bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Losartan on Portal hypertension and Liver Cirrhosis: A Systematic Review
Authors: Avasthi Deepti , Avasthi Salil
Published: September 2024

Background

Portal hypertension, a complication of chronic liver disease, results from elevated pressure between the portal vein and the inferior vena cava. While non-selective beta-blockers are established for reducing portal pressure, the efficacy of losartan, an angiotensin II receptor blocker, remains debated. This study evaluated losartan’s impact on portal pressure and clinical outcomes in patients with cirrhosis and portal hypertension.

Objectives

To appraise evidence on the role of losartan in reducing portal pressure and associated clinical outcomes in cirrhotic patients with portal hypertension.

Methods

A comprehensive literature search was conducted in PubMed, Cochrane Library, Medline, and Web of Science. All the research and review of literature was conducted within the time period from August 20th, 2024 till August 31st, 2024 (within 1 month of submission of the paper). The Risk of Bias Visualization Tool (Robvis 2.0) and ROBINS-I were used to assess study quality. Data was extracted and analyzed using Microsoft Excel.

Results

Among 426 potential studies, 12 met the inclusion criteria. Both losartan and propranolol reduced hepatic venous pressure gradient (HVPG), with some studies suggesting a more pronounced effect of losartan. Meta-analysis found no significant difference in HVPG reduction (p = 0.22), but losartan significantly reduced wedged hepatic venous pressure (WHVP) compared to propranolol (p = 0.03). Losartan also affected mean arterial pressure, renal function, and hepatic fibrosis.

Conclusions

Losartan shows potential in treating portal hypertension by reducing portal pressure and fibrosis. It may be particularly beneficial for patients unresponsive to beta-blockers, addressing both hemodynamic and structural components, and improving sodium handling in complex cases.
Effects of respite services on fluctuations in caregivers’ stress: A pilot study using a daily diary
Authors: Abe Koji , Kubota Wataru
Published: September 2024

Objectives

Family caregivers for people with dementia report daily fluctuations in stress levels. Much prior research on caregivers’ daily stress fluctuations has used a daily diary method. However, only a few studies have used this method with family caregivers to examine the effects of respite services. This study aimed to use a daily diary method to assess the effects of respite services on stress and depression in family caregivers.

Methods

Participants included 13 family caregivers of persons with dementia using respite services in rural areas of Japan. Participants completed self-administered questionnaires every day for seven days, including the use or non-use of respite services, cognitive and daily living function, depression, and stress appraisal. Generalized linear mixed models with data nested within persons were used for the analysis.

Results

Few significant effects of services were found on caregivers’ depression and stress appraisals at the between-person level. However, within-person level analyses using generalized mixed models showed that respite services significantly reduced stress appraisal.

Conclusion

The findings demonstrate the stress-buffering effect of respite service for caregivers and the applicability of a daily diary method to the small sample.
Pulsed Field Ablation of Small Vessel-Related Arrhythmias: A New Catheter and Methods
Authors: Xuan Fengqi , Li Yunhao , Zhang Jie , Lin Long , Zhang Daoyang , Zhang Qi , Zhang Ping , Zhang Yujie , Ma Wei , Wang Zulu , Han Yaling , Liang Ming
Published: September 2024

Objectives

Some arrhythmia targets are located in the epicardium or deep myocardium, which could be reached through the vascular approach. However, it is difficult to deliver ablation catheters to the distal vessels and their branches. In small vessels, the energy released is limited, and the risk of ablation is increased. The objective of this study was to design a linear catheter with pulsed field energy that is suitable for ablation in the distal vessels and to verify its efficacy and safety in canines.

Methods

A total of eight canines were randomly assigned to two observation groups: a 48-hour group (N=4) and a 30-day group (N=4). A 3 F 10-pole pulsed field ablation catheter was employed to ablate in the great cardiac vein, the middle cardiac vein, the anterior interventricular vein, and the distal small branches of the cardiac venous system. The characteristics of the ablation lesions were observed both grossly and microscopically.

Results

The surgical procedure was completed successfully. Pulsed field energy can travel through the fatty tissue to form a lesion in the cardiomyocytes. The mean depth of the lesion in the 30-day group (2.37±0.53 mm) was found to be reduced by 39% (P<0.001) in comparison to that observed in the 48-hour group (3.92±0.62 mm). Additionally, a transition zone of incomplete injury was discerned in the junction area of the 48-hour group. Canines exhibited no adverse effects intraoperatively nor postoperatively, and no appreciable damage was observed in the adjacent small arteries or the surrounding organs.

Conclusion

The pulsed field energy from small blood vessels can cause lasting, continuous lesions to the myocardium and is safe to use. The 3 F liner pulsed field ablation catheter has been proven to be efficacious and safe, with promising indications for future application.
Prevalence and Determinants of Prehospital Impression of Stroke in Ischemic Stroke Patients
Authors: Caffarelli Mauro , Wood Andrew J. , Crowe Remle P , Amorim Edilberto , Kamel Hooman , Kim Anthony S. , Guterman Elan L.
Published: September 2024

BACKGROUND

Emergency Medical Services (EMS) clinicians are front-line in evaluating patients with stroke in the community. Their ability to correctly identify stroke influences downstream management decisions. We sought to use a large national database of prehospital clinical data to determine risk factors associated with missed EMS stroke identification.

