Physiological Observations Research Articles

Reduced tumor growth in EP2 knockout mice is related to signaling pathways favoring an increased local anti‑tumor immunity in the tumor stroma.

Inflammatory signaling through prostaglandin E2 receptor subtype 2 (EP2) is associated with malignant tumor growth in both experimental models and cancer patients. Thus, the absence of EP2 receptors in host tissues appears to reduce tumor growth and systemic inflammation by inducing major alterations in gene expression levels across tumor tissue compartments. However, it is not yet well-established how signaling pathways in tumor tissue relate to simultaneous signaling alterations in the surrounding tumor-stroma, at conditions of reduced disease progression due to decreased host inflammation. In the present study, wild-type tumor cells, producing high levels of prostaglandin E2 (MCG 101 cells, EP2+/+), were inoculated into EP2 knockout (EP2−/−) and EP2 wild-type (EP2+/+) mice. Solid tumors were dissected into tumor- and tumor-stroma tissue compartments for RNA expression microarray screening, followed by metabolic pathway analyses. Immunohistochemistry was used to confirm adequate dissections of tissue compartments, and to assess cell proliferation (Ki-67), prostaglandin enzymes (cyclooxygenase 2) and immunity biomarkers (CD4 and CD8) at the protein level. Microarray analyses revealed statistically significant alterations in gene expression in the tumor-stroma compartment, while significantly less pathway alterations occurred in the tumor tissue compartment. The host knockout of EP2 receptors led to a significant downregulation of cell cycle regulatory factors in the tumor-stroma compartment, while interferon γ-related pathways, chemokine signaling pathways and anti-tumor chemokines [chemokine (C-X-C motif) ligand 9 and 10] were upregulated in the tumor compartment. Thus, such gene alterations were likely related to reduced tumor growth in EP2-deficient hosts. On the whole, pathway analyses of both tumor- and tumor-stroma compartments suggested that absence of host EP2 receptor signaling reduces ‘remodeling’ of tumor microenvironments and increase local immunity, probably by decreased productions of stimulating growth factors, perhaps similar to well-recognized physiological observations in wound healing.

Starch Degradation and Sucrose Accumulation of Lily Bulbs after Cold Storage.

Functional lilies are a group of edible lily cultivars with great potential for landscape application. Low-temperature storage can significantly improve their taste, but the knowledge of this process is largely unknown. In this study, we used the functional lilies ‘Fly Shaohua’ and ‘Fly Tiancheng’ as materials. Through physiological observation and transcriptome analysis during the bulbs’ cold storage, it was found that the starch degradation and sucrose accumulation in bulbs contributed to taste improvement. After 60 d of cold storage, the sucrose accumulation was highest and the starch content was lower in the bulbs, suggesting this time-point was optimal for consumption. Accompanying the fluctuation of sucrose content during cold storage, the enzyme activities of sucrose phosphate synthase and sucrose synthase for sucrose synthesis were increased. Transcriptome analysis showed that many differentially expressed genes (DEGs) were involved in the starch and sucrose metabolism pathway, which might promote the conversion of starch to sucrose in bulbs. In addition, the DEGs involved in dormancy and stress response were also determined during cold storage, which might explain the decreased sucrose accumulation with extended storage time over 60 d due to the energy consumption for dormancy release. Taken together, our results indicated sucrose accumulation was a main factor in the taste improvement of lily bulbs after cold storage, which is attributable to the different gene expression of starch and sucrose metabolism pathways in this process.

Caloric stimulation of the labyrinth and some forgotten pioneers

Introduction Understanding the physiology of the caloric stimulation of the vestibular end organ was a seminal discovery in the history of neurotology. Robert Barany has been traditionally credited with this (1906). However, well before Barany, three scientists observed, qualified and quantified a similar phenomenon with different explanations. They were Charles Edouard Brown Sequard (1858), A Bornhardt (1876) and Benno Baginsky (1881). Materials and methods Articles with key words containing ‘caloric test’ and the ‘vestibular system’ were searched and studied from a historical perspective in scientific research repositories and journals on the history of medicine. Contemporaneous articles of the three scientists were analysed and inferences drawn. Results and discussion Charles Edouard Brown Sequard noticed the caloric effect on the ear causing giddiness in 1853, A Bornhardt observed nystagmus on application of ice cold water/hot iron rod to the semicircular canals in 1876 and Benno Baginsky in 1881 identified the correct pressure/temperature on the external/middle ear to elicit a caloric response. They also stumbled across key observations of vestibular physiology which were later confirmed in the 20th century. Conclusions This paper resurrects the works of these three forgotten pioneers and their contributions to our understanding of the physiology of the vestibular system.

