bluuebunny/crossref_metadata_2025 huggingface dataset:
Strengthening Deep-learning Models for Intracranial Hemorrhage Detection: Strongly Annotated Computed Tomography Images and Model Ensembles
Authors: Kang Dong-Wan , Park Gi-Hun , Ryu Wi-Sun , Schellingerhout Dawid , Kim Museong , Kim Yong Soo , Park Chan-Young , Lee Keon-Joo , Han Moon-Ku , Jeong Han-Gil , Kim Dong-Eog
Published: August 2023

Multiple attempts at intracranial hemorrhage (ICH) detection using deep-learning techniques have been made and plagued with clinical failures. Most studies for ICH detection have insufficient data or weak annotations. We sought to determine whether a deep-learning algorithm for ICH detection trained on a strongly annotated dataset outperforms that trained on a weakly annotated dataset, and whether a weighted ensemble model that integrates separate models trained using datasets with different ICH subtypes is more accurate. We used publicly available brain CT scans from the Radiological Society of North America (27,861 CT scans, 3,528 ICHs) and AI-Hub (53,045 CT scans, 7,013 ICHs) for training datasets. For external testing, 600 CT scans (327 with ICH) from Dongguk University Medical Center and 386 CT scans (160 with ICH) from Qure.ai were used. DenseNet121, InceptionResNetV2, MobileNetV2, and VGG19 were trained on strongly and weakly annotated datasets and compared. We then developed a weighted ensemble model combining separate models trained on all ICH, subdural hemorrhage (SDH), subarachnoid hemorrhage (SAH), and small-lesion ICH cases. The final weighted ensemble model was compared to four well-known deep-learning models. Six neurologists reviewed difficult ICH cases after external testing. InceptionResNetV2, MobileNetV2, and VGG19 models outperformed when trained on strongly annotated datasets. A weighted ensemble model combining models trained on SDH, SAH, and small-lesion ICH had a higher AUC than a model only trained on all ICH cases. This model outperformed four well-known deep-learning models in terms of sensitivity, specificity, and AUC. Strongly annotated data are superior to weakly annotated data for training deep-learning algorithms. Since no model can capture all aspects of a complex task well, we developed a weighted ensemble model for ICH detection after training with large-scale strongly annotated CT scans. We also showed that a better understanding and management of cases challenging for AI and human is required to facilitate clinical use of ICH detection algorithms.

Key Points

QuestionCan a weighted ensemble method and strongly annotated training datasets develop a deep-learning model with high accuracy to detect intracranial hemorrhage?

FindingsA deep-learning algorithm for detecting ICH trained with a strongly annotated dataset outperformed models trained with a weakly annotated dataset. After ensembling separate models that were trained with only SDH, SAH, and small-lesion ICH, a weighted ensemble model had a higher AUC.

MeaningThis study suggests that to enhance the performance of deep-learning models, researchers should consider the distinct imaging characteristics of each hemorrhage subtype and use strongly annotated training datasets.
“Someone who hates themselves doesn’t come for their drugs”:Experiences of Mental Health Along the HIV Care Continuum in South-Central, Uganda
Authors: West Nora S. , Ddaaki William , Murray Sarah M. , Nakyanjo Neema , Isabirye Dauda , Nakubulwa Rosette , Nalugoda Fred , Surkan Pamela J. , Hutton Heidi E. , Kennedy Caitlin E.
Published: August 2023

Introduction

Poor mental health occurs more frequently among people living with HIV. Understanding what mental health problems occur and at what point during the continuum of HIV care is critical to ensure these problems are identified and appropriately addressed. We explored how mental health is experienced along the HIV care continuum in Rakai, Uganda.

Methods

We conducted qualitative semi-structured in-depth interviews with 20 adults living with HIV and 10 health workers from March to December 2020. Interviews followed a timeline approach. Responses were analyzed using content analysis.

Results

At the time of HIV diagnosis, nearly all participants described a range of strong emotions, including shock, fear and intense worry. Most participants described continued fear and intense worry leading up to, and at the time of, ART initiation. However, they said these emotions often subside after ART is initiated and viral suppression is achieved. Across interviews and at multiple points of the continuum, participants discussed how fear and worry led individuals to be “thinking too much” or be in “deep thoughts” and experience self-hatred. Individuals who stopped taking ART were thought to have more severe mental health problems (“madness”, psychosis, suicidality). Participants were divided about the mental health of persons who returned to care after disengagement.

Conclusion

In this setting, mental health problems experienced by people living with HIV are dynamic across the care continuum. With expanded HIV testing campaigns and Universal Test and Treat policies, targeted interventions for psychosocial support at the time of testing and ART initiation remain critical.
Quantification of blood glial fibrillary acidic protein using a second-generation microfluidic assay. Validation and comparative analysis with two established assays
Authors: Fazeli Badrieh , Gómez de San José Nerea , Jesse Sarah , Senel Makbule , Oeckl Patrick , Erhart Deborah K , Otto Markus , Halbgebauer Steffen , Tumani Hayrettin
Published: August 2023

Background

Increased levels of glial fibrillary acidic protein (GFAP) in blood have been identified as a valuable biomarker for some neurological disorders, such as Alzheimer’s disease and multiple sclerosis. However, most blood GFAP quantifications so far were performed using the same bead-based assay, and to date a routine clinical application is lacking.

