Autonomic Laboratory Research Articles

Microfluidic-Assisted Human Cancer Cells Culturing Platform for Space Biology Applications.

In the paper, the lab-on-chip platform applicable for the long-term cultivation of human cancer cells, as a solution meeting the demands of the CubeSat biological missions, is presented. For the first time, the selected cancer cell lines—UM-UC-3 and RT 112 were cultured on-chip for up to 50 days. The investigation was carried out in stationary conditions (without medium microflow) in ambient temperature and utilizing the microflow perfusion system in the incubation chamber assuring typical cultivation atmosphere (37 °C). All the experiments were performed to imitate the conditions that are provided before the biological mission starts (waiting for the rocket launch) and when the actual experiment is initialized on a CubeSat board in space microgravity. The results of the tests showed appropriate performance of the lab-on-chip platform, especially in the context of material and technological biocompatibility. Cultured cells were characterized by adequate morphology—high attachment rate and visible signs of proliferation in each of the experimental stage. These results are a good basis for further tests of the lab-on-chip platform in both terrestrial and space conditions. At the end of the manuscript, the authors provide some considerations regarding a potential 3-Unit CubeSat biological mission launched with Virgin Orbit company. The lab-on-chip platform was modelled to fit a 2-Unit autonomous laboratory payload.

Perspectives on Water Quality Monitoring Approaches for Behavioral Change Research

This review considers enhanced approaches to river water quality monitoring in north-western Europe following a series of study visits (11 sites in 7 countries). Based on the evidence gathered, options were identified and evaluated for their suitability to deliver specific water quality monitoring objectives and with a focus on effecting behavioral change. Monitoring programs were diverse, ranging from enhanced grab sampling and laboratory analysis to sub-hourly sampling of multiple parameters and nutrients in autonomous high-specification, bank-side or mobile laboratories. Only one program out of all the cases evaluated could readily identify influences that had produced behavioral change among stakeholders. This was principally because the other programs were focused on top-down policy change or surveillance rather than specifically focused on influencing behavior. Nevertheless, program researchers were clear that stakeholder engagement potential was very high and that the sites acted as important focus points for discussion on water quality issues, and so part of a suite of tools that might ultimately change behavior. This identifies a space where water quality monitoring solutions could be adapted for behavioral change research.

Exploration of Ultralarge Compound Collections for Drug Discovery.

Designing new medicines more cheaply and quickly is tightly linked to the quest of exploring chemical space more widely and efficiently. Chemical space is monumentally large, but recent advances in computer software and hardware have enabled researchers to navigate virtual chemical spaces containing billions of chemical structures. This review specifically concerns collections of many millions or even billions of enumerated chemical structures as well as even larger chemical spaces that are not fully enumerated. We present examples of chemical libraries and spaces and the means used to construct them, and we discuss new technologies for searching huge libraries and for searching combinatorially in chemical space. We also cover space navigation techniques and consider new approaches to de novo drug design and the impact of the "autonomous laboratory" on synthesis of designed compounds. Finally, we summarize some other challenges and opportunities for the future.

Establishment of Normative Data for Autonomic Function Tests in Indian Population.

Background:Normative data for autonomic function tests (AFT) is not available for Indian population.Objective:The aim of the study was to establish normative data in AFT and its correlation with age, gender, and body mass index.Material and Methods:The study was done on 254 healthy subjects of age ≥18 years. All AFTs were done in autonomic laboratory at the Department of Neurology, Christian Medical College and Hospital, Ludhiana. Cardiovascular tests (heart rate response to deep breathing, HR changes in Valsalva maneuver and head-up tilt test (HUT)) and quantitative sudomotor axon reflex testing (QSART) were performed in all the subjects. Fifty subjects underwent thermoregulatory sweat test (TST).Results:The mean age (SD) of study participants was 43 (16.0) years (range 20–84), and 129 (50.8%) were men. The normative value range (2.5–97.5 percentile) for HR difference, E: I ratio, and Valsalva ratio (VR) was 3.5–47.0, 1.05–1.93, and 1.11–2.64, respectively, for all the subjects. HR difference and E: I ratio showed an significant inverse relation with age (r = -0.623 and r = -0.584, respectively). VR also showed an inverse relation with age (r = -0.575, P =< 0.001), and female had a lower value than male (1.63 vs 1.78, P =< 0.001). In QSART, mean (SD) sweat volume was higher in males 0.630 (0.230) compared to females 0.513 (0.132) for all sites, P < 0.001, and similar trend was noticed for sweat area in TST.Discussion and Conclusion:Normative AFT data has been established for Indian population for the first time. The values are comparable to previously published studies.

