transmit 7T MRI, and changed management in 58% of patients scanned.

Key points

We scanned 31 patients with parallel transmit and conventional 7T MRI, finding previously-unreported structural lesions in 9 patients (29% of cases).

In 13% of cases pTx 7T MRI showed that an equivocal lesion at 3T MRI was likely significant.

In 13% of cases pTx 7T MRI showed that an equivocal lesion at 3T MRI could be disregarded.

Both qualitative and quantitative quality assessments indicate superiority of pTx images over CP.

Future clinical implementations of 7T MRI for epilepsy should utilise parallel transmit where possible.
GraftIQ: A Hybrid Multi-Class Neural Network Integrating Clinical Insight for Multi-Outcome Prediction in Liver Transplant Recipients
Authors: Sharma Divya , Gotlieb Neta , Chahal Daljeet , Naimimohasses Sara , Ray Ankit , Han Yoojin , Gehlaut Sara , Shojaee Maryam , Sivanendran Surabie , Naghibzadeh Maryam , Azhie Amirhossein , Keshavarzi Sareh , Duan Kai , Lilly Leslie , Selzner Nazia , Tsien Cynthia , Jaeckel Elmar , Xu Wei , Bhat Mamatha
Published: November 2024

Background and Aims

Liver transplant recipients (LTRs) are at risk of developing graft injury, leading to cirrhosis and reduced survival. Liver biopsy remains the gold standard method for the diagnosis of graft pathology but is invasive and risky. Our study aimed to develop a novel hybrid multi-class neural network (NN) model ‘GraftIQ’ integrating clinician expertise for non-invasive diagnosis of graft pathology.

Methods

Graft injury diagnosis was based on liver biopsies from LTRs (1992-2020). Demographic, clinical, and laboratory data from the 30 days before biopsy were used to train a multi-class NN model to classify biopsies into six categories. The dataset was split into 70% training and 30% test sets, with external validation on additional biopsies from 2020-2024. To enhance predictive capabilities, clinician expertise was integrated with neural network predictions using Bayesian fusion to combine clinician-provided probabilities with data-driven outcomes.

Results

Our dataset comprises 5,217 biopsies categorized into six graft etiology groups. In response to findings from expert versus machine implementation analysis, Bayesian fusion of clinical expertise and NN predictions enhanced predictive performance. GraftIQ (MulticlassNN + clinical insight) achieved an overall AUC of 0.902 (95% CI: 0.884, 0.919), improving from an AUC of 0.885 using the NN alone. Robustness validated through 10-fold internal cross-validation and external validation, showed AUC improvements of 10-16% compared to conventional machine learning approaches.

Conclusion

Our multi-class neural network model demonstrates high accuracy in predicting common causes of graft pathology. Through the integration of clinician expertise, we observed an improvement in its performance, affirming the effectiveness of GraftIQ as a valuable clinical decision support tool.

Availability of code

https://github.com/divya031090/multiclassNN
Ayahuasca-Inspired DMT/HAR Formulation Reduces Brain Differentiation Between Self and Other Faces
Authors: Suay Dila , Aicher Helena D. , Kometer Micheal , Mueller Michael J. , Caflisch Luzia , Hempe Alexandra , Steinhart Camilla P. , Elsner Claudius , Wicki Ilhui A. , Müller Jovin , Meling Daniel , Dornbierer Dario A. , Scheidegger Milan , Bottari Davide
Published: November 2024

Background

Psychedelics are known to profoundly alter perception and self-referential processing, yet their specific effects on face recognition—a key aspect of social cognition—remain underexplored.

Objective

This study investigates the effects of an ayahuasca-inspired novel DMT/HAR (N,N-dimethyltryptamine/Harmine) formulation and Harmine alone on face recognition and self-referential processing, as measured by event-related potentials (ERPs).

Methods

In a within-subject, double-blind, placebo-controlled design, 31 healthy male participants underwent EEG recording during a visual oddball task involving Self, Familiar, and Unknown Faces. The study compared the effects of a DMT/HAR formulation, harmine alone, and placebo on key visual ERP components: P1, N170, and P300.