Methods

In this study, we validated a novel second-generation (2ndgen) Ella assay to quantify serum GFAP. Furthermore, we compared its performance with a bead-based single molecule array (Simoa) and a homemade blood GFAP assay in a clinical cohort of neurological diseases, including 210 patients.

Results

Validation experiments resulted in an intra-assay variation of 10%, an inter-assay of 12%, a limit of detection of 0.9 pg/mL, a lower limit of quantification of 2.8_pg/mL, and less than 20% variation in serum samples exposed to up to five freeze-thaw cycles, 120_hours at 4 °C and room temperature. Measurement of the clinical cohort using all assays revealed the same pattern of GFAP distribution in the different diagnostic groups. Moreover, we observed a strong correlation between the 2ndgen Ella and Simoa (r=0.91 (95% CI: 0.88 - 0.93), p<0.0001) and the homemade immunoassay (r=0.77 (95% CI: 0.70 - 0.82), p<0.0001).

Conclusions

Our results demonstrate a high reliability, precision and reproducibility of the 2ndgen Ella assay. Although a higher assay sensitivity for Simoa was observed, the new microfluidic assay might have the potential to be used for GFAP analysis in daily clinical workups due to its robustness and ease of use.

What is already known on this topic

Blood glial fibrillary acidic protein (GFAP) levels are an emerging biomarker for diagnosing, prognosis and treatment monitoring for AD, MS and other neurological disorders. However, so far, the application in clinical routine remains a challenge.

What this study adds

This study validated a novel, easy-to-use second-generation microfluidic assay for the quantitative measurement of blood GFAP. Moreover, its performance was compared to two other GFAP immunoassays, including single molecule array.

How this study might affect research, practice or policy

This study proved the reliability, precision and reproducibility of the novel second-generation microfluidic assay, which might be more easily implemented in daily clinical routine analyses and therefore facilitates the application of GFAP as a biomarker for neurological diseases.
An After-Action Review of COVID-19 Cases and Mitigation Measures at US Mission India, March 2020-July 2021
Authors: Singh Jaspreet , Yadav Rajesh , Robinson Samantha , Vanelli Mark , Nyendak Melissa , Desai Meghna
Published: August 2023

Introduction

Between March 2020-June 2021, over 30 million COVID-19 cases were reported in India. We assessed the COVID-19 response across the US Mission India (US Embassy New Delhi, US Consulates – Mumbai, Hyderabad, Chennai and Kolkata) to plan future mitigation efforts and fill gaps in knowledge about COVID-19 transmission in a unique community like the US Mission.

Method

We described COVID-19 mitigation activities undertaken by the five US Mission India posts and conducted a secondary analysis of case investigation and contact tracing program data collected by the Health Unit from March 2020–July 2021.

Results

US Mission in India, in collaboration with multiple internal agencies, initiated COVID-19 mitigation activities in March 2020. Activities included educational sessions, training for infection prevention and control, health and safety assessments, and the development of standard operating procedures (SOPs). The Health Unit and US CDC India office initiated COVID-19 case investigations and conducted contact tracing. Between March 2020-July 2021, 636 COVID-19 cases (72% males), including 48 clusters (size range 2-10 cases), were reported. Overall case fatality rate was 1.5%. Of case patients, 82% (523) were Indians, and 18% (113) were Americans. On presentation, 22% (138/625) of cases were asymptomatic. The median time from symptom onset to notification to the Health Unit was three days (Interquartile range 1-5). The Health Unit identified 2,484 contacts (positivity rate 25%). Frequency of case presentation in the US Mission India closely resembled the pattern of COVID-19 waves in India. The attack rates ranged over the time period between 10-19%, the highest at 19% in Delhi.

Conclusions

COVID-19 mitigation strategies were implemented in collaboration with multiple agencies and helped prevent the transmission of COVID-19 and large COVID-19 clusters in the US Mission India.
Trends of enterovirus D68 concentrations in wastewater in two California communities parallel trends of statewide confirmed cases, February 2021 – April 2023
Authors: Boehm Alexandria B. , Wadford Debra A. , Hughes Bridgette , Duong Dorothea , Chen Alice , Padilla Tasha , Wright Chelsea , Moua Lisa , Bullick Teal , Salas Maria , Morales Christina , White Bradley J. , Glaser Carol A. , Vugia Duc J. , Yu Alexander T. , Wolfe Marlene K
Published: August 2023

In this retrospective study, enterovirus D68 (EVD68) genomic RNA in wastewater solids was measured longitudinally at two California wastewater treatment plants twice per week for 26 months. EVD68 RNA was undetectable except when concentrations increased between mid-July and mid-December 2022, during which time EVD68 cases were confirmed in the state.
Lysophosphatidylcholines are associated with P-tau181 levels in early stages of Alzheimer’s Disease
Authors: Kalia Vrinda , Reyes-Dumeyer Dolly , Dubey Saurabh , Nandakumar Renu , Lee Annie J. , Lantigua Rafael , Medrano Martin , Rivera Diones , Honig Lawrence S. , Mayeux Richard , Miller Gary W. , Vardarajan Badri N.
Published: August 2023

Background

We investigated systemic biochemical changes in Alzheimer’s disease (AD) by investigating the relationship between circulating plasma metabolites and both clinical and biomarker-assisted diagnosis of AD.