METHODS

Retrospective study examining EMS evaluation of adults with Emergency Department (ED) stroke diagnosis. We leveraged the ESO Data Collaborative research dataset containing EHR data from 2019-2022 that has a subset of encounters with linked hospital diagnostic codes. Our primary outcome was the presence of an EMS diagnosis of stroke. We evaluated the association between demographic and clinical variables with EMS stroke identification using Pearson χ2 test for demographic variables and multivariable GLM for clinical variables with adjustment for demographic variables.

RESULTS

We identified 34,504 EMS encounters for patients with ED stroke diagnosis. Of these, 11,077 (32.1%) strokes had missed EMS stroke identification and instead had an EMS impression of “Generalized Weakness” (25.9%), “Altered Level of Consciousness” (24.9%), and “Dizziness” (7.2%). Patients more likely to have missed prehospital stroke identification were of Black race (p=0.0001) and Hispanic ethnicity (p=0.0001). Clinical variables associated with higher risk of missed EMS stroke identification were suspected alcohol or drug use (RR 1.48, 95% CI 1.37-1.59), low GCS (RR 1.17, 95% CI 1.10-1.24), tachycardia (RR 1.05, 95% CI 1.01-1.09), and hypotension (RR 1.47, 95% CI 1.34-1.61).

CONCLUSIONS

Approximately 1-in-3 patients transported by EMS did not have their stroke identified in the prehospital setting. Factors associated with lower odds of missed EMS stroke identification provide a starting point for future performance improvement initiatives.
Repeated low-intensity focused ultrasound led to microglial profile changes in TgF344-AD rats
Authors: Abjean Laurene , Novell Anthony , Larrat Benoît , Gueorguiev Boris Rafael , Cailly Thomas , Fossey Christine , Fabis Frédéric , Salomir Rares , Tsartsalis Stergios , Tournier Benjamin B. , Millet Philippe , Ceyzériat Kelly
Published: September 2024

Alzheimer’s disease (AD), the most common cause of dementia, represents one of the main clinical challenges of the century as the number of patients is predicted to triple by 2050. Despite the recent approval of three monoclonal antibodies targeting Amyloid β (Aβ) aggregates by the Food and Drug Administration (FDA), immunotherapies still face challenges due to the difficulty of antibodies crossing the blood-brain barrier (BBB). This necessitates administering large doses of drugs to achieve their therapeutic effects, which is associated with significant side effects. In this context, low-intensity focused ultrasound (LiFUS) appears as an innovative and non-invasive method which, in association with intravenous injection of microbubbles (MB), leads to a transient BBB opening. This innovative strategy has been extensively studied in different preclinical models and more recently in human clinical trials, particularly in the context of AD. LiFUS+MB seems to increase the inflammatory response at short term, but the time course of this response is not consistent between studies, certainly due to the discrepancy between LiFUS protocols used. Moreover, the impact at longer term is understudied and the mechanisms underlying this effect are still not well understood. In our study, we therefore used the TgF344-AD rat model of AD, to investigate the effect of a single or multiple exposures to LiFUS+MB in the entire brain, on inflammatory response and amyloid load. The ultrasound attenuation through the skull was corrected to apply a peak negative acoustic pressure of 450 kHz in all treated animals. Single LiFUS+MB exposure induces a slight astrocyte and microglial response 24 hours post-treatment whereas repeated LiFUS treatment seems to induce microglial reprogramming, leading to the adaptation of gene expression related to key functions such as inflammatory response, mitochondrial and energetic metabolism. In our rat model and LiFUS+MB protocol conditions, multiple exposures did not modulate soluble/poorly aggregated forms nor the highly aggregated forms of Aβ40and Aβ42. For therapeutic AD management, LiFUS+MB could be combined with drugs such as immunotherapies. In a proof-of-concept experiment, we validated that LiFUS was also efficient to improve the brain entry of the anti-Aβ antibody, Aducanumab.
A unique interplay of access and selection shapes peritoneal metastasis evolution in colorectal cancer
Authors: Wassenaar Emma CE , Gorelick Alexander N , Hung Wei-Ting , Cheek David M , Kucukkose Emre , Lee I-Hsiu , Blohmer Martin , Degner Sebastian , Giunta Peter , Wiezer Rene MJ , Raicu Mihaela G , Ubink Inge , Klaasen Sjoerd J , Lansu Nico , Watson Emma V , Corcoran Ryan B , Boland Genevieve , Getz Gad , Kops Geert JPL , Juric Dejan , Lennerz Jochen K , Boerma Djamila , Kranenburg Onno , Naxerova Kamila
Published: September 2024