Results

DMT/HAR increased P1 amplitude and decreased N170 amplitude across all face categories, indicating enhanced early visual processing and disrupted face structural encoding. DMT/HAR also reduced P300 amplitude specifically for self-faces, diminishing neural differentiation between self and other faces.

Conclusion

The DMT/HAR formulation significantly blurs the neural distinction between self and other faces, suggesting a potential mechanism by which psychedelics diminish attentional focus on self-referential information, thereby enhancing empathy and unity. These insights into serotonergic modulation of face recognition could inform therapeutic strategies for disorders characterized by altered self-processing.
Primary Care Providers’ Perspectives on Receiving Tier 1 Genomic Results from a National Study – the Million Veteran Program Return Of Actionable Results (MVP-ROAR) Study
Authors: Johannsen Anna L. , Danowski Morgan E. , Sitter Kailyn E. , Preys Charlene L. , Gerety Haley C. , Brunette Charles A. , Christensen Kurt D. , Gaziano J. Michael , Knowles Joshua W. , Muralidhar Sumitra , Sturm Amy C. , Sun Yan V. , Whitbourne Stacey B. , Yi Thomas ,   the VA Million Veteran Program, Vassy Jason L.
Published: November 2024

Background

Patients are increasingly obtaining genetic health information and integrating it into their care with the help of their primary care provider (PCP). However, PCPs may not be adequately prepared to effectively utilize genetic results . Across the VA health system, the Million Veteran Program-Return of Actionable Results-Familial Hypercholesterolemia (MVP-ROAR) study clinically confirms and returns genetic results associated with familial hypercholesterolemia (FH), identified in a national biobank program.

Methods

PCPs who received their patient’s genetic results through the MVP-ROAR Study were invited to participate in semi-structured interviews, which explored PCPs’ familiarity with FH, how the results impacted medical management, and suggestions for process improvement. Interviews were transcribed and analyzed using directed content analysis and constant comparison methods to identify key themes.

Results

Interviews with nine PCPs revealed varied levels of familiarity with genetic testing and FH. Most PCPs did not distinguish FH from common high cholesterol issues and already used similar treatment approaches. Many PCPs did not recall receiving results from the MVP-ROAR Study. Alerts in medical records were deemed effective for communicating results. PCPs valued genetics in informing patient care and identifying at-risk family members but noted several implementation barriers, such as additional workload and unclear medical management benefits. Recommendations for improving results disclosure included simplifying the genetic testing report and associated support documents.

Conclusion

The study represents the first investigation into PCPs’ experiences with receiving genetic test results from a biobank linked to a national healthcare system. Results suggest that PCPs generally view genetic testing as beneficial, though they may not significantly alter medical management. PCPs expressed that integrating genetics into routine care may be burdensome and require additional training, which may not be practical. The study underscores the need for accessible genetic information, which could be aided by specialized support roles or different clinical specialties assisting with incorporating genetic results into patient care.
Single cells can resolve graded stimuli
Authors: Kramar Mirna , Hahn Lauritz , Walczak Aleksandra M , Mora Thierry , Coppey Mathieu
Published: November 2024

Cells use signalling pathways as windows into the environment to gather information, transduce it into their interior, and use it to drive behaviours. MAPK (ERK) is a highly conserved signalling pathway in eukaryotes, directing multiple fundamental cellular behaviours such as proliferation, migration, and differentiation, making it of few central hubs in the signalling circuitry of cells. Despite this versatility of behaviors, population-level measurements have reported low information content (< 1 bit) relayed through the ERK pathway, rendering the population barely able to distinguish the presence or absence of stimuli. Here, we contrast the information transmitted by a single cell and a population of cells. Using a combination of optogenetic experiments, data analysis based on information theory framework, and numerical simulations we quantify the amount of information transduced from the receptor to ERK, from responses to singular, brief and sparse input pulses. We show that single cells are indeed able to resolve between graded stimuli, yielding over 2 bit of information, however showing a large population heterogeneity.
Aridity and coexistence with vascular plants determine the dynamics of coastal dune bryophyte communities
Authors: Varela Z. , Chozas S. , Dias S. Lobo , Giráldez P. , Monteiro J. , Branquinho C. , Hortal J.
Published: November 2024