Methods

We used an untargeted approach with liquid chromatography coupled to high-resolution mass spectrometry to measure exogenous and endogenous small molecule metabolites in plasma from 150 individuals clinically diagnosed with AD and 567 age-matched elderly without dementia of Caribbean Hispanic ancestry. Plasma biomarkers of AD were also measured including P-tau181, Aβ40, Aβ42, total tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Association of individual and co-expressed modules of metabolites were tested with the clinical diagnosis of AD, as well as biologically-defined AD pathological process based on P-tau181 and other biomarker levels.

Results

Over 4000 metabolomic features were measured with high accuracy. First principal component (PC) of lysophosphatidylcholines (lysoPC) that bind to or interact with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AHA) was associated with decreased risk of AD (OR=0.91 [0.89-0.96], p=2e-04). Restricted to individuals without anAPOEε4 allele(OR=0.89 [0.84-0.94], p= 8.7e-05), the association remained. Among individuals carrying at least oneAPOEε4allele, PC4 of lysoPCs moderately increased risk of AD (OR=1.37 [1.16-1.6], p=1e-04). Essential amino acids including tyrosine metabolism pathways were enriched among metabolites associated with P-tau181 levels and heparan and keratan sulfate degradation pathways were associated with Aβ42/Aβ40 ratio reflecting different pathways enriched in early and middle stages of disease.

Conclusions

Our findings indicate that unbiased metabolic profiling can identify critical metabolites and pathways associated with β-amyloid and phosphotau pathology. We also observed anAPOEε4dependent association of lysoPCs with AD and that biologically-based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.

Graphical Abstract
Feasibility of FFR-CT and CCTA features to predict the hemodynamic changes of high take-off coronary artery
Authors: Ni Jiong , Cheng Shuihua , Wang Peijun , Ge Chenjin
Published: August 2023

Background

High take-off coronary artery (HTCA) is a neglected coronary artery anomaly with debated clinical importance. Determining the pathophysiological significance of this anomaly remains challenging. The aim of this study was to explore clinical symptoms, anatomic features based on CCTA and FFR-CT which will help to predict significant hemodynamic change of HTCA.

Methods

This retrospective study recruited 72 patients with HTCA undergoing CCTA and invasive coronary angiography. Demographic, clinical characteristics, anatomic and functional features based on CCTA were collected to identified independent risk factors by multivariate logistical analysis. Receiver operating characteristic curve analysis was performed to determine the predictive accuracy of these factors.

Results

Chest pain and the angle at the HTCA were identified as independent risk factors (p=0.005, p=0.002) associated hemodynamical significant HTCA. The value of FFR-CT was consistency with FFR in HTCA patients (VIF=73.811). The index of FFR-CT had significantly larger AUC than the index of chest pain (p=0.003) and similar AUC with the angel at the HTCA (p=0.059). Compared with combined index of angle at HTCA plus chest pain, FFR-CT had a larger AUC (p=0.000). The similar AUC was found between FFR-CT and the combined index of chest pain, angle at the HTCA plus FFR-CT (p=0.2359).

Conclusions

FFR-CT, chest pain and angel at HTCA based on CCTA played a great role to predict significant hemodynamic changes of HTCA. FFR-CT had a superior diagnostic performance to predict abnormal hemodynamic changes in patients with HTCA.
Knowledge, Attitudes and Demand Toward Cardiovascular Polygenic Risk Testing in Clinical Practice: Cross-Sectional Survey of Patients
Authors: Brar Shanjot , Townsend Jared , Phulka Joban , Halperin Laura , Liew Janet , Parker Jeremy , Brunham Liam R. , Laksman Zachary
Published: August 2023

Background

The goal of this study was to assess patients’ prior exposure and current level of knowledge of polygenic risk scores (PRSs). We also explored reactions to receiving a high-risk or low-risk score, and gauged the overall attitudes and demand patients have with regards to PRSs.

Methods

We developed an online investigator-designed survey based on existing validated tools and previously designed surveys on genetic testing. There were two versions of the survey, one including a hypothetical high-risk PRS and one with a low-risk PRS. We administered the survey among patients attending a specialized cardiovascular prevention clinic.

Results

A total of 226 participants responded to the survey. The study population was predominantly high-income earning, educated, and of European descent. 177 patients (79%) had never read or heard about polygenic testing. 209 patients (93%) had never discussed polygenic testing with their health care professional (HCP). 208 patients (93%) had never received polygenic testing.

The average score on the knowledge quiz was 2.47/10 [95% C.I. (2.17, 2.78)]. Participants that received a high-risk survey scored 20.52/35 [95% C.I. (16.14, 24.9)] with regards to negative emotions while low-risk survey participants scored 17.96/35 [95% C.I. (13.98, 21.94)] (p<0.001). Participants that received a high-risk survey scored 5.78/10 [95% C.I. (3.77, 7.79)] with regards to uncertainty and low-risk survey participants scored 4.34/10 [95% C.I. (2.50, 6.18)] (p<0.001). Participants that received a high-risk survey scored 12.42/15 [95% C.I. (10.43, 14.41)] for demand and low-risk survey participants scored 12.22/15 [95% C.I. (9.66, 14.78)] (p=0.549).