Whether metastasis in humans can be accomplished by most primary tumor cells or requires the evolution of a specialized trait remains an open question. To evaluate whether metastases are founded by non-random subsets of primary tumor lineages requires extensive, difficult-to-implement sampling. We have realized an unusually dense multi-region sampling scheme in a cohort of 26 colorectal cancer patients with peritoneal metastases, reconstructing the evolutionary history of on average 28.8 tissue samples per patient with a microsatellite-based fingerprinting assay. To assess metastatic randomness, we evaluate inter- and intra-metastatic heterogeneity relative to the primary tumor and find that peritoneal metastases are more heterogeneous than liver metastases but less diverse than locoregional metastases. Metachronous peritoneal metastases exposed to systemic chemotherapy show significantly higher inter-lesion diversity than synchronous, untreated metastases. Projection of peritoneal metastasis origins onto a spatial map of the primary tumor reveals that they often originate at the deep-invading edge, in contrast to liver and lymph node metastases which exhibit no such preference. Furthermore, peritoneal metastases typically do not share a common subclonal origin with distant metastases in more remote organs. Synthesizing these insights into an evolutionary portrait of peritoneal metastases, we conclude that the peritoneal-metastatic process imposes milder selective pressures onto disseminating cancer cells than the liver-metastatic process. Peritoneal metastases' unique evolutionary features have potential implications for staging and treatment.
Acrylic Acid Modified Poly-ethylene Glycol Microparticles for Affinity-Based release of Insulin-Like Growth Factor-1 in Neural Applications
Authors: Ferrer Pablo Ramos , Sakiyama-Elbert Shelly
Published: September 2024

Sustained release of bioactive molecules via affinity-based interactions presents a promising approach for controlled delivery of growth factors. Insulin-like growth factor-1 (IGF-1) has gained increased attention due to its ability to promote axonal growth in the central nervous system. In this work, we aimed to evaluate the effect of IGF-1 delivery from polyethylene-glycol diacrylate (PEG-DA) microparticles using affinity-based sustained release on neurons. We developed PEG-DA-based microparticles with varying levels of acrylic acid (AA) as a comonomer to tune their overall charge. The particles were synthesized via precipitation polymerization under UV light, yielding microparticles (MPs) with a relatively low polydispersity index. IGF-1 was incubated with the PEG-DA particles overnight, and formulations with a higher AA content resulted in higher loading efficiency and slower release rates over 4 weeks, suggesting the presence of binding interactions between the positively charged IGF-1 and negatively charged particles containing AA. The released IGF-1 was tested in dorsal root ganglion (DRG) neurite outgrowth assay and found to retain its biological activity for up to two weeks after encapsulation. Furthermore, the trophic effect of IGF-1 was tested with stem cell-derived V2a interneurons and found to have a synergistic effect when combined with neurotrophin-3 (NT3). To assess the potential of a combinatorial approach, IGF-1-releasing MPs were encapsulated within a hyaluronic acid (HA) hydrogel and showed promise as a dual delivery system. Overall, the PEG-DA MPs developed herein deliver bioactive IGF-1 for a period of weeks and hold potential to enable axonal growth of injured neurons via sustained release.
Multiplatform lipid analysis of the brain of aging mice by mass spectrometry
Authors: Panda Punyatoya , Ferreira Christina R. , Cooper Bruce R. , Schaser Allison J. , Aryal Uma K.
Published: September 2024

Lipids are an integral part of brain structure and function and represent about 50% of the dry weight of the brain. Despite their importance, the complexity and variations in the abundance of brain lipids due to aging remain poorly understood. For maximum coverage and multi-platform validation, we applied three complementary mass spectrometry-based analytical approaches: multiple reaction monitoring (MRM) profiling, untargeted liquid chromatography tandem mass spectrometry (LC-MS/MS), and desorption electrospray ionization-MS imaging (DESI-MSI). We used three different age groups of mice, namely adult (3-4 months), middle-aged (10 months) and old (19-21 months). Phospholipids including phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) showed higher abundance, while phosphatidylinositols (PI) and phosphatidylserines (PS) generally showed lower abundance in the brains of old mice compared to adults or middle-aged mice. Polyunsaturated fatty acids, such as docosahexaenoic acid (DHA) and arachidonic acid (AA), as well as hexosylceramides (HexCer), sulfated hexosylceramides (SHexCer) and sphingomyelins (SM) were among the most abundant lipid species in the brains of old mice. DESI-MSI showed variations in the spatial distribution of many of the lipids confirmed by MRM and LC-MS/MS profiling. Interrogation of lipidomic data with recent proteomics data obtained from the same tissues revealed changes in the abundance and phosphorylation levels of several proteins potentially linked to ceramide (Cer), hexosylceramide (HexCer), fatty acids (FA), phosphatidylinositol (PI), sphingomyelin (SM) and sulfatides (SHexCer) metabolism and correlated well with the multiplatform lipid surveillance. Our findings offer insight into age-dependent changes in brain lipid profiles and their potential contribution to age-related cognitive decline.
Determination of Capsaicin content and pungency levels in Dalle Khursani accessions, a polyploidCapsicumspecies specific to Darjeeling-Sikkim Himalaya, India
Authors: Ghimiray Tulsi Saran , Majumdar Biswajit , Man Sourav
Published: September 2024

The genus Capsicum includes more than 30 species, of which only five are cultivated. The pungency in chillies is primarily due to the accumulation of capsaicinoids such as capsaicin and dihydrocapsaicin, which varies significantly among species and varieties. Dalle Khursani, a unique landrace of Capsicum sp specific to the Darjeeling-Sikkim Himalaya in India, is highly valued for its pungency. However, very limited research exists on the variation of capsaicin content across different accessions of Dalle Khursani.