Short-term Heart Rate Variability to Evaluate Cardiovascular Autonomic Neuropathy in Newly Diagnosed Type 2 Diabetes Mellitus Patients: A Cross-sectional Study

Introduction: Cardiovascular Autonomic Neuropathy (CAN) may be seen in patients of Type 2 Diabetes Mellitus (T2DM). In many previous studies it was seen that there is reduced heart rate variability in DM patients. Reduced heart rate variability is earliest indicator for the CAN. In different earlier studies, it was found that results of Short-term Heart Rate Variability (HRV) analysis of five minutes is comparable to standard 24 hours HRV analysis. In DM patients CAN is mostly found to be associated with a longer duration of disease, but according to some studies CAN may be present in newly diagnosed diabetes patients also, but the percentage is lower. Aim: To assess the short-term HRV profile as cardiovascular risks among newly diagnosed T2DM patients and to find the correlation of HRV parameters with duration of disease and biochemical parameters; Fasting Plasma Glucose (FPG) and Postprandial Plasma Glucose (PPPG) for early detection and management of CAN. Materials and Methods: The present study was a cross-sectional study conducted in the Department of Physiology in collaboration with the Department of Endocrinology at R.G. Kar Medical College and Hospital, Kolkata, West Bengal, India, from September 2020 to August 2021 on 56 newly diagnosed T2DM (age group 30 to 64 years). Study subjects were grouped according to the Standard deviation of NN intervals (SDNN) (millisecond) value as cardiovascular risk factor. Group 1 was the low risk group, group 2 was the moderate risk group, group 3 was the high-risk group. HRV testing was done with Physiograph Polyrite-D instrument with bio-amplifiers, 4 channels and accessories (RMS latest software-Version 3.0.16) in Autonomic Function Research Laboratory to measure HRV parameters. After collecting data, analysis was done using Statistical Package for Social Sciences (IBM, SPSS) version 23.0 Unpaired student’s t-test, Chi-square test, Analysis of Variance (ANOVA) test, Pearson correlation test were performed and statistical significance of different parameters were evaluated. It was considered statistically significant when p-value &lt;0.05. Results: By assessing HRV parameters as cardiovascular risk factors among newly diagnosed T2DM patients the present study showed there was significantly (p-value=0.0065) high LF/HF ratio in males (1.70±1.19) than in females (0.99±0.69). The SDNN value was significantly highest in low cardiovascular risk group (137.29±25.49 ms) and lowest in high cardiovascular risk group (26.07±12.03 ms) (p-value=0.00001). Low Frequency and High Frequency Ratio (LF:HF ratio) was significantly more in age group of 51-60 years. Among all the patients, 34 (61%) patients had increased parasympathetic activity and 22 (39%) subjects had increased sympathetic activity. Female patients showed significantly more increased parasympathetic 24 (75%) activity than males 10 (41.7%). There was a significant association between SDNN values with the duration of disease (p-value=0.004). Conclusion: The present study showed that cardiac autonomic neuropathy is present even at the time of diagnosis of newly diagnosed T2DM as there was sympathovagal imbalance. Female patients have more parasympathetic drive than males which indicates that females are more cardioprotective.