Conclusions

Patients have limited prior exposure and knowledge of PRSs. Compared to receiving a low-risk score, participants receiving a high-risk score have more negative emotions and feelings of uncertainty. Despite the lack of knowledge, and the high rate of negative emotions and uncertainty, demand for PRSs in cardiology practice is high and expected to increase.
Cardiac Abnormalities in Hispanic Women with Prior De Novo Hypertensive Disorders of Pregnancy
Authors: Quesada Odayme , Kulandavelu Shathiyah , Vladutiu Catherine J. , DeFranco Emily , Minissian Margo B. , Makarem Nour , Bello Natalie A. , Wong Melissa S. , Pabón Maria , Chandra Alvin A. , Avilés-Santa Larissa , Rodríguez Carlos J. , Merz C. Noel Bairey , Sofer Tamar , Hurwitz Barry E , Talavera Gregory A. , Claggett Brian L. , Solomon Scott D. , Cheng Susan
Published: August 2023

Background

Hypertensive disorders of pregnancy (HDP) are associated with longer-term maternal risks for cardiovascular disease for reasons that remain incompletely understood.

Methods

The Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a multi-center community-based cohort of Hispanic/Latino adults recruited 2008 to 2011 was used to evaluate the associations of history of de novo HDP (gestational hypertension, preeclampsia, eclampsia) with echocardiographic measures of left ventricular (LV) structure and function in Hispanic/Latina women with ≥1 prior pregnancy and the proportion of association mediated by current hypertension.

Results

The study cohort included 5,168 Hispanic/Latina women. Prior de novo HDP was reported by 724 (14%) of the women studied with an average age of 58.7 ± 9.7 years at time of echocardiogram and was associated with lower ejection fraction −0.66 (−1.21, −0.11), greater relative wall thickness (RWT) 0.09 (0, 0.18), and 1.39 (1.02, 1.89) greater odds of abnormal LV geometry after adjusting for blood pressure and other risk factors. The proportion of association mediated by current hypertension between HDP and LV ejection fraction was 0.09 (95% CI 0.03, 0.45), any abnormal LV geometry was 0.14 (0.12, 0.48), LV RWT 0.28 (0.16, 0.51), concentric LVH was 0.31 (0.19, 0.86), and abnormal LV diastolic dysfunction was 0.58 (0.26, 1.79).

Conclusions

In a large cohort of Hispanic/Latina women those with de novo HDP had detectable and measurable subclinical alterations in cardiac structure and both systolic and diastolic dysfunction that were only partially mediated by current hypertension.
Risk factors and outcomes associated with heart failure with preserved and reduced ejection fraction in persons with chronic kidney disease
Authors: Bansal Nisha , Zelnick Leila , Scherzer Rebecca , Estrella Michelle , Shlipak Michael
Published: August 2023

Background

Heart failure (HF) is associated with poor outcomes in persons with chronic kidney disease (CKD), yet there are limited data on whether outcomes differ by HF subtype. This study aimed to examine associations of incident preserved (HFpEF) versus reduced (HFrEF) ejection fraction (EF) with risk of progression to end-stage-kidney-disease (ESKD) and mortality.

Methods

We studied individuals with mild to severe CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study who were free of HF at cohort entry. Incident HF hospitalizations were adjudicated during study follow-up and classified into HFpEF (EF>50%) or HFrEF (EF<50%) based on echocardiograms performed during the hospitalization or at a research study visit within one year of the hospitalization. ESKD was defined as need for chronic dialysis or kidney transplant during follow-up. Cox proportional hazards were used to evaluate the association of time-updated HF subtype with risk of ESKD and mortality, adjusting for demographics, comorbidities and medication use.

Results

Among the 3,557 study participants without HF at cohort entry, mean age was 57 years and mean eGFR 45 ml/min/1.73 m2at baseline. Incidence rates for HFpEF and HFrEF were 0.9 (95% CI 0.8, 1.0) and 0.7 (95% CI 0.6, 0.8) per 100 person-years, respectively. Adjusted associations of incident HF with progression to ESKD were similar for HFpEF (HR 1.59, 95% CI: 1.24, 2.02) and HFrEF (HR 1.26, 95% CI: 0.93, 1.70) (test for difference p-value=0.35). The adjusted associations of HFpEF and HFrEF HF with mortality were stronger for HFrEF (HR 1.68, 95% CI: 1.34, 2.11) compared with HFpEF (HR 1.24, 95% CI: 1.00, 1.54) (test for difference p-value = 0.02).