The present study was undertaken to evaluate the capsaicin content and pungency levels of seven accessions collected from diverse altitudinal locations. High-Performance Liquid Chromatography (HPLC) was used to quantify capsaicin content.

The concentration of capsaicin varied between 19.05 mg/g to 28.54 mg/g with the corresponding Scoville Heat Units (SHU) ranging from 304,863 to 456,636 revealing the presence of significant variations for pungency within the accessions of Dalle Khursani that may be attributed to genetic or environmental factors. Accessions DK-02 and DK-03 exhibited the highest capsaicin levels despite differing altitudinal growing environments. The results suggest a strong genetic influence on capsaicinoid content, with environmental factors playing a lesser role. For the first time, the capsaicin content and pungency levels in Dalle Khursani accessions are reported in this study.
The relationship between brain activation and mitochondrial complex I protein levels during cognitive function in healthy humans: an [18F]BCPP-EF PET and functional MRI study of task switching
Authors: Shatalina Ekaterina , Whitehurst Thomas , Chika Onwordi Ellis , Whittington Alexander , Mansur Ayla , Arumuham Atheeshaan , Reis Marques Tiago , Gunn Roger N. , Natesan Sridhar , Nour Matthew M. , Rabiner Eugenii A. , Wall Matthew B. , Howes Oliver D.
Published: September 2024

Mitochondrial complex I is the largest enzyme complex in the respiratory chain and can be non-invasively measured using [18F]BCPP-EF positron emission tomography (PET). Neurological conditions associated with mitochondria complex I pathology are also associated with altered blood oxygen level dependent (BOLD) response and impairments in cognition. To evaluate the link between mitochondrial complex I, cognition and associated neural activity, 23 cognitively healthy adults underwent a [18F]BCPP-EF PET scan and a functional magnetic resonance imaging (fMRI) scan during which they performed a task switching exercise. We found significant positive associations between [18F]BCPP-EF volume of distribution (VT), which measures mitochondrial complex I levels and the task switching fMRI response (Partial Least Squares (PLS) Canonical Analysis (CA), first component r=0.51, p=0.03). Exploratory Pearson's correlations showed significant positive associations between mitochondrial complex I levels and the fMRI response in regions including the dorsolateral prefrontal cortex (r=0.61, p=0.0019), insula (r=0.46, p=0.0264) parietal-precuneus (r=0.51, p=0.0139) and anterior cingulate cortex (r=0.45, p=0.0293). Mitochondrial complex I levels across task-relevant regions were also predictive of task switching accuracy (PLS-Regression (PLS-R), R2=0.48, RMSE=0.154, p=0.011) and of switch cost (PLS-R, R^2=0.38, RMSE=0.07, p=0.048). Our findings suggest that higher mitochondrial complex I levels may underlie an individual's ability to exhibit a stronger BOLD response during task switching and are predictive of better task switching performance. This provides the first evidence linking the BOLD response with mitochondrial complex I and suggests a possible biological mechanism for aberrant BOLD response in conditions associated with mitochondrial complex I dysfunction, that should be tested in future studies.
Spontaneous brain activity and synaptic density in schizophrenia: a combined [11C]UCB-J PET and fMRI study
Authors: Shatalina Ekaterina , Onwordi Ellis Chika , Whitehurst Thomas , Whittington Alexander , Mansur Ayla , Arumuham Atheeshaan , Marques Tiago Reis , Gunn Roger N. , Natesan Sridhar , Rabiner Eugenii A. , Wall Matthew B. , Howes Oliver D
Published: September 2024

Schizophrenia is associated with altered Amplitude of Low Frequency Fluctuations (ALFF), a functional Magnetic Resonance Imaging (fMRI) measure of spontaneous brain activity at rest. ALFF in healthy controls has been linked with presynaptic density levels measured by [11C]UCB-J positron emission tomography (PET). Given the growing body of evidence for low presynaptic density levels in schizophrenia, we set out to test if altered [11C]UCB-J binding may be associated with changes in ALFF in schizophrenia, and secondly to test whether the relationships between ALFF and [11C]UCB-J binding differ at the group level.

Subjects with schizophrenia had higher ALFF in the medial prefrontal cortex and other regions, in line with published meta-analyses. In control subjects, there was a significant positive relationship between [11C]UCB-J distribution volume ratio (DVRcs) and ALFF in the medial prefrontal cortex (r=0.54, p=0.0365, n=16), but not in subjects with schizophrenia (r=–0.14, p=0.5564, n=22); r-coefficients significantly differed between groups (Zobserved=2.07, p=0.019). At the whole brain level, there were significant positive correlations between [11C]UCB-J DVRcs and ALFF in control subjects in the putamen, insular cortex, precentral gyrus and occipital regions, while in the schizophrenia group, there were significant positive correlations in the bilateral dorsolateral prefrontal cortex and negative correlations in the cuneus, parietal lobule and supramarginal gurus. Correlation coefficients were significantly different between groups across all cortical and subcortical regions with both higher and lower correlation coefficients in the control group.

