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ENeuro Jun 2024Measuring the dynamic relationship between neuromodulators, such as dopamine, and neuronal action potentials is imperative to understand how these fundamental modes of...
Measuring the dynamic relationship between neuromodulators, such as dopamine, and neuronal action potentials is imperative to understand how these fundamental modes of neural signaling interact to mediate behavior. We developed methods to measure concurrently dopamine and extracellular action potentials (i.e., spikes) in monkeys. Standard fast-scan cyclic voltammetric (FSCV) electrochemical (EChem) and electrophysiological (EPhys) recording systems are combined and used to collect spike and dopamine signals, respectively, from an array of carbon fiber (CF) sensors implanted in the monkey striatum. FSCV requires the application of small voltages at the implanted sensors to measure redox currents generated from target molecules, such as dopamine. These applied voltages create artifacts at neighboring EPhys-measurement sensors which may lead to misclassification of these signals as physiological spikes. Therefore, simple automated temporal interpolation algorithms were designed to remove these artifacts and enable accurate spike extraction. We validated these methods using simulated artifacts and demonstrated an average spike recovery rate of 84.5%. We identified and discriminated cell-type specific units in the monkey striatum that were shown to correlate to specific behavioral task parameters related to reward size and eye-movement direction. Synchronously recorded spike and dopamine signals displayed contrasting relations to the task variables, suggesting a complex relationship between these two modes of neural signaling. Future application of our methods will help advance our understanding of the interactions between neuromodulator signaling and neuronal activity, to elucidate more detailed mechanisms of neural circuitry and plasticity mediating behaviors in health and in disease. We present a simple method for recording synchronous molecular and neuronal spike signals. Conventional electrophysiological and electrochemical instruments are combined without the need for additional hardware. A custom-designed algorithm was made and validated for extracting neuronal action potential signals with high fidelity. We were able to compute cell-type specific spike activity along with molecular dopamine signals related to reward and movement behaviors from measurements made in the monkey striatum. Such combined measurements of neurochemical and extracellular action potentials may help pave the way to elucidating mechanisms of plasticity, and how neuromodulators and neurons are orchestrated to mediate behavior.
PubMed: 38918051
DOI: 10.1523/ENEURO.0001-24.2024 -
JCI Insight Jun 2024The average time-to-degree for completing a life sciences PhD in the U.S. is longer for single-degree than dual-degree trainees, supporting a perception that the PhD...
The average time-to-degree for completing a life sciences PhD in the U.S. is longer for single-degree than dual-degree trainees, supporting a perception that the PhD training of MD-PhDs is less rigorous or fulsome. To determine whether the duration and impact of graduate training is influenced by degree format, we analyzed data for the 2011-2016 graduates of three Harvard Medical School PhD programs. Linear mixed effects models were used to determine the association between degree type (MD-PhD vs. PhD) and research outcomes, including time-to-degree, time-to-thesis-defense, and publications submitted during the PhD. Although pursuing an MD-PhD was associated with a 1.5-year shorter time-to-PhD-degree, basing this calculation on the official PhD period does not account for completion of early PhD requirements, including research rotations and qualifying coursework, during the first two years of medical school. There was no association between degree format and the total number of first-authored or overall publications, although pursuing a dual degree was associated with increased impact metrics of published papers. The results highlight that despite the optically shorter PhD durations of MD-PhD graduates based on graduate program enrollment period, research training is on par with their single-degree peers, rendering MD-PhD graduates well equipped to become successful scientific investigators.
PubMed: 38917318
DOI: 10.1172/jci.insight.182288 -
PloS One 2024The underwater laser polarization detection technology integrates the polarization characteristics of light into the detection and identification of underwater targets....
The underwater laser polarization detection technology integrates the polarization characteristics of light into the detection and identification of underwater targets. Addressing the challenge of poor accuracy in identifying targets in strong underwater scattering environments, this article proposes an overall scheme for a laser polarization underwater detection device that suppresses scatter using polarized pulse signals. By overcoming key technological barriers in the design of polarization-preserving optical detection systems and utilizing the method of differential amplitude to measure polarization, a laser polarization underwater detection device was developed and underwater polarization detection experiments were conducted, achieving precise detection of underwater targets. The results indicate that the underwater detection device we designed has a root mean square error of less than 5.7% to detect the polarization of the target, demonstrating the accuracy and precision of the underwater detection device.