Conclusions

In a large U.S. CKD population, the rates of HFpEF hospitalizations were greater than that of HFrEF. Both types of HF had similar associations with risk of ESKD; however, there was a stronger association of HFrEF with mortality. Prevention and treatment of both HFpEF and HFrEF should be central priorities to improve clinical outcomes in patients with CKD.
Enhancement of brain atlases with laminar coordinate systems: Flatmaps and barrel column annotations
Authors: Bolaños-Puchet Sirio , Teska Aleksandra , Hernando Juan B. , Lu Huanxiang , Romani Armando , Schürmann Felix , Reimann Michael W.
Published: August 2023

Digital brain atlases define a hierarchy of brain regions and their locations in three-dimensional Cartesian space. They provide a standard coordinate system in which diverse datasets can be integrated for visualization and analysis. Although this coordinate system has well-defined anatomical axes, it does not provide the best context to work with the complex geometries of layered brain regions such as the neocortex. To address that, we introducelaminar coordinate systemsthat consider the curvature and the laminar structure of the region of interest. These new coordinate systems consist of a principal axis, locally aligned to the vertical direction and measuring depth, and two other axes that describe a flatmap, a two-dimensional representation of the horizontal extents of layers. The main property of the flatmap is that it allows seamless mapping of information back and forth between 2D and 3D spaces, in a way consistent with the principal axis. It involves a structured dimensionality reduction where information is aggregated along depth. We propose a method to enhance brain atlases with laminar coordinate systems and flatmaps based on user specifications and define a set of metrics to characterize the quality of flatmaps. We applied our method to an atlas of rat somatosensory cortex based on Paxinos and Watson’s rat brain atlas, enhancing it with a laminar coordinate system adapted to the geometry of this region. Further, we applied our method to enhance the Allen Mouse Brain Atlas Common Coordinate Framework version 3 with a flatmap of the whole isocortex. We used this flatmap to produce new annotations of 33 individual barrels and barrel columns in the barrel cortex. Thanks to the properties of the flatmap, the resulting annotations are non-overlapping and follow the curvature of the cortex. Additionally, we introduced several applications highlighting the utility of laminar coordinate systems for data visualization and data-driven modeling. We provide a free software implementation of our methods for the benefit of the community.
Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice
Authors: Pan Allen L. , Audrain Mickael , Sakakibara Emmy , Joshi Rajeev , Zhu Xiaodong , Wang Qian , Wang Minghui , Beckmann Noam D. , Schadt Eric E. , Gandy Sam , Zhang Bin , Ehrlich Michelle E. , Salton Stephen R.
Published: August 2023

Background

Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal network that regulates late-onset Alzheimer’s disease. Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model.

Methods

AAV5-DUSP6 or AAV5-GFP (control) were stereotactically injected into the dorsal hippocampus (dHc) of female and male 5xFAD or wild type mice to overexpress DUSP6 or GFP. Spatial learning memory of these mice was assessed in the Barnes maze, after which hippocampal tissues were isolated for downstream analysis.

Results

Barnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß1-40and Aß1-42levels, and amyloid precursor protein processing enzyme BACE1, in male but not in female mice. Microglial activation and microgliosis, which are increased in 5xFAD mice, were significantly reduced by dHc DUSP6 overexpression in both males and females. Transcriptomic profiling of female 5xFAD hippocampus revealed upregulated expression of genes involved in inflammatory and extracellular signal-regulated kinase (ERK) pathways, while dHc DUSP6 overexpression in female 5xFAD mice downregulated a subset of genes in these pathways. A limited number of differentially expressed genes (DEGs) (FDR<0.05) were identified in male mice; gene ontology analysis of DEGs (p<0.05) identified a greater number of synaptic pathways that were regulated by DUSP6 overexpression in male compared to female 5xFAD. Notably, the msh homeobox 3 gene,Msx3, previously shown to regulate microglial M1/M2 polarization and reduce neuroinflammation, was one of the most robustly upregulated genes in female and male wild type and 5xFAD mice overexpressing DUSP6.

Conclusions

In summary, our data indicate that DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD.
KCC2 as a novel biomarker and therapeutic target for motoneuron degenerative disease
Authors: Sahara Khademullah C. , Bourbonnais Julien , Chaineau Mathilde M. , Castellanos-Montiel María José , Keramidis Iason , Legault Alexandra , Paquet Marie-Ève , Abrahao Agessandro , Zinman Lorne , Robertson Janice , Durcan Thomas M. , Woodin Melanie A. , Godin Antoine G. , Koninck Yves De
Published: August 2023

Hyperexcitability in cells throughout the corticospinal tract is a presymptomatic feature of amyotrophic lateral sclerosis (ALS) associated with lethal motor degeneration1–6. Disinhibition is a possible cause of this hyperexcitability, potentially implicating the central nervous system-specific potassium-chloride cotransporter, KCC2, a core regulator of the strength of GABAergic neurotransmission linked to several neurological disorders7–11. Here, we show that KCC2 is downregulated in the membrane of motor cortex neurons from post-mortem SOD1-, C9orf72- and sporadic ALS is patients. Increased protein levels of KCC2 were found in plasma and cerebral spinal fluid of ALS patients and mice harbouring the SOD1*G93A mutation. Longitudinal analysis of disease progression in both SOD1*G93A and Prp-TDP43*A315T mice revealed a decrease of KCC2 membrane levels in cortical and spinal motor neurons which were already present at the presymptomatic phase. Using KCC2-enhancing compounds, CLP290 and prochlorperazine (PCPZ) restored KCC2 membrane expression and function, delayed motor deficit onset, and extended lifespan up to two months in mutant mice. Human-derived neurons differentiated from iPSC harbouring the SOD1*G93A mutation displayed KCC2 deficits which PCPZ treatment rescued. Acute administration of KCC2 enhancers restored chloride transport in presymptomatic and symptomatic mice and reversed motor neuron hyperexcitability in awake behaving mutant mice. These findings identify KCC2 as both an early biomarker and a disease-modifying therapeutic target for ALS.
Using LLM Models and Explainable ML to Analyse Biomarkers at Single Cell Level for Improved Understanding of Diseases
Authors: Elsborg Jonas , Salvatore Marco
Published: August 2023