Our results suggest a link between spontaneous brain activity and presynaptic density in control subjects and that this relationship may be disrupted in schizophrenia patients, despite higher ALFF in this group, indicating altered neurobiological mechanisms. Widespread significant differences in ALFF-[11C]UCB-J DVRcs correlation coefficients between controls and schizophrenia subjects highlight the complexity of synaptic dysfunction in schizophrenia and underscore the need for further research to explore the underlying biological mechanisms.
Causality Mapping Using Resting-state fMRI Reveals Hyperactivity and Hypoconnectivity in Schizophrenia Patients
Authors: Tahir Alishba , Abdullah Wajiha , Azeem Wjeeh ul , Khalid Muhammad Farhan , Abualait Turki , Shakil Sadia , Ahmed Fayyaz , Bashir Shahid , Chaudhary Safee Ullah
Published: September 2024

Schizophrenia (SZ) is a debilitating disorder in which patients exhibit psychotic behavior due to aberrant connectivity between different regions of the brain. Advances in neuroimaging have now enabled the diagnosis and analysis of SZ in order to elucidate the whole brain functional connectivity networks. In the present study, we have used resting-state functional magnetic resonance imaging (rs-fMRI) to elucidate the causal relationships amongst the differentially activated brain regions between SZ patients (n=10) and healthy controls (n=10). Vector auto-regression (VAR) model and Granger causality (GC) were then applied to construct a functional connectivity network and analyze the causal effects in SZ patients. Our results revealed that the average voxel activation in the frontal lobe (FL), basal ganglia (BG), and ventricular system (VS) was significantly higher in patients indicating hyper-activity as compared to controls. Conversely, cerebellum white matter (CBWM) showed higher activation in the controls as compared to patients. A higher Pearson correlation was observed between the controls as compared to patients while VAR and GC showed higher functional connectivity among all the regions of interest (ROIs) along with more causal relations in the controls. Finally, mediation analysis showed that right middle superior frontal gyrus acts as a strong partial mediator between left accumbens area and left middle superior frontal gyrus. Taken together, this study decodes the dysregulated brain activity in schizophrenia showing hyperactivation in patients when compared with the healthy controls which leads to alterations in neural connections resulting in hypoconnectivity.
Evolution under competition increases phytoplankton production by reducing the density-dependence of net energy fluxes and growth
Authors: Briddon Charlotte L. , Estevens Ricardo , Ghedini Giulia
Published: September 2024

Competition can drive rapid evolution but forecasting how species evolve in communities remains difficult. Life history theory predicts that evolution in crowded environments should maximise population production, with intra- and inter-specific competition producing similar outcomes if species compete for similar resources. Despite its appeal, this prediction has rarely been tested in communities. To test its generality and identify its physiological basis, we experimentally evolved four species of marine phytoplankton (spanning three orders of magnitude in cell size) alone or together in a community for 4.5 months. We then quantified changes in their metabolism, demography, and competitive ability at two timepoints (∼60 and 120 generations) in common garden experiments. One species was outcompeted during the evolution experiment. For the other three, we found the same evolutionary outcome: species evolved greater biovolume production regardless of competition treatment but did so either by increasing max. population size or individual cell size. Biovolume production increased because of the differential evolution of photosynthesis and respiration under intense competition. These metabolic changes meant that intraspecific competition decreased and cells maintained higher rates of net energy production and growth as populations neared the stationary phase. Overall, these results show that intra- and inter-specific competition influence physiological and population parameters similarly in species that compete for essential resources. Life history theory thus provides a valuable base for predicting how species evolve in communities, and our results show how these predictions connect with the evolution of metabolism and competitive ability.
The representation of visual motion and landmark position aligns with heading direction in the zebrafish interpeduncular nucleus
Authors: Lavian Hagar , Prat Ot , Petrucco Luigi , Štih Vilim , Portugues Ruben
Published: September 2024

Sensory information is fundamental for navigation. Visual motion is used by animals to estimate their traveling distance and direction, and visual landmarks allow animals to tether their location and orientation to their environment. How such signals are integrated in the vertebrate brain is poorly understood. Here we investigate the representation of directional whole field visual motion and landmark position in a circuit in the larval zebrafish consisting of the habenula, interpeduncular nucleus (IPN) and anterior hindbrain (aHB). This circuit has been recently implicated in the representation of heading direction. Using calcium imaging we show that these stimuli are represented in the habenula, IPN and aHB. We further show that their representation in the IPN of both these stimuli is topographically arranged in a way that aligns itself with the representation of the heading signal in this region. We use neuronal ablations to show that the landmark responses, but not the whole field motion responses, require intact habenula input to the IPN. Overall our findings suggest the IPN as a site for integration of the heading signal from the aHB with visual information, shedding light on how different types of navigational signals are processed in the vertebrate brain.
Local Mean Suppression Filter for Effective Background Identification in Fluorescence Images
Authors: Kochetov Bogdan , Uttam Shikhar
Published: September 2024