ASSOCIATION OF DURATION OF TYPE 2 DIABETES MELLITUS WITH HEART RATE VARIABILITY AMONG NEWLY DIAGNOSED PATIENTS

AIM:To nd out any correlation of HRVparameters with duration of disease among newly diagnosed type 2 diabetes mellitus. MATERIALS AND METHODS: A cross sectional study was conducted for one year span from September 2020 to August 2021,in the Department of Physiology, R.G. Kar medical college in collaboration with Department of Endocrinology, R.G. Kar Medical College,Kolkata.56 Patients diagnosed to have T2DM within the age group of 30 and 64years (both genders) attending DIABETIC CLINIC run by the Department of Endocrinology at R.G. Kar Medical College and Hospital were screened to the Autonomic Function Research Laboratory of Physiology in the Department of Physiology, R.G. Kar Medical College and Hospital, Kolkata, West Bengal, India. Computer with software for HRV analysis Physiograph Polyrite-D instrument with bio-ampliers, 4channels and accessories(RMS latest software-Version 3.0.16) was used to analyse time domain and frequency domain parameters of short term heart rate variability of 5 minutes duration. RESULTS: Pearson correlation study showed signicant positive correlation of LF:HF ratio with duration of T2DM among newly diagnosed cases and statistically signicant negative correlation was found between duration of T2DM with SDNN. CONCLUSION :we can conclude that duration of disease of diabetes mellitus is associated with sympathovagal imbalance.So CAN screening should be routinely done in all patients even if type 2 diabetes mellitus is newly diagnosed.

Comparison of time domain heart rate variability parameters between smokers and non-smokers

Background: Cigarette smoking induced sympathetic overdrive is one of the major independent modifiable risk factors for cardiovascular mortality and morbidity. There is altered autonomic activity with increased adrenergic activity in chronic smoking which also predisposes to cardiovascular morbidity and mortality. There are several tests that can determine the Autonomic Activity. Among them, heart rate variability (HRV), especially the time domain parameters of it, is simple, easy to perform, and non-invasive test for diagnosing autonomic dysfunction in the smokers. Aims and Objectives: The aims of this study were to compare the time domain parameters of HRV in smokers and non-smokers. Materials and Methods: The present study was carried out at autonomic function laboratory and cardiovascular function laboratory, Department of Physiology, Government Medical College, Bhavnagar, among 200 subjects, out of which 100 were smokers and 100 were non-smokers, in age group of 20–50 years. Results: There was a significant increase in mean heart rate, blood pressure, and R-R interval in smokers as compared to the non-smokers. There was also a significant decrease in all time domain parameters of HRV which suggests profound sympathetic overdrive and a decrease in vagal tone due to the actions of nicotine presents in tobacco smoke. Conclusions: Cigarette smoking plays a major role in degradation and decreased function of autonomic nervous system.

Autonomous retrosynthesis of gold nanoparticles via spectral shape matching

A Riemannian metric for spectral data is introduced to efficiently compute shape matching distances for material retrosynthesis in high-throughput autonomous laboratories.

IBM builds on its autonomous laboratory

IBM has signed collaborations for its RoboRXN cloud-based autonomous laboratory with Atinary Technologies, Thieme Chemistry, Arctoris, Chemspeed Technologies, and Syngenta. For example, IBM says it will improve synthesis planning by incorporating synthesis data sets from Thieme’s human-curated organic chemistry resource. And Syngenta will implement RoboRXN in materials discovery . Separately, IBM says it has upgraded RoboRXN’s security and added models that help identify environmentally friendly enzymes for drug and materials discovery.

IBM builds on its autonomous laboratory

IBM builds on its autonomous laboratory

Estimating Resting HRV during fMRI: A Comparison between Laboratory and Scanner Environment.

Heart rate variability (HRV) is regularly assessed in neuroimaging studies as an indicator of autonomic, emotional or cognitive processes. In this study, we investigated the influence of a loud and cramped environment during magnetic resonance imaging (MRI) on resting HRV measures. We compared recordings during functional MRI sessions with recordings in our autonomic laboratory (LAB) in 101 healthy subjects. In the LAB, we recorded an electrocardiogram (ECG) and a photoplethysmogram (PPG) over 15 min. During resting state functional MRI, we acquired a PPG for 15 min. We assessed anxiety levels before the scanning in each subject. In 27 participants, we performed follow-up sessions to investigate a possible effect of habituation. We found a high intra-class correlation ranging between 0.775 and 0.996, indicating high consistency across conditions. We observed no systematic influence of the MRI environment on any HRV index when PPG signals were analyzed. However, SDNN and RMSSD were significantly higher when extracted from the PPG compared to the ECG. Although we found a significant correlation of anxiety and the decrease in HRV from LAB to MRI, a familiarization session did not change the HRV outcome. Our results suggest that psychological factors are less influential on the HRV outcome during MRI than the methodological choice of the cardiac signal to analyze.