The bryophyte communities of Atlantic coastal dunes help stabilising these habitats by promoting nutrient fixation, contributing to soil consolidation and enhancing water retention. Because of climate change and sea level rise, negative impacts on this dune vegetation have already been recorded, including habitat loss, shifts in species distribution and the spread of invasive bryophyte species. Moreover, in this stressful environment, biotic interactions may play a key in shaping plant diversity at these scales. We characterised coastal dune vegetation in 32 sampling sites along a latitudinal aridity gradient across the western Iberian Atlantic. We aimed to assess the potential interactions among moss species and between mosses and vascular plants, and analyse their relationship with abiotic factors to explain the community dynamics of dune bryophytes, and forecast how these communities may respond to climate change. Our results showed that the moss community is mainly influenced by aridity and temperature, with biotic interactions playing a minor, yet significant, role. As aridity increases, moss cover in these dune environments will decrease, and interactions with other plants are unlikely to compensate for this decline, thus in a climate change scenario we expect a decrease in coastal bryophyte community as well as the ecosystem services they provide; simultaneously the spread of the alien moss speciesCampylopus introflexus, linked to lower aridity, may also slow down. Consequently, the changing climate will shift optimal conditions for moss species to higher latitudes, pushing competition further north
Association between Accelerometer-Measured Irregular Sleep Duration and Longitudinal Changes in Body Mass Index in Older Adults
Authors: Kianersi Sina , Potts Kaitlin S , Wang Heming , Sofer Tamar , Noordam Raymond , Rutter Martin , Redline Susan , Huang Tianyi
Published: November 2024

Irregular sleep duration may disrupt circadian rhythms and contribute to metabolic, behavioral, and mood changes, potentially increasing the risk for obesity. However, quantitative data on the relationship between sleep duration irregularity and weight change are lacking. In this prospective study, we analyzed data from 10,572 participants (mean age: 63 years) in the UK Biobank who wore accelerometers for a week between 2013-2015 and had two body mass index (BMI; kg/m2) measurements on average 2.5 years apart. Irregular sleep duration was assessed by the within-person standard deviation (SD) of 7-night accelerometer-measured sleep duration. Participants with sleep duration SD >60 minutes versus ≤30 minutes had 0.24 kg/m2(95% CI: 0.08, 0.40) higher BMI change (kg/m2), standardized to three-year intervals, and 80% (95% CI: 1.28, 2.52) higher risk for incident obesity, after adjusting for sociodemographic factors, shift work, and baseline BMI or follow-up period (p-trend<0.02 for both). These associations remained consistent after adjusting for lifestyle, comorbidities, and other sleep factors, including sleep duration. Age, sex, baseline BMI, and genetic predisposition to higher BMI (measured with a polygenic risk score) did not appear to modify the association. Since irregular sleep duration is common, trials of interventions targeting sleep irregularity might lead to new public health strategies that tackle obesity.
Somatic mutation and selection at epidemiological scale
Authors: Lawson Andrew R. J. , Abascal Federico , Nicola Pantelis A. , Lensing Stefanie V. , Roberts Amy L. , Kalantzis Georgios , Baez-Ortega Adrian , Brzozowska Natalia , El-Sayed Moustafa Julia S. , Vaitkute Dovile , Jakupovic Belma , Nessa Ayrun , Wadge Samuel , Paterson Anna L. , Rassl Doris M. , Alcantara Raul E. , O’Neill Laura , Widaa Sara , Austin-Guest Siobhan , Neville Matthew D. C. , Przybilla Moritz J. , Cheng Wei , Morra Maria , Sykes Lucy , Mayho Matthew , Müller-Sienerth Nicole , Williams Nick , Alexander Diana , Harvey Luke M. R. , Clarke Thomas , Byrne Alex , Blundell Jamie R. , Young Matthew D. , Mahbubani Krishnaa T. A. , Saeb-Parsy Kourosh , Martin Hilary C. , Stratton Michael R. , Campbell Peter J. , Rahbari Raheleh , Small Kerrin S. , Martincorena Iñigo
Published: November 2024