Anatomically and physiologically informed computational model of hepatic contrast perfusion for virtual imaging trials.

Virtual (in silico) imaging trials (VITs), involving computerized phantoms and models of the imaging process, provide a modern alternative to clinical imaging trials. VITs are faster, safer, and enable otherwise-impossible investigations. Current phantoms used in VITs are limited in their ability to model functional behavior such as contrast perfusion which is an important determinant of dose and image quality in CT imaging. In our prior work with the XCAT computational phantoms, we determined and modeled inter-organ (organ to organ) intravenous contrast concentration as a function of time from injection. However, intra-organ concentration, heterogeneous distribution within a given organ, was not pursued. We extend our methods in this work to model intra-organ concentration within the XCAT phantom with a specific focus on the liver. Intra-organ contrast perfusion depends on the organ's vessel network. We modeled the intricate vascular structures of the liver, informed by empirical and theoretical observations of anatomy and physiology. The developed vessel generation algorithm modeled a dual-input-single-output vascular network as a series of bifurcating surfaces to optimally deliver flow within the bounding surface of a given XCAT liver. Using this network, contrast perfusion was simulated within voxelized versions of the phantom by using knowledge of the blood velocities in each vascular structure, vessel diameters and length, and the time since the contrast entered the hepatic artery. The utility of the enhanced phantom was demonstrated through a simulation study with the phantom voxelized prior to CT simulation with the relevant liver vasculature prepared to represent blood and iodinated contrast media. The spatial extent of the blood-contrast mixture was compared to clinical data. The vascular structures of the liver were generated with size and orientation which resulted in minimal energy expenditure required to maintain blood flow. Intravenous contrast was simulated as having known concentration and known total volume in the liver as calibrated from time-concentration curves. Measurements of simulated CT ROIs were found to agree with clinically observed values of early arterial phase contrast enhancement of the parenchyma ( HU). Similarly, early enhancement in the hepatic artery was found to agree with average clinical enhancement HU). The computational methods presented here furthered the development of the XCAT phantoms allowing for multi-timepoint contrast perfusion simulations, enabling more anthropomorphic virtual clinical trials intended for optimization of current clinical imaging technologies and applications.

Bridging physiological and perceptual views of autism by means of sampling-based Bayesian inference.

Theories for autism spectrum disorder (ASD) have been formulated at different levels, ranging from physiological observations to perceptual and behavioral descriptions. Understanding the physiological underpinnings of perceptual traits in ASD remains a significant challenge in the field. Here we show how a recurrent neural circuit model that was optimized to perform sampling-based inference and displays characteristic features of cortical dynamics can help bridge this gap. The model was able to establish a mechanistic link between two descriptive levels for ASD: a physiological level, in terms of inhibitory dysfunction, neural variability, and oscillations, and a perceptual level, in terms of hypopriors in Bayesian computations. We took two parallel paths-inducing hypopriors in the probabilistic model, and an inhibitory dysfunction in the network model-which lead to consistent results in terms of the represented posteriors, providing support for the view that both descriptions might constitute two sides of the same coin.

Prognostic value of National Early Warning Scores (NEWS2) and component physiology in hospitalised patients with COVID-19: a multicentre study

BackgroundNational Early Warning Scores (NEWS2) are used to detect all-cause deterioration. While studies have looked at NEWS2, the use of virtual consultation and remote monitoring of patients with COVID-19 mean...

Loss of OsEAF6, a Subunit of the Histone Acetyltransferase Complex, Causes Hybrid Breakdown in Intersubspecific Rice Crosses.

Gene duplication plays an important role in genetic diversification, adaptive evolution, and speciation. Understanding the mechanisms and effects of postzygotic isolation genes is important for further studies of speciation and crop breeding. The duplicate recessive genes hwe1 and hwe2 cause hybrid breakdown, characterized by poor vegetative growth and reproductive dysgenesis in intersubspecific crosses between Oryza sativa ssp. indica and japonica. Using a map-based cloning strategy, we found that HWE1 and HWE2 encode the Esa1-associated factor 6 (EAF6) protein, a component of histone acetyltransferase complexes. The indica hwe1 and japonica hwe2 alleles lacked functional EAF6, demonstrating that the double recessive homozygote causes hybrid breakdown. Morphological and physiological observations showed that weak plants with double recessive homozygotes had serious morphological defects with a wide range of effects on development and organs, leading to leaves with reduced chlorophyll content, flower and pistil malformation, and anomalies of gametogenesis. These findings suggest that EAF6 plays a pivotal role in the transcriptional regulation of essential genes during the vegetative and reproductive development of rice.

Seed Germination Mechanism of Carex rigescens Under Variable Temperature Determinded Using Integrated Single-Molecule Long-Read and Illumina Sequence Analysis.