We present an easy-to-use, nonlinear filter for effective background identification in fluorescence microscopy images with dense and low-contrast foreground. The pixel-wise filtering is based on comparison of the pixel intensity with the mean intensity of pixels in its local neighborhood. The pixel is given a background or foreground label depending on whether its intensity is less than or greater than the mean respectively. Multiple labels are generated for the same pixel by computing mean expression values by varying neighborhood size. These labels are accumulated to decide the final pixel label. We demonstrate that the performance of our filter favorably compares with state-of-the-art image processing, machine learning, and deep learning methods. We present three use cases that demonstrate its effectiveness, and also show how it can be used in multiplexed fluorescence imaging contexts and as a denoising step in image segmentation. A fast implementation of the filter is available in Python 3 onGitHub.
Foundry-fabricated dual-color nanophotonic neural probes for photostimulation and electrophysiological recording
Authors: Roszko David A. , Chen Fu-Der , Straguzzi John , Wahn Hannes , Xu Alec , McLaughlin Blaine , Yin Xinxin , Chua Hongyao , Luo Xianshu , Lo Guo-Qiang , Siegle Joshua H. , Poon Joyce K. S. , Sacher Wesley D.
Published: September 2024

Significance

Compact tools capable of delivering multicolor optogenetic stimulation to deep tissue targets with sufficient span, spatiotemporal resolution, and optical power remain challenging to realize. Here, we demonstrate foundry-fabricated nanophotonic neural probes for blue and red photostimulation and electrophysiological recording, which use a combination of spatial multiplexing and on-shank wavelength-demultiplexing to increase the number of on-shank emitters.

Aim

We demonstrate Si photonic neural probes with 26 photonic channels and 26 recording sites, which were fabricated on 200-mm diameter wafers at a commercial Si photonics foundry. Each photonic channel consists of an on-shank demultiplexer and separate grating coupler emitters for blue and red light, for a total of 52 emitters.

Approach

We evaluate neural probe functionality through bench measurements andin vivoexperiments by photostimulating through 16 of the available 26 emitter pairs.

Results

We report neural probe electrode impedances, optical transmission, and beam profiles. We validated a packaged neural probe in optogenetic experiments with mice sensitive to blue or red photostimulation.

Conclusions

Our foundry-fabricated nanophotonic neural probe demonstrates dense dual-color emitter integration on a single shank for targeted photostimulation. Given its two emission wavelengths, high emitter density, and long site span, this probe will facilitate experiments involving bidirectional circuit manipulations across both shallow and deep structures simultaneously.
Mixture Models for Dating with Confidence
Authors: Darlim Gustavo , Höhna Sebastian
Published: September 2024

Robust estimation of divergence times is commonly performed using Bayesian inference with relaxed clock models. The specific choice of relaxed clock model and tree prior model can impact divergence time estimates, thus necessitating model selection among alternative models. The common approach is to select a model based on Bayes factors estimated via computational demanding approaches such as stepping stone sampling. Here we explore an alternative approach: mixture models that analytically integrate over all candidate models. Our mixture model approach only requires one Markov chain Monte Carlo analysis to both estimate the parameters of interest (e.g., the time-calibrated phylogeny) and to compute model posterior probabilities. We demonstrate the application of our mixture model approach using three relaxed clock models (uncorrelated exponential, uncorrelated lognormal and independent gamma rates) combined with three tree prior models (constant-rates pure birth process, constant-rate birth-death process and piecewise-constant birth-death process) and mitochondrial genome dataset of Crocodylia. We calibrate the phylogeny using well-defined fossil node calibrations. Our results show that Bayes factors estimated using stepping stone sampling are unreliable due to noise in repeated analyses while our analytical mixture model approach shows higher precision and robustness. Thus, divergence time estimates under our mixture model are comparably robust as previous relaxed clock approaches but model selection is significantly faster and avoids marginal likelihood estimation. Finally, our time-calibrated phylogeny of Crocodylia presents a robust benchmark for further studies in the group.
A Unified Theory of Response Sparsity and Variability for Energy-Efficient Neural Coding
Authors: Huang Mingyi , Lin Wei , Roe Anna Wang , Yu Yuguo
Published: September 2024