Single-cell RNA sequencing (scRNA-seq) technology has significantly advanced our understanding of the diversity of cells and how this diversity is implicated in diseases. Yet, translating these findings across various scRNA-seq datasets poses challenges due to technical variability and dataset-specific biases. To overcome this, we present a novel approach that employs both an LLM-based framework and explainable machine learning to facilitate generalization across single-cell datasets and identify gene signatures to capture disease-driven transcriptional changes.

Our approach uses scBERT, which harnesses shared transcriptomic features among cell types to establish consistent cell-type annotations across multiple scRNA-seq datasets. Additionally, we employ a symbolic regression algorithm to pinpoint highly relevant yet minimally redundant models and features for inferring a cell type’s disease state based on its transcriptomic profile. We ascertain the versatility of these cell-specific gene signatures across datasets, showcasing their resilience as molecular markers to pinpoint and characterize disease-associated cell types.

Validation is carried out using four publicly available scRNA-seq datasets from both healthy individuals and those suffering from ulcerative colitis (UC). This demonstrates our approach’s efficacy in bridging disparities specific to different datasets, fostering comparative analyses. Notably, the simplicity and symbolic nature of the retrieved gene signatures facilitate their interpretability, allowing us to elucidate underlying molecular disease mechanisms using these models.
Lung-innervating neurons expressingTmc3can induce broncho-constriction and dilation with direct consequences for the respiratory cycle
Authors: Kortmann Jens , Huang Kevin , Tsai Ming-Chi , Barck Kai , Jacobson Amanda , Austin Cary D , Dunlap Debra , Chalouni Cecile , Jeet Surinder , Balestrini Alessia , Storm Elaine , Wilson Mark S , Deng Lunbin , Dourado Michelle , Hackos David , Riol-Blanco Lorena , Kaminker Joshua S. , Turley Shannon J.
Published: August 2023

Sensory neurons of the vagal ganglia (VG) innervate lungs and play a critical role in maintaining airway homeostasis. However, the specific VG neurons that innervate lungs, and the mechanisms by which these neurons sense and respond to airway insults, are not well understood. Here, we identify a subpopulation of lung-innervating VG neurons defined by their expression ofTmc3. Single cell transcriptomics illuminated several subpopulations ofTmc3+sensory neurons, revealing distinctPiezo2- andTrpv1-expressing subclusters. Furthermore,Tmc3deficiency in VG neurons leads to global and subcluster specific transcriptional changes related to metabolic and ion channel function. Importantly, we show that broncho-constriction and dilation can be modulated through inhibition or activation ofTmc3+VG neurons resulting in a decrease or increase of end-expiratory lung volume, respectively. Together, our data show thatTmc3is a marker of lung-innervating neurons and may play a pivotal role in maintaining fundamental inspiratory and expiratory processes.

Significance

Harnessing the neuronal mechanisms that regulate lung function offers potential alternatives to existing corticosteroid treatment regimens for respiratory illness associated with acute bronchoconstriction including asthma, COPD, and emphysema. Our findings defineTransmembrane channel-like 3,Tmc3, as a marker of lung-innervating sensory neurons, identify distinct subpopulations ofTmc3+ neurons with unique transcriptional profiles, and show that activation or inhibition of these neurons has a significant impact on airway function. Our work highlights potential avenues of novel targeted intervention in respiratory conditions driven by dysfunctional neuronal reflexes.
The association between brain serotonin 2A receptor binding and neuroticism in healthy individuals: A Cimbi database independent replication study
Authors: Høgsted Emma S. , Beliveau Vincent , Ozenne Brice , Madsen Martin K , Svarer Claus , Dam Vibeke NH. , Johansen Annette , Fisher Patrick M. , Knudsen Gitte Moos , Frokjaer Vibe G , Sankar Anjali
Published: August 2023

Background

Using the [18F]altanserin tracer to image serotonin 2A receptors (5-HT2AR), we previously showed that there exists a positive association between cortical 5-HT2AR binding and the inward facets of neuroticism, namely depression, anxiety, self-consciousness, and vulnerability. Fairly recently, the [11C]Cimbi-36 tracer was also shown to be a suitable radioligand for imaging 5-HT2Areceptors in the human brain. In the present study, we examined whether our previously reported finding of the association between 5-HT2AR binding and the inward facets of neuroticism can be replicated in an independent sample of healthy individuals scanned using the newer [11C]Cimbi-36 tracer. Furthermore, to determine whether this association of 5-HT2AR binding with neuroticism merely reflects its known relation to stress-coping related indices such as cortisol dynamics. The present study also investigated the potential role of cortisol awakening response on the association between 5-HT2AR binding and the inward facets of neuroticism.