Autonomic Dysfunction among Migraineurs with and without Complaints of Orthostatic Intolerance: Evidence for Small Fiber Nerve Damage

Background and Objective: Migraineurs often complain of orthostatic intolerance (OI), and its recognition is vital to appropriate treatment. This study attempts to identify and characterize autonomic dysfunction, comparing a sample of migraineurs with OI with a sample of migraineurs without OI. Methods: In a prospective cohort study, we examined one migraine sample complaining of OI for &gt; 6 months (Group 1) and another group without OI (Group 2), using a 70-degree, 45-minute head-up passive tilt-table (HUT45) test, electrocardiographic R-R interval measurements during deep breathing, blood pressure and heart rate monitoring during Valsalva and release, QSART, and skin biopsy for nerve fiber density. We compared results with standard, 10-minute head-up passive tilt-table (HUT10) results to determine which test promoted greater sensitivity, specificity and diagnostic accuracy. Descriptive statistics were computed for each group, defined by the presence or absence of OI. We conducted several receiver operating characteristic analyses to determine whether certain clinical characteristics were predictive of symptoms of OI. Results: Thirty-nine Group 1 and 22 Group 2 subjects were studied and were similar demographically. Thirty eight of 39 (97.4%) Group 1, versus 15/22 (68.2%) Group 2 subjects, manifested abnormal HUT45 results, a significant difference (p=0.002). The HUT45 showed higher sensitivity (0.59; 95% CI: 0.42-0.74) than the standard 10-minute tilt-table test (HUT10) for all expressions of OI (0.31; 95% CI: 0.17-0.48). No differences in autonomic laboratory or skin biopsy findings distinguished the groups. We detected biopsy-proven small fiber neuropathy in 22/39 (56.4%) Group 1 and 10/22 (45.5%) Group 2 subjects. Discussion and Conclusions: In migraineurs, OI is an expression of autonomic dysfunction. We found evidence for a peripheral autonomic deficit on skin biopsy in 45% or more of both groups of migraineurs. Extending the head-up tilt table test to 45-minutes increases diagnostic sensitivity, spares patients misdiagnosis and unnecessary testing, and satisfies the principle of ecological validity.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE: GRADING OF SEVERITY AS REFLECTED BY SHORT TERM HEART RATE VARIABILITY.

Chronic obstructive pulmonary disease (COPD) is a broad spectrum respiratory illness where there are structural and functional changesin the lungs. According to WHO, COPD is a leading global burden and by 2030 it will be the third leading cause of death worldwide. The structural and functional changes in the lungs in COPD patients tend to inuence the cardiac autonomic functions and heart rate variability (HRV). Previousstudiesshow that there is decrease in heart rate variability in COPD patients. In many previousstudies, it isfound that results ofshort term HRV analysis of 5minutes is comparable to standard 24hours HRV analysis and is very patient friendly and reproducible procedure to analyse the cardiac autonomic functions. So determination of parameters of cardiac autonomic functions with the help of short term HRV analysis in COPD patients is helpful in determining the pathophysiology and subsequent management of such patients. A Descriptive and observational study was conducted upon 100 previously diagnosed COPD patients at the Autonomic function research Laboratory, Department of Physiology, R G Kar Medical College and Hospital, Kolkata, West Bengal. The study includes short term (5min) HRV analysis in COPD patients between the age group 18years and 60years after fullling appropriate inclusion and exclusion criteria and the results were analyzed using proper statistical software. After analysis of different data it was found that there is decrease in heart rate variability (in both Time domain and Frequency domain analysis) in case of COPD and also the decrease is more in case of increasing severity grading of COPD. Sympathetic activity increases and vagal or parasympathetic activity upon heart rate decreases with the increase in COPD grading. Further studies with more number of subjects will be helpful in assessing pathophysiology and management of COPD patients with the help of HRV analysis.

Cardiology meets neurology: clinical presentation and management of patients with primary neurogenic disorders and orthostatic intolerance.

Patients with primary neurogenic disorders such as pure autonomic failure or multiple system atrophy may initially present with cardiocirculatory symptoms such as orthostatic intolerance or fluctuations in heart rate with symptomatic tachycardia. It is therefore clinically important to identify such patients since circulatory manifestations are only one of aseries of symptoms resulting from autonomic dysfunction in various organ systems. These patients require amultimodal diagnostic and therapeutic approach and should undergo extensive evaluation in aspecialized autonomic nervous system (ANS) outpatient unit. Based on aclinical case presentation, the current review summarizes the diagnostic and therapeutic approach to key cardiovascular symptoms of primary autonomic disorders and their neurological work-up in aspecialized autonomic function laboratory.