Topics: Lasers; Scattering, Radiation; Water; Light
PubMed: 38917184
DOI: 10.1371/journal.pone.0305929 -
PloS One 2024Prostate stem cell antigen (PSCA) is associated with disease progression, promotion of angiogenesis, invasion, metastasis and immune evasion in cancer. However, its...
Prostate stem cell antigen (PSCA) is associated with disease progression, promotion of angiogenesis, invasion, metastasis and immune evasion in cancer. However, its expression pattern and diagnostic and prognostic potential have not been thoroughly analysed from a pan-cancer perspective. This study aimed to examine the effects of PSCA on the prognosis and inflammatory cell infiltration patterns of various cancer types. We analysed the relationship between PSCA expression and immunological subtypes in tumor microenvironment (TME) and the role of molecular subtypes, potentially promising immune biomarkers and tumour-infiltrating lymphocytes (TILs) in various cancer types, especially lung adenocarcinoma (LUAD). In addition, we investigated the prognostic significance of PSCA expression in LUAD. The co-expression network of PSCA was found to be mainly involved in the regulation of immune responses and antigen processing and expression and was significantly enriched in pathological and substance metabolism-related pathways in cancer. Altogether, this study reveals that PSCA is a promising target for immunotherapy in patients with cancer.
Topics: Humans; Antigens, Neoplasm; Prognosis; Tumor Microenvironment; Lymphocytes, Tumor-Infiltrating; Neoplasm Proteins; GPI-Linked Proteins; Biomarkers, Tumor; Neoplasms; Adenocarcinoma of Lung; Lung Neoplasms; Gene Expression Regulation, Neoplastic; Male
PubMed: 38917176
DOI: 10.1371/journal.pone.0298469 -
PloS One 2024The aim of this pilot study was to determine whether viewing an immersive 3D movie with large disparities in a cinema resulted in improved visual acuity (VA),...
PURPOSE
The aim of this pilot study was to determine whether viewing an immersive 3D movie with large disparities in a cinema resulted in improved visual acuity (VA), stereoscopic depth perception (ST), and improved eye alignment in residual amblyopic children and children without amblyopia.
METHODS
A total of 24 children aged between 5 and 12 years with a history of anisometropic and/or strabismic amblyopia, that had been previously treated and who currently have residual amblyopia (N = 14), and in children with typical development without amblyopia (N = 10) viewed the movie in 3D Sing 2 in a cinema for 110 minutes. Visual acuity, stereoacuity and ocular deviation were assessed before viewing the movie, and three months later. Stereoacuity and ocular deviation were also measured immediately after viewing the movie.
RESULTS
We observed an improvement in visual acuity in the non-dominant (amblyopic) eye 3 months after viewing the movie in the amblyopic group (P<0.001). Stereopsis improved immediately after viewing the movie (P = 0.02), and after 3 months by ≈ 40% (P = 0.01). Moreover, improvements in stereopsis were also observed in children without amblyopia (P = 0.04). No significant changes in ocular deviation were observed in either group.
CONCLUSIONS
These pilot results suggest that brief exposure to large disparities by viewing a 3D movie in a cinema can help to improve stereopsis and visual acuity in children aged 5‒12 years with previously treated amblyopia, and provide a rationale for a randomized clinical trial.
Topics: Humans; Amblyopia; Child; Pilot Projects; Visual Acuity; Female; Male; Child, Preschool; Depth Perception; Motion Pictures
PubMed: 38917142
DOI: 10.1371/journal.pone.0305401 -
JCI Insight Jun 2024Autosomal dominant optic atrophy plus (ADOA+) is characterized by primary optic nerve atrophy accompanied by a spectrum of degenerative neurological symptoms. Despite...