Understanding how cortical neurons use dynamic firing patterns to represent sensory signals is a central challenge in neuroscience. Decades of research have shown that cortical neuronal activities exhibit high variance, typically quantified by the coefficient of variation (CV), suggesting intrinsic randomness. Conversely, substantial evidence indicates that cortical neurons display high response sparseness, indicative of efficient encoding. The apparent contradiction between these neural coding properties—stochastic yet efficient—has lacked a unified theoretical framework. This study aims to resolve this discrepancy. We conducted a series of analyses to establish a direct relational function between CV and sparseness, proving they are intrinsically correlated or equivalent across different statistical distributions in neural activities. We further derive a function showing that both irregularity and sparsity in neuronal activities are positive functions of energy-efficient coding capacity, quantified by Information-Cost Efficiency (ICE). This suggests that the observed high irregularity and sparsity in cortical activities result from a shared mechanism optimized for maximizing information encoding capacity while minimizing cost. Furthermore, we introduce a CV-maximization algorithm to generate kernel functions replicating the receptive fields of the primary visual cortex. This finding indicates that the neuronal functions in the visual cortex are optimal energy-efficient coding operators for natural images. Hence, this framework unifies the concepts of irregularity and sparsity in neuronal activities by linking them to a common mechanism of coding efficiency, offering deeper insights into neural coding strategies.
Oscillatory dynamics of sustained attention states
Authors: Solís-Vivanco Rodolfo , Barne Louise , Harris Anthony , Liu Xin , Lavie Nilli
Published: September 2024

Sustained attention enables individuals to concentrate on a task over an extended period of time. This ability is known to fluctuate, resulting in periods of effective task focus (‘in the zone’) and periods of increased performance variability and susceptibility to errors (‘out of the zone’). Little is known about the oscillatory neural dynamics that underlie each of these states and their transitions during sustained attention tasks. To address this, we had thirty young adults perform the gradual onset continuous performance task (gradCPT), during which their EEG and behavioural responses were recorded. States of sustained attention (in vs. out of the zone) throughout the task were identified based on the variance time course of participants’ reaction times. Out of the zone states were associated with increased errors of commission and reduced perceptual sensitivity compared to in the zone states, as expected. Importantly, a significant decline in theta oscillations at mid-prefrontal regions was found in out of the zone (vs. in the zone) states over a ∼400 ms period around the transition point between stimuli, and the extent of this decline predicted commission errors, RT variability, and response bias. In addition, individual differences in the variability of frontal theta rhythm were associated with RT variability. Finally, participants exhibiting greater theta variability showed a more pronounced decline in perceptual sensitivity when out of the zone and less stable RTs compared to those with lower variability. Our results suggest that states of diminished sustained attention, even during short lapses, are characterized by a reduction in frontal theta activity, and that fluctuations in this rhythm covary with fluctuations in attentional control.
Lipophilic molecular rotor to assess the viscosity of oil core in nano-emulsion droplets
Authors: Elhassan Mohamed , Faivre Carla , Anton Halina , Conzatti Guillaume , Didier Pascal , Vandamme Thierry , Elamin Alteyeb S. , Collot Mayeul , Anton Nicolas
Published: September 2024

Hypothesis

Characterization of nanoscale formulations is a continuous challenge. Size, morphology and surface properties are the most common characterizations. However, physicochemical properties inside the nanoparticles, like viscosity, cannot be directly measured. Herein, we propose an original approach to measuring dynamic viscosity using a lipidic molecular rotor solubilized in the core of nano-formulations. These molecules undergo conformational changes in response to viscosity variations, leading to observable changes in fluorescence intensity and lifetime, able to sense the volume properties of dispersed nano-domains.

Experiments

The lipophilic molecular rotor (BOPIDY derivatives) was specifically synthesized and characterized as oil viscosity sensing in large volumes. A second part of the study compares these results with rBDP-Toco in nano-emulsions. The objective is to evaluate the impact of the formulation, droplet size and composition on the viscosity of the droplet’s core.

Findings

The lipophilic rotor showed a universal behavior whatever the oil composition, giving a master curve. Applied to nano-formulations, it discloses the viscosity in the nano-emulsion droplets, enabling the detection of slight variations between reference oil samples and the nano-formulated ones. This new tool opens the way to the fine characterization of complex colloids and multi-domain nano and micro systems, potentially applied to hybrid materials and biomaterials.
A slippery slope: assessing the amphibian extinction crisis through the lens of climate refugia
Authors: Andersen Desiree , Borzée Amaël , Jang Yikweon
Published: September 2024

In a time of increasing climate uncertainty, it is ever important to identify and preserve refuges for species, optimizing the effort to cover the largest possible number of clades. Climatic refugia are areas of climatic stability that will remain suitable for species over time under multiple climate change scenarios. Amphibians are important indicators of biodiversity and ecosystem health, in addition to being the most threatened class of vertebrates and can therefore serve as proxies to designate protected areas. In this study, we use ecological modeling to delineate current distributions of all amphibian species with adequate data globally. We then projected these distributions to four climate change scenarios, and four time periods, under two climate models representing low and high climate sensitivity. Climate refugia by species were calculated as the average of all climate change scenarios and time periods and were calculated separately for the two climate models of low and high sensitivity. We additionally extracted areas of current distributions and refugia to geographic regions, Udvardy biomes, and global protected areas. With the high climate sensitivity model (CNRM-CM6-1), 2,959 species would experience a refugia area that is reduced from their current distribution, with 139 species having no refugia area. Under the low climate sensitivity model (MIROC6), 2,864 species would have a reduction in area, with 136 having no refugia. While both climate models yielded similar results in terms of percent change, the MIROC6 model overall had less of a negative impact on species’ refugia. The results of this study present a somber warning of the amphibian extinction crisis in contrast to some of the recent literature, as well as encouragement for managers to act in order to preserve species and the ecosystems they represent.
Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma
Authors: Kader Tanjina , Lin Jia-Ren , Hug Clemens , Coy Shannon , Chen Yu-An , de Bruijn Ino , Shih Natalie , Jung Euihye , Pelletier Roxanne J. , Leon Mariana Lopez , Mingo Gabriel , Omran Dalia Khaled , Lee Jong Suk , Yapp Clarence , Satravada Baby Anusha , Kundra Ritika , Xu Yilin , Chan Sabrina , Tefft Juliann B. , Muhlich Jeremy , Kim Sarah , Gysler Stefan M. , Agudo Judith , Heath James R. , Schultz Nikolaus , Drescher Charles , Sorger Peter K , Drapkin Ronny , Santagata Sandro
Published: September 2024