TS-HDS and FGFR3 antibodies in small fiber neuropathy and Dysautonomia.

The specificity of trisulfated heparin disaccharide/fibroblast growth factor receptor 3 (TS-HDS/FGFR3) antibodies in the diagnosis of autoimmune small fiber neuropathy (SFN) is unclear. This was a retrospective study of patients evaluated for SFN and dysautonomia in the Brigham and Women's Faulkner Hospital Autonomic Laboratory in 2019-2020. Associations were assessed between TS-HDS/FGFR3 antibodies and SFN markers, including epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD), and autonomic dysfunction assessed by Valsalva maneuver, deep breathing, sudomotor, and tilt testing. Of 322 patients; 28% had elevated anti-TS-HDS, 17% had elevated anti-FGFR3, 96% had autonomic dysfunction, 71% had abnormal ENFD, and 49% had abnormal SGNFD. TS-HDS/FGFR3 antibodies were present in patients with autonomic dysfunction irrespective of whether they had normal or abnormal skin biopsies unless ENFD/SGNFD were combined for anti-FGFR3 seropositivity. TS-HDS/FGFR3 antibodies are present in patients with evidence of autonomic dysfunction. Further studies are needed to document the clinical value of these antibodies in assessment of immune mediated dysautonomia.

A comparative study between single lead AD8232 heart rate monitor and standard electrocardiograh to acquire electrocardiographic data for cardiac autonomic function testing

Objectives: The present study was to develop and design a simple and low cost ECG setup for patient care. The device is a low cost and simple approach for acquiring ECG data. The present study mainly focuses on reliability and consistency for acquiring the ECG data. It should be simple to use, portable and low cost to implement. Methods: The following study was conducted between two groups of subjects; each group contains n=40 subjects. First the subjects were recruited to the department of physiology autonomic function laboratory and the demographic and anthropometric data was acquired. The subjects were allowed to rest for some time. Single lead ECG was obtained using AD8232 custom designed module and was connected to a laptop as signal was captured by audacity software and compared against a medical grade ECG monitor and the results were analyzed. Findings: From our study it is clearly evident that there is a strong positive correlation of ECG data obtained between AD8232 and standard clinically approved ECG monitor r=0.9 (p 0.001). Now it is clearly evident that we can use AD8232 module instead of standard ECG device for basic monitoring. Novelty: The new device developed successfully captured single lead ECG which is a low cost implementation around |2350 (table given in annexure). Capturing ECG with microphone input is quite new way of acquiring ECG signals. The new device was easy to set up, no special software is needed to acquire the signal runs on USB voltage which is 5v. The device is simple to use, open source hardware and consistent with the recordings when compared with the standard ECG monitor. The latest device can be configured in many ways for future applications using open source sound capturing software. Audacity open source software. Keywords: Portable ECG; single lead; USB; open source; AC; DC; AD8232; GPL

Characterization of Autonomic Dysfunction Among Migraineurs With and Without Complaints of Orthostatic Intolerance