As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations (1–10. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq)11, a duplex sequencing method with error rates <5 errors per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 49 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.
Quality of vaccination-induced T cell responses is conveyed by polyclonality and high, but not maximum, antigen receptor avidity
Authors: Kocher Katharina , Drost Felix , Tesfaye Abel Mekonnen , Moosmann Carolin , Schuelein Christine , Grotz Myriam , D'Ippolito Elvira , Graw Frederik , Spriewald Bernd , Busch Dirk H. , Bogdan Christian , Tenbusch Matthias , Schubert Benjamin , Schober Kilian
Published: November 2024

While the quantity of vaccination-induced T cells represents a routine immunogenicity parameter, the quality of such responses is poorly understood. We here report on a clinical cohort of 29 human healthy individuals who received three mRNA vaccinations against SARS-CoV-2 before any breakthrough infection. We characterized the magnitude, phenotype and clonal composition of CD8 T cell responses against 16 epitope specificities by ELISpot, flow cytometry as well as single-cell RNA, TCR and surface protein sequencing. To test the functionality of identified clonotypes, 106 T cell receptors (TCR) from five epitope-specific repertoires were re-expressed and tested for peptide sensitivity. While recruited repertoires were overall enriched for high-avidity TCRs, differential clonal expansion was not linked to fine avidity differences. Instead, maintenance of polyclonality ensured robustness in counteracting mutational escape of epitopes. Our findings on the induction and maintenance of high-functionality polyclonal T cell repertoires shed light on T cell quality as a neglected criterion in the assessment of vaccine immunogenicity.
Hydrophobic tails enable diverse functions of the extracellular chaperone clusterin
Authors: Yuste-Checa Patricia , Carvajal Alonso I. , Mi Chenchen , Paatz Sarah , Ulrich Hartl F. , Bracher Andreas
Published: November 2024

Clusterin, a conserved secretory glycoprotein abundant in blood plasma and cerebrospinal fluid, functions as a molecular chaperone and apolipoprotein (Wyatt et al. 2013, Raulin et al. 2022). Dysregulation of clusterin is linked to late-onset Alzheimer’s disease, cardiovascular pathology and cancer (Rohne et al. 2016, Satapathy and Wilson 2021, Wilson et al. 2023). Despite its prominent role in extracellular proteostasis, the chaperone mechanism of clusterin has remained unclear. Here we present crystal structures of human clusterin, revealing a discontinuous three-domain architecture. Structure-based mutational analysis demonstrated that two intrinsically disordered, hydrophobic peptide tails enable diverse clusterin activities. Resembling the N-terminal substrate binding regions of so-called small heat shock proteins, these sequences mediate clusterin’s chaperone function in suppressing amyloid-β, tau and α-synuclein aggregation. In conjunction with highly conserved surface areas, the tail segments also participate in clusterin binding to very low density lipoprotein receptor (VLDLR) and cellular uptake. Moreover, the disordered tails cooperate with an adjacent amphipathic helix in lipoprotein formation, but remain accessible for chaperone function in the lipoprotein complex. The remarkable versatility of these sequences allows clusterin to function alone or bound to lipid in maintaining solubility of aberrant extracellular proteins and facilitating their clearance by endocytosis and lysosomal degradation.
The global dispersal of visceral leishmaniasis occurred within human history
Authors: Reis-Cunha João Luís , Grace Cooper Alastair , Ahmed Sophia , Harnqvist Simon E. , Lynch Cián M. , Boité Mariana Côrtes , Barcellos Gabrielle , Lachaud Laurence , Bastien Patrick , Munt Harry , Mottram Jeremy C. , Cupolillo Elisa , Jeffares Daniel C.
Published: November 2024

TheLeishmania donovanispecies complex (LdSC) causes visceral leishmaniasis (VL), is present in Africa, Europe, the Middle East, Asia and the Americas, and causes 20-40,000 fatalities per year. Previous analyses concluded that dispersal of this species complex occurred 1-10 million years ago. Using updated methods and data, we show that a ten-thousand year old East African population dispersed globally only within the last 2,000 years, consistent with human migration, war and colonisation as driving factors.
Consistent hierarchies of single-neuron timescales in mice, macaques and humans
Authors: Zeisler Zachary R , Love Marques , Rutishauser Ueli , Stoll Frederic M , Rudebeck Peter H
Published: November 2024