Autosomal dominant optic atrophy plus (ADOA+) is characterized by primary optic nerve atrophy accompanied by a spectrum of degenerative neurological symptoms. Despite ongoing research, no effective treatments are currently available for this condition. Our study provided evidence for the pathogenicity of an unreported c.1780T>C variant in the OPA1 gene through patient-derived skin fibroblasts and an engineered HEK293T cell line with OPA1 downregulation. We demonstrated that OPA1 insufficiency promoted mitochondrial fragmentation and increased DRP1 expression, disrupting mitochondrial dynamics. Consequently, this disruption enhanced mitophagy and caused mitochondrial dysfunction, contributing to the ADOA+ phenotype. Notably, the Drp1 inhibitor, mitochondrial division inhibitor-1 (Mdivi-1), effectively mitigated the adverse effects of OPA1 impairment. These effects included reduced Drp1 phosphorylation, decreased mitochondrial fragmentation, and balanced mitophagy. Thus, we propose that intervening in DRP1 with Mdivi-1 could correct mitochondrial abnormalities, offering a promising therapeutic approach for managing ADOA+.
PubMed: 38916953
DOI: 10.1172/jci.insight.180582 -
Translational Vision Science &... Jun 2024We sought to develop and evaluate a practical framework that supports structurally enhanced perimetric examinations.
PURPOSE
We sought to develop and evaluate a practical framework that supports structurally enhanced perimetric examinations.
METHODS
Two perimetric strategies were compared: standard Zippy Estimation through Sequential Testing (ZEST) procedure, a traditional visual field test with population-based prior distributions, and structural-ZEST (S-ZEST), enhanced with individual optical coherence tomography data to determine the starting parameters. The integration and collection of data was facilitated by a bespoke application developed in Shiny R (R Studio). The test was implemented using the Open Perimetry Interface on the Compass perimeter (CentreVue-iCare, Italy). The strategies were evaluated via simulations and on 10 visually healthy participants. The usability of the application was assessed in a simulated environment with 10 test users.
RESULTS
In simulations, the S-ZEST improved test speed in patients with glaucoma. In the practical implementation, there was a statistically significant decrease in the testing time (approximately 26%) and in the number of presentations per test with S-ZEST (P < 0.001). The structure-function relationship was similar between the two strategies. The time taken for users to complete the sequence of actions on the application was 52.9 ± 11.5 seconds (mean ± standard deviation).
CONCLUSIONS
Structurally enhanced perimetric examination can significantly improve test time in healthy subjects and can be delivered through a user-friendly interface. Further testing will need to assess feasibility and performance of S-ZEST in patients with glaucoma.
TRANSLATIONAL RELEVANCE
We have developed a user-friendly web application based within the Shiny environment for R, which implements an automated extraction of optical coherence tomography data from raw files and performs real-time calculations of structural features to inform the perimetric strategy.
Topics: Humans; Tomography, Optical Coherence; Visual Field Tests; Male; Female; Visual Fields; Middle Aged; Adult; Glaucoma; Aged; Healthy Volunteers
PubMed: 38916881
DOI: 10.1167/tvst.13.6.19 -
Translational Vision Science &... Jun 2024Surgical innovation in ophthalmology is impeded by the physiological limits of human motion, and robotic assistance may facilitate an expansion of the surgical...
PURPOSE
Surgical innovation in ophthalmology is impeded by the physiological limits of human motion, and robotic assistance may facilitate an expansion of the surgical repertoire. We conducted a systematic review to identify ophthalmic procedures in which robotic systems have been trialled, evaluate their performance, and explore future directions for research and development of robotic techniques.
METHODS
The Cochrane Library, Embase, MEDLINE, Scopus, and Web of Science were searched. Screening adhered to five criteria: (1) English language; (2) primary research article; (3) human patients; (4) ophthalmological surgery; and (5) robot-assisted surgery. Quality assessment was conducted with Joanna Briggs Institute Tools for Critical Appraisal. The study protocol was registered prospectively (PROSPERO ID CRD42023449793).
RESULTS
Twelve studies were included. In comparative studies, there was no difference in the occurrence of ocular harms in robot-assisted procedures and conventional surgery. However, robotic assistance did not demonstrate consistent benefits over manual surgery in terms of effectiveness or practicality, likely reflecting the learning curve associated with these systems. Single studies indicated the potential of robotic assistance to improve the consistency of subretinal drug infusion and efficiency of instrument manipulation in vitreoretinal surgery.
CONCLUSIONS
Proof-of-concept studies have demonstrated the potential of robotic assistance to facilitate procedures otherwise infeasible or impractical, and may broaden access to surgery. However, robot-assisted surgery has not yet demonstrated any significant benefits over standard surgical practice. Improving the speed and reducing perioperative requirements of robot-assisted surgery are particular priorities for research and innovation to improve the practicality of these novel techniques.