Methods

Sixty-nine healthy volunteers underwent a [11C]CIMBI-36 scan for the assessment of 5-HT2AR binding, completed the standardized NEO-PI-R personality questionnaire, and provided salivary samples for the determination of cortisol awakening response. A linear latent variable model (LVM) was used to examine the association between 5-HT2AR binding and the inward facets of neuroticism with adjustment for age, sex, cortisol awakening response, and MR scanner. A second latent variable model examined the potential moderating effect of cortisol awakening response on the association between 5-HT2AR binding and the inward facets of neuroticism.

Results

We replicated a positive association between 5-HT2AR binding and the inward facets of neuroticism (r=0.37, p=0.015). We saw no moderating effect of the cortisol awakening response on this association (p=0.98).

Conclusions

In an independent cohort of healthy individuals imaged with the [11C]CIMBI-36 tracer, we confirm the link between serotonin 2A receptor binding and the inward-directed facets of neuroticism that is independent of cortisol dynamics.
The evolution of autonomy from two cooperative specialists in fluctuating environments
Authors: Chen Xiaoli , Wang Miaoxiao , Luo Laipeng , Liu Xiaonan , An Liyun , Nie Yong , Wu Xiao-Lei
Published: August 2023

From microbes to humans, organisms perform numerous tasks for their survival, including food acquisition, migration, and reproduction. A complex biological task can be performed by either an autonomous organism or by cooperation among several specialized organisms. However, it remains unclear how autonomy and cooperation evolutionarily switch. For example, it remains unclear whether and how a group of cooperative specialists can evolve into an autonomous organism. Here, we address this question by experimentally evolving a mutualistic microbial consortium composed of two specialists that cooperatively degrade naphthalene. We observed that autonomous genotypes capable of performing the entire naphthalene degradation pathway evolved from two cooperative specialists and came to dominate the microbial community. This evolutionary transition was driven by the horizontal gene transfer between the two specialists. However, this evolution was exclusively observed to occur in the fluctuating environment supplied with either naphthalene or pyruvate, where mutualism and competition between the two specialists alternated. The naphthalene-supplied environment exerts selective pressure that favors the expansion of autonomous genotypes but was associated with both low cell density and low coexistence levels. In contrast, the pyruvate-supplying environment promoted the coexistence and cell density of the cooperative specialists, thereby increasing the likelihood of horizontal gene transfer. Using a mathematical model, we quantitatively demonstrate that environmental fluctuations facilitate the evolution of autonomy through HGT when the relative growth rate and carrying capacity of the cooperative specialists allow enhanced coexistence and higher cell density in the competitive environment. Together, our results demonstrate that mutualistic cooperation can evolve into autonomous organisms through direct genetic exchange under specific conditions, including the alternation of mutualism and competition in fluctuating environments in a manner frequently occurring in nature.
Alpha Oscillations Encode Bayesian Belief Updating Underlying Attentional Allocation in Dynamic Environments
Authors: Li Siying , Seger Carol A. , Liu Meng , Dong Wenshan , Liu Wanting , Chen Qi
Published: August 2023

In a dynamic environment, expectations of the future constantly change based on updated evidence and affect the dynamic allocation of attentional resources.To further investigate the neural mechanisms underlying efficient allocation of attention, we employed a modified Central Cue Posner paradigm in which the probability of cues being valid (that is, accurately indicated the upcoming target location) was manipulated. The proportion of attentional resources allocated to the cued location (α), which was sensitive to precision of predictions on previous trials, was estimated using a hierarchical Bayesian model and was included as a regressor in the analyses of electrophysiological (EEG) data. Our results revealed that before the target appeared, the attentional modulation of alpha oscillations (8∼13Hz) for high-certainty cues (88% valid) were significantly predicted by the attentional resources measure (α). This relationship was not observed under low-certainty conditions (69% and 50% valid cues). After the target appeared, the attentional resources measure (α) correlated with alpha band oscillations only in the valid cue condition and not in the invalid condition. These results provide new insights on how trial-by-trial Bayesian belief updating relates to alpha band encoding environmentally-sensitive allocation of visual spatial attention.
Visual adaptation of opsin gene expression to the aquatic environment in sea turtles
Authors: Terai Yohey , Osada Misa , Kondo Satomi , Tokita Masayoshi
Published: August 2023

Several vertebrate taxa, cetaceans, sirenia, pinnipeds, and sea snakes have adapted to the marine aquatic environment. In the species of these taxa, marine adaptation has resulted in shifts in the absorption spectra of opsin pigments and/or the degeneration or duplication of opsin genes. Thus, marine adaptation has strongly affected the evolution of opsins. In sea turtles, however, the effect of adaptation from freshwater to marine environments on opsin evolution has not been studied. In this study, we determined the high-throughput RNA sequences extracted from eyes of two sea turtles (green turtle:Chelonia mydas, loggerhead:Caretta caretta) and two freshwater turtle species (three-keeled pond turtle:Mauremys reevesii, softshell turtle:Pelodiscus sinensis) and investigated the amino acid evolution and expression of the opsin gene. We found that most of the sea turtle lineage-specific amino acid substitutions did not alter amino acid properties and did not include previously known substitutions for turning absorption spectra of opsin pigments, suggesting no adaptive amino acid substitutions in the opsins during marine adaptation in sea turtles. Instead, the blue-sensitive opsin (SWS2) gene expression was higher in sea turtles than in freshwater turtles. These results suggest that sea turtles may have adapted their vision to the blue light-rich marine environment by increasingSWS2expression.
Spatiotemporal dynamics of cytokines expression dictate fetal liver hematopoiesis
Authors: Peixoto Marcia Mesquita , Soares-da-Silva Francisca , Bonnet Valentin , Ronteix Gustave , Santos Rita Faria , Mailhe Marie-Pierre , Feng Xing , Pereira João Pedro , Azzoni Emanuele , Anselmi Giorgio , de Bruijn Marella , Baroud Charles N. , Pinto-do-Ó Perpétua , Cumano Ana
Published: August 2023