The intrinsic timescales of single neurons are thought to be hierarchically organized across the cortex. This conclusion, however, is primarily based on analyses of neural responses from macaques. Whether hierarchical variation in timescales is a general brain organizing principle across mammals remains unclear. Here we took a cross-species approach and estimated neuronal timescales of thousands of single neurons recorded across multiple areas in mice, monkeys, and humans using a task-agnostic method. We identify largely consistent hierarchies of timescales in frontal and limbic regions across species: hippocampus had the shortest timescale whereas anterior cingulate cortex had the longest. Within this scheme, variability across species was found, most notably in amygdala and orbitofrontal cortex. We show that variation in timescales is not simply related to differences in spiking statistics nor the result of cytoarchitectonic features such as cortical granularity. Thus, hierarchically organized timescales are a consistent organizing principle across species and appear to be related to a combination of intrinsic and extrinsic factors.
Sequence clustering with PaSiMap in Jalview
Authors: Morell Thomas , Procter James , Barton Geoffrey J. , Diederichs Kay , Mayans Olga , Fleming Jennifer R.
Published: November 2024

Pairwise similarity mapping, implemented in the software PaSiMap, can be used as an alternative to principal component analysis (PCA) to analyse protein-sequence relationships. It provides the advantage of distinguishing between systematic and random differences in the dataset. Here, we present a protocol to use PaSiMap inside Jalview. You will be guided through the installation and use of the required software. Furthermore, we present an R script to prepare publication-ready graphs of the obtained data and aid in the subsequent data analysis.
Metabolic Control of Glycosylation Forms for Establishing Glycan-Dependent Protein Interaction Networks
Authors: Liu Xingyu , Yi Li , Lin Zongtao , Chen Siyu , Wang Shunyang , Sheng Ying , Lebrilla Carlito B. , Garcia Benjamin A. , Xie Yixuan
Published: November 2024

Protein-protein interactions (PPIs) provide essential insights into the complex molecular mechanisms and signaling pathways within cells that regulate development and disease-related phenotypes. However, for membrane proteins, the impact of various forms of glycosylation has often been overlooked in PPI studies. In this study, we introduce a novel approach, glycan-dependent affinity purification followed by mass spectrometry (GAP-MS), to assess variations in PPIs for any glycoprotein of interest under different glycosylation conditions. As a proof of principle, we selected four glycoproteins—BSG, CD44, EGFR, and SLC3A2—as baits to compare their co-purified partners across five metabolically controlled glycan conditions. The findings demonstrate the capability of GAP-MS to identify PPIs influenced by altered glycosylation states, establishing a foundation for systematically exploring the Glycan-Dependent Protein Interactome (GDPI) for other glycoproteins of interest.
Directed insulin secretion occurs at precise cortical regions with optimal ELKS content that are devoid of microtubules
Authors: Fye Margret , Sangowdar Pranoy , Jaythilake Anissa , Noguchi Pi’ilani , Gu Guoqiang , Kaverina Irina
Published: November 2024

To maintain normal blood glucose levels, pancreatic beta cells secrete insulin into the bloodstream at specialized regions at the cell periphery, often called secretion hot spots. While many secretory machinery components are located all over the cell membrane, directed secretion relies on distinct cortical patches of the scaffolding protein ELKS and the microtubule (MT)-anchoring protein LL5β. However, using TIRF microscopy of intact mouse islets to precisely localize secretion events within ELKS/LL5β patches, we now show that secretion is restricted to only 5% of ELKS/LL5β patch area. Moreover, the majority of secretion occurs at the margins of ELKS patches. This suggests that additional factor(s) must be responsible for hot spot definition. Because the MT cytoskeleton plays a regulatory role in the insulin secretion process via both delivery and removal of secretory granules from the secretion sites, we test whether local MT organization defines secretory activity at hot spots. We find that the majority of secretion events occur at regions devoid of MTs. Based on our findings, we present a model in which local MT disassembly and optimal ELKS content are strong predictors of directed insulin secretion.