The turfgrass species Carex rigescens has broad development and utilization prospects in landscaping construction. However, seed dormancy and a low germination rate have inhibited its application. Furthermore, the molecular mechanisms of seed germination in C. rigescens have not been thoroughly studied. Therefore, in the present study, PacBio full-length transcriptome sequencing combined with Illumina sequencing was employed to elucidate the germination mechanism of C. rigescens seeds under variable temperatures. In general, 156,750 full-length non-chimeric sequences, including those for 62,086 high-quality transcripts, were obtained using single-molecule long read sequencing. In total, 40,810 high-quality non-redundant, 1,675 alternative splicing, 28,393 putative coding sequences, and 1,052 long non-coding RNAs were generated. Based on the newly constructed full-length reference transcriptome, 23,147 differentially expressed genes were identified. We screened four hub genes participating in seed germination using weighted gene co-expression network analysis. Combining these results with the physiological observations, the important roles of sucrose and starch metabolic pathways in germination are further discussed. In conclusion, we report the first full-length transcriptome of C. rigescens, and investigated the physiological and transcriptional mechanisms of seed germination under variable temperatures. Our results provide valuable information for future transcriptional analyses and gene function studies of C. rigescens.

Precise Fluid-Solid Simulation of Human Left Ventricle along with Aortic Valve during Systole

This paper presents an accurate blood flow model with tissue deformation of the human left ventricle, including the aortic valve. A two-way fluid-solid Interaction (FSI) algorithm is employed to simulate the performance of the human left ventricle during systole. The initial geometry of the left ventricle is extracted from CT scan images of a healthy person. The simulation results produced the systolic anterior motion of the Left Ventricle (LV) identical with the CT scan images at later times during systole. Besides, the numerical results for left ventricular volume change, maximum blood velocity at the aortic valve, and its maximum opening are in good agreement with physiological data. Although no clear image of the aortic valve is apparent in CT images, the FSI simulation predicted the maximum opening of the aortic valve to be 4.38 cm2 which is consistent with physiological observation on a healthy individual. As an application of the above algorithm, a model of Hypertrophic Cardiomyopathy (HCM) or septal wall thickening disease is constructed and studied during systole. This simulation provides an understanding of heart performance under HCM conditions. According to the simulation outcomes, the mitral valve approaches the septal wall under HCM due to the change in pressure gradient and the drag force on the mitral valve. This blockage of the LV blood passage by the mitral valve results in stagnation pressure loss and weaker hearth pumping power. Therefore, the maximum opening of the aortic valve, in this case, is 2.28 cm2, which is much lower than the physiological range, indicating the drastic effect of HCM on the performance of the aortic valve and systolic performance.

Analysis of Potential Utilization of Landfill Materials (Case Study: Sumur Batu Landfill, Bekasi)

One of the efforts to overcome the critical problem of land usage for landfill and regenerate waste is to reuse the expired landfill after managing them. The purpose of this study is to determine the potential utilization of waste from landfill mining activities. At 15 sample depth points in zone 1 of Sumur Batu Landfill from 2004-2007 waste, the composition of mining landfill waste consists of 29% soil/organic fraction; 25% other waste; 23% plastic; 11% overburden; 5% diaper waste; 2% cloth; 2% wood; 1% glass; 1% rubber; and 1% metal. The particle size of the landfill waste has a diameter distribution of >38.1 mm to <2mm which is almost evenly distributed with values ranging from 9-20%. The calorific value of combustible waste is 3, 569.47 kcal/kg. The chemical characteristics of the landfill soil mining fraction consisted of C-Organic 29.55%, NTK 0.65%, C/N 29.59, and Total-P 22.84%. Dosage variation of landfill mining soil fraction as a planting medium with soil used for research, respectively 1:4, 1:5, and 1:6, and soil with Bokham compost as control. The use of landfill soil fraction as a planting medium with 3 types of soil, namely clay, laterite, and acid clay causes a decrease in the growth of mung beans (Vignaradiata L.). However, the 1:4 landfill soil fraction dose gave a positive response to the physiological observations of plants compared to the other two doses of variation. The potential for landfill waste is 100, 000 tons, the total cost of landfill mining activities is Rp. 25, 829, 996, 775, and the total benefits of landfill mining activities are Rp.26, 347, 223, 544, with the use of combustible waste to produce electricity and/or heat using an incinerator, the benefit ratio value is 1.02 which is means that the activities of the Zone 1 of Sumur Batu Landfill is feasible to carry out. Based on these data, with organic waste as the dominant waste in the Sumur Batu Landfill, the best possibility in utilizing waste is to use the waste as soil fertilizer.

Inpatient COVID-19 mortality has reduced over time: Results from an observational cohort.