High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC-class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer.

STATEMENT OF SIGNIFICANCE

This study maps the immune response in fallopian tube precursors of high-grade serous ovarian cancer, highlighting localized interferon signaling, CIN, and competing immune surveillance and suppression along the progression axis. It provides an explorable public spatial profiling atlas for investigating precancer mechanisms, biomarkers, and early detection and interception strategies.
Exploring the use of environment-agent-based models for risk assessment of Great Lakes piping plovers
Authors: Edwards Brandon P.M. , Jacobs Shoshanah , Gillis Daniel
Published: September 2024

The Piping PloverCharadrius melodusis an endangered species of shorebird endemic to North America. This species has been the centre of many modelling studies in the last decade. One model type that has been underused in Piping Plover studies is agent-based modelling, which can be used as an accurate risk assessment tool in simulating effects of anthropogenic activities on a given animal species. Recent innovations in ecological modelling have given rise to the environmental agent-based model (enviro-ABM), which efficiently stores information about spatially indexed environmental cells and treat those as agents. This restricts computation to only focus on environmental cells containing the species we are studying, allowing for a more efficient simulation. Using Python, a high-level programming language popular in scientific computing, we develop an enviro-ABM to provide simulations of Piping Plover hatchling growth during a given breeding season. We experiment with increasing levels of human presence and human exclosure size and observe their effects on the growth rate of the simulated Piping Plover hatchlings. Our simulations showed a clear decrease in Piping Plover growth rate as anthropogenic presence increased in the simulated environment. However, when we added a 100 m human exclosure around the nest, the effects of the anthropogenic presence were mitigated at each level. We conclude that an enviro-ABM can be used to assist with conservation and management decisions, with the caveat that the model be constantly updated and informed with results of field studies, especially those pertaining to foraging and energetics of Piping Plovers.
A joint framework for studying population structure using principal component analysis and F-statistics
Authors: Popli Divyaratan , Peter Benjamin M.
Published: September 2024

Principal component analysis (PCA) andF-statistics are routinely used in population genetic and archaeogenetic studies. Here, we present a statistical framework to combine them into a joint analysis, showing where they coincide, and where slightly different assumptions made can lead to different outcomes. In particular, we discuss the differences of probabilistic PCA, Latent Subspace Estimation and classical PCA, and show thatF-statistics are more naturally interpreted in a probabilistic PCA framework. We also show that individual-basedF-statistics can be accurately estimated from probabilistic PCA in the presence of large amounts of missing data. We compare estimates from probabilistic PCA-based framework to ADMIXTOOLS 2 using simulations and published data, and show that this joint estimation framework addresses limitations of estimating F-statistics and PCA independently.
Leveraging cell type-specificity for gene set analysis of single cell transcriptomics
Authors: Frost H. Robert
Published: September 2024

Although single cell RNA-sequencing (scRNA-seq) provides unprecedented insights into the biology of complex tissues, analyzing such data on a gene-by-gene basis is challenging due to the large number of tested hypotheses and consequent low statistical power and difficult interpretation. These issues are magnified by the increased noise, significant sparsity and multi-modal distributions characteristic of single cell data. One promising approach for addressing these challenges is gene set testing, or pathway analysis. Unfortunately, statistical and biological differences between single cell and bulk transcriptomic data make it challenging to use existing gene set collections, which were developed for bulk tissue analysis, on scRNA-seq data. In this paper, we describe a procedure for customizing gene set collections originally created for bulk tissue analysis to reflect the structure of gene activity within specific cell types. Our approach leverages information about mean gene expression in the 81 human cell types profiled via scRNA-seq by the Human Protein Atlas (HPA) Single Cell Type Atlas. This HPA information is used to compute cell type-specific gene and gene set weights that can be used to filter or weight gene set collections. As demonstrated through the analysis of immune cell scRNA-seq data using gene sets from the Molecular Signatures Database (MSigDB), accounting for cell type-specificity can significantly improve gene set testing power and interpretability. An example vignette along with gene and gene set weights for the 81 HPA SCTA cell types and the MSigDB collections are available athttps://hrfrost.host.dartmouth.edu/SCGeneSetOpt/.