TRANSLATIONAL RELEVANCE
This systematic review summarizes the potential and limitations of robotic systems for assisting eye surgery and outlines what is required for these systems to benefit patients and surgeons.
Topics: Humans; Robotic Surgical Procedures; Ophthalmologic Surgical Procedures; Eye Diseases
PubMed: 38916880
DOI: 10.1167/tvst.13.6.20 -
Microbiology Spectrum Jun 2024Tuberculosis (TB) is a leading cause of death among infectious diseases worldwide due to latent TB infection, which is the critical step for the successful pathogenic...
UNLABELLED
Tuberculosis (TB) is a leading cause of death among infectious diseases worldwide due to latent TB infection, which is the critical step for the successful pathogenic cycle. In this stage resides inside the host in a dormant and antibiotic-tolerant state. Latent TB infection can also lead to multisystemic diseases because invades virtually all organs, including ocular tissues. Ocular tuberculosis (OTB) occurs when the dormant bacilli within the ocular tissues reactivate, originally seeded by hematogenous spread from pulmonary TB. Histological evidence suggests that retinal pigment epithelium (RPE) cells play a central role in immune privilege and in protection from antibiotic effects, making them an anatomical niche for invading . RPE cells exhibit high tolerance to environmental redox stresses, allowing phagocytosed bacilli to maintain viability in a dormant state. However, the microbiological and metabolic mechanisms determining the interaction between the RPE intracellular environment and phagocytosed are largely unknown. Here, liquid chromatography-mass spectrometry metabolomics were used to illuminate the metabolic state within RPE cells reprogrammed to harbor dormant bacilli and enhance antibiotic tolerance. Timely and accurate diagnosis as well as efficient chemotherapies are crucial in preventing the poor visual outcomes of OTB patients. Unfortunately, the efficacy of current methods is highly limited. Thus, the results will lead to propose a novel therapeutic option to synthetically kill the dormant inside the RPE cells by modulating the phenotypic state of and laying the foundation for a new, innovative regimen for treating OTB.
IMPORTANCE
Understanding the metabolic environment within the retinal pigment epithelium (RPE) cells altered by infection with and mycobacterial dormancy is crucial to identify new therapeutic methods to cure ocular tuberculosis. The present study showed that RPE cellular metabolism is altered to foster intracellular to enter into the dormant and drug-tolerant state, thereby blunting the efficacy of anti-tuberculosis chemotherapy. RPE cells serve as an anatomical niche as the cells protect invading bacilli from antibiotic treatment. LC-MS metabolomics of RPE cells after co-treatment with HO and infection showed that the intracellular environment within RPE cells is enriched with a greater level of oxidative stress. The antibiotic tolerance of intracellular within RPE cells can be restored by a metabolic manipulation strategy such as co-treatment of antibiotic with the most downstream glycolysis metabolite, phosphoenolpyruvate.
PubMed: 38916325
DOI: 10.1128/spectrum.00788-24 -
Bioinformatics Advances 2024Genomics-based diagnostic methods that are quick, precise, and economical are essential for the advancement of precision medicine, with applications spanning the...
MOTIVATION
Genomics-based diagnostic methods that are quick, precise, and economical are essential for the advancement of precision medicine, with applications spanning the diagnosis of infectious diseases, cancer, and rare diseases. One technology that holds potential in this field is optical genome mapping (OGM), which is capable of detecting structural variations, epigenomic profiling, and microbial species identification. It is based on imaging of linearized DNA molecules that are stained with fluorescent labels, that are then aligned to a reference genome. However, the computational methods currently available for OGM fall short in terms of accuracy and computational speed.
RESULTS
This work introduces OM2Seq, a new approach for the rapid and accurate mapping of DNA fragment images to a reference genome. Based on a Transformer-encoder architecture, OM2Seq is trained on acquired OGM data to efficiently encode DNA fragment images and reference genome segments to a common embedding space, which can be indexed and efficiently queried using a vector database. We show that OM2Seq significantly outperforms the baseline methods in both computational speed (by 2 orders of magnitude) and accuracy.
AVAILABILITY AND IMPLEMENTATION
https://github.com/yevgenin/om2seq.
PubMed: 38915884
DOI: 10.1093/bioadv/vbae079