BackgroundThe Covid-19 pandemic in the United Kingdom has seen two waves; the first starting in March 2020 and the second in late October 2020. It is not known whether outcomes for those admitted with severe Covid were different in the first and second waves.MethodsThe study population comprised all patients admitted to a 1,500-bed London Hospital Trust between March 2020 and March 2021, who tested positive for Covid-19 by PCR within 3-days of admissions. Primary outcome was death within 28-days of admission. Socio-demographics (age, sex, ethnicity), hypertension, diabetes, obesity, baseline physiological observations, CRP, neutrophil, chest x-ray abnormality, remdesivir and dexamethasone were incorporated as co-variates. Proportional subhazards models compared mortality risk between wave 1 and wave 2. Cox-proportional hazard model with propensity score adjustment were used to compare mortality in patients prescribed remdesivir and dexamethasone.ResultsThere were 3,949 COVID-19 admissions, 3,195 hospital discharges and 733 deaths. There were notable differences in age, ethnicity, comorbidities, and admission disease severity between wave 1 and wave 2. Twenty-eight-day mortality was higher during wave 1 (26.1% versus 13.1%). Mortality risk adjusted for co-variates was significantly lower in wave 2 compared to wave 1 [adjSHR 0.49 (0.37, 0.65) p<0.001]. Analysis of treatment impact did not show statistically different effects of remdesivir [HR 0.84 (95%CI 0.65, 1.08), p = 0.17] or dexamethasone [HR 0.97 (95%CI 0.70, 1.35) p = 0.87].ConclusionThere has been substantial improvements in COVID-19 mortality in the second wave, even accounting for demographics, comorbidity, and disease severity. Neither dexamethasone nor remdesivir appeared to be key explanatory factors, although there may be unmeasured confounding present.

Randomized Open Controlled Clinical Trial to Evaluate the Effect of Patol Shunthi Ghruth in Urdhwag Amlapitta.

Amlapittais a life-style related disease prevalent all over the world. Amlapittais disorder caused by habitat, irregular diet schedule and activities but also as a result of Psychological and physiological observation. Amlapitta is a common functional disease of Annavaha srotas. Materialistic life style provokes people to run behind a busy, stressful life which is least concern towards proper food habits.As the life is becoming very fast and the rate of urbanisation is growing. Adhyashana(eating after meal),Vishamashana(diet on irregular time and quantity), and wrong behavioural patterns such asVegadharana(suppression of urges) leads to vitiation ofDoshas. Pittahas been vitiated, junk food and drink that are incompatible, spoiled, and very sour and that is capable of causing vitiation of pittaand increase dravaand amla gunaof pitta.

Research on Classroom Teaching Quality Evaluation Method Based on Machine Vision Analysis

Concentration is one of the key factors of human intelligent behaviour. Especially in recent years, our attention to learners has received extensive attention. Many evaluation methods are put forward for the evaluation of concentration, including questionnaire, physiological observation and computer vision. In the classroom of primary and secondary schools, students' concentration in class is an important factor that affects students' achievement and teaching effect, so it is a major concern of many parents. Firstly, the analytic hierarchy process is used to construct the evaluation index system, then the multi-population genetic algorithm is used to optimize the design of BP neural network, and finally the BP neural network is used to evaluate the teaching quality. In the traditional classroom environment, students' classroom participation research is mostly obtained through questionnaires designed after class. The lack of real-time learning monitoring and analysis in the classroom is far from meeting the needs of modern education development. Therefore, there is an urgent need for Research on an automatic learning state evaluation method that uses artificial intelligence technology to evaluate students' full and whole process, assist teachers to understand and master students' learning state, adopt targeted teaching methods, and improve students' personalized training level.

A critical review and analysis of Amlapitta from Samhitas.

Amlapittais very common disease in present era. Amlapittais a life-style related disease prevalent all over the world.Amlapittais disorder caused by habitat, irregular diet schedule and acivities but also as a result of Psychological and physiological observation. As the life is becoming very fast and the rate of urbanisation is growing. Pittahas been vitiated uses food and drink that are incompatible, spoiled, and very sour and that is capable of causing vitiation of pittaand increase dravaand amlagunaof pitta. Aacharya Kashyapahas mentioned as the involvement of three Doshasin Amlapittawhile Madhavkarahas mentioned that the pittais dominant in this disease. Aacharya Charakahas not mentioned Amlapittaas a separate disease but as a symptom. Aacharya Charakhas described amlapittain Granhi(intermittent loose motions followed by constipation) as one of its Lakshana(symptom). Various acharyas has explained amlapittain different way with all nidan panchakof this disease but Sampraptiof Amlapitta is clearly mentioned in