During embryogenesis, yolk-sac and intra-embryonic-derived hematopoietic progenitors, comprising the precursors of adult hematopoietic stem cells, converge into the fetal liver. With a new staining strategy, we defined all non-hematopoietic components of the fetal liver and found that hepatoblasts are the major producers of hematopoietic growth factors. We identified mesothelial cells, a novel component of the stromal compartment, producing Kit ligand, a major hematopoietic cytokine.

A high-definition imaging dataset analyzed using a deep-learning based pipeline allowed the unambiguous identification of hematopoietic and stromal populations, and enabled determining a neighboring network composition, at the single cell resolution.

Throughout active hematopoiesis, progenitors preferentially associate with hepatoblasts, but not with stellate or endothelial cells. We found that, unlike yolk sac-derived progenitors, intra-embryonic progenitors respond to a chemokine gradient created by CXCL12-producing stellate cells. These results revealed that FL hematopoiesis is a spatiotemporal dynamic process, defined by an environment characterized by low cytokine concentrations.
Cognitive effort increases the intensity of rewards
Authors: Wahab Mejda , Mead Nicole L. , Desmercieres Stevenson , Lardeux Virginie , Dugast Emilie , Baumeister Roy F. , Solinas Marcello
Published: August 2023

An important body of literature suggests that exerting intense cognitive effort causes mental fatigue and can lead to unhealthy behaviors such as indulging in high-calorie food and taking drugs. Whereas this effect has been mostly explained in terms of weakening cognitive control, cognitive effort may also bias behavioral choices by amplifying the hedonic and emotional impact of rewards. We report parallel findings with animals and humans supporting this hypothesis. In rats, exerting cognitive effort immediately before access to cocaine self-administration significantly increased drug intake. In addition, exerting cognitive effort increased the psychostimulant effect of cocaine. The effects of cognitive effort on addiction-related behaviors were eliminated and even reversed when animals could rest in their home-cage for 2-4h before access to cocaine self-administration. Among humans, we found that expending cognitive effort increased consumption of tasty (but unhealthy) food by increasing the hedonic enjoyment of consuming the food. In addition, the effects were specific for emotionally relevant stimuli (i.e., food rewards) and did not generalize to judgment about neutral objects. Altogether these data suggest that intense cognitive effort can increase the perceived intensity of rewards and lead to their overconsumption. This effect may contribute to bad decision making induced by excessive cognitive effort and make people more vulnerable to indulge in unhealthy behaviors such as use of addictive drugs.

Significance Statement

People dieting or recovering from addiction frequently report that relapses occur during periods of stress and mental fatigue. Multiple processes may contribute to this, including beliefs about the stress-reducing effects of drugs, beliefs about one’s inability to continue resisting, and lack of energy needed to sustain resistance. Here, we suggest an additional possible process: during a state of mental fatigue, rewards become all the more satisfying, thereby also increasing subsequent desire for them. We report two lines of experiments, one with rats and one with human participants, to show that intense cognitive effort leads to increased enjoyment of rewards and hence increased consumption.
Osterix-driven LINC complex disruptionin vivodiminishes bone microarchitecture in 8-week male mice but not after 6-week voluntary wheel running
Authors: Birks Scott , Howard Sean , O’Rourke Caroline , Thompson William R , Lau Anthony , Uzer Gunes
Published: August 2023

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex is a crucial connective component between the nuclear envelope and the cytoskeleton involving various cellular processes including nuclear positioning, nuclear architecture, and mechanotransduction. How LINC complexes regulate bone formationin vivo, however, is not well understood. To start bridging this gap, here we created a LINC disruption murine model using transgenic mice expressing Cre recombinase enzyme under the control of the Osterix (Osx-Cre) which is primarily active in pre-osteoblasts and floxed Tg(CAG-LacZ/EGFP-KASH2) mice. Tg(CAG-LacZ/EGFP-KASH2) mice contain a lox-STOP-lox flanked LacZ gene which is deleted upon cre recombination allowing for the overexpression of an EGFP-KASH2 fusion protein. This overexpressed protein disrupts endogenous Nesprin-Sun binding leading to disruption of LINC complexes. Thus, crossing these two lines results in aOsx-drivenLINCdisruption (ODLD) specific to pre-osteoblasts. In this study, we investigated how this LINC disruption affects exercise induced bone accrual. ODLD cells had decreased osteogenic and adipogenic potentialin vitrocompared to non-disrupted controls and sedentary ODLD mice showed decreased bone quality at 8-weeks. Upon access to a voluntary running wheel ODLD animals showed increased running time and distance; however, our 6-week exercise intervention did not significantly affect bone microarchitecture and bone mechanical properties.