Purpose and Hypothesis: To identify and distinguish central autonomic dysfunction from peripheral autonomic dysfunction (or both) in migraineurs suffering from orthostatic intolerance (OI) compared to migraineurs not suffering from OI. We hypothesize that OI manifests from a predominantly central autonomic component. Methods: We studied two populations of migraineurs, one group complaining of symptoms of OI for 6 months or longer and a group without OI symptoms, using a 70-degree, 45-minute passive head-up tilt-table test (HUT), R-R interval measurements during deep breathing, blood pressure and heart rate monitoring during Valsalva maneuver and release, Quantitative Sudomotor Axon Reflex Test (QSART), and skin biopsy for intraepidermal nerve fiber density. Categorical differences between the two populations were compared using exact likelihood ratio chi-square tests, and 95% confidence intervals for sensitivity, specificity, positive and negative predictive values were calculated. Results: Thirty-seven migraineurs with OI (Group 1) and 22 migraineurs without (Group 2) were studied and were demographically similar except for a greater representation of migraines with brainstem auras in Group 1 (27% v 5%; p= 0.032). Ninety-seven percent of Group 1 patients, versus 68% Group 2, manifested abnormal 45-minutes HUT, a significant difference (p=0.020, Fisher’s exact test). The first 5-minute evaluation of the HUT exhibited high specificity (1.00; 95% CI: 0.85-1.00) for the diagnosis of postural tachycardia syndrome (POTS) with a positive predictive value of 1.00 (0.59, 1.00; p=0.037). The HUT extended to 45-minutes however showed greater sensitivity compared with the 10-minute HUT (0.95; 95% CI:0.82-0.99; p=0.020). We found no differences between groups in autonomic laboratory or skin biopsy findings. Fifty-seven percent of Group 1 and 50% of Group 2 exhibited biopsy-proven small fiber neuropathy (SFN), a difference that did not reach statistical significance. Conclusions: We failed to confirm our hypothesis that OI is a manifestation of a central autonomic dysfunction in migraineurs. The finding of SFN in a majority of subjects points to peripheral autonomic contributions and raises the possibility of an underlying systemic disorder. Extending HUT table testing to 45-minutes increases diagnostic sensitivity and better reflects life events. Funding Statement: This study was supported by a grant from the Bakken Heart-Brain Institute, Cleveland Clinic, Cleveland, Ohio, USA. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study was approved by the Cleveland Clinic’s Institutional Review Board. Informed consent was obtained from all participants in the study.

A mobile DNA laboratory for forensic science adapted to coronavirus SARS-CoV-2 diagnosis

The Forensic Science Institute of the French “Gendarmerie Nationale” (IRCGN™) developed in 2015 an ISO 17025 certified mobile DNA laboratory for genetic analyses. This Mobil’DNA laboratory is a fully autonomous and adaptable mobile laboratory to perform genetic analyses in the context of crime scenes, terrorism attacks or disasters. To support the hospital task force in Paris during the peak of the COVID-19 epidemic, we adapted this mobile genetic laboratory to perform high-throughput molecular screening for coronavirus SARS-CoV-2 by real-time PCR. We describe the adaptation of this Mobil’DNA lab to assist in Coronavirus SARS-CoV-2 diagnosis.

Self-driving laboratory for accelerated discovery of thin-film materials.

Discovering and optimizing commercially viable materials for clean energy applications typically takes more than a decade. Self-driving laboratories that iteratively design, execute, and learn from materials science experiments in a fully autonomous loop present an opportunity to accelerate this research process. We report here a modular robotic platform driven by a model-based optimization algorithm capable of autonomously optimizing the optical and electronic properties of thin-film materials by modifying the film composition and processing conditions. We demonstrate the power of this platform by using it to maximize the hole mobility of organic hole transport materials commonly used in perovskite solar cells and consumer electronics. This demonstration highlights the possibilities of using autonomous laboratories to discover organic and inorganic materials relevant to materials sciences and clean energy technologies.

Team-Based Learning for Scientific Computing and Automated Experimentation: Visualization of Colored Reactions

The increasing integration of software and automation in modern chemical laboratories prompts special emphasis on two important skills in the chemistry classroom. First, students need to learn the technical skills involved in modern scientific computing and automation. Second, applying these techniques in practice requires effective collaboration in teams. This work aims at developing a teaching module to help students gain both skills. In particular, we describe a modular and collaborative approach for introducing undergraduate students to scientific computing in the context of automated and autonomous chemical laboratories. Using online collaboration tools, students work in parallel teams to develop central components of an automated computer vision system that monitors color changes in ongoing chemical reactions. These components include three different aspects: image capture, communication, and data visualization. The image capture team collects and stores the images of the chemical reaction, the communication team processes the images, and the visualization team develops the tools for analyzing the processed image data. Using this educational framework, students built an open-source Python tool called AutoVis that enables the automated tracking of color and intensity changes in a liquid. The software is tested by simulating chemical reactions with dilute solutions of food coloring in water. It is shown that the system reliably tracks color and intensity, providing feedback to the experimentalist and enabling further computational analysis. Over the course of the project, students gain proficiency in scientific computing using Python and collaborate on software development using GitHub. In this way, they learn the role of software in chemical laboratories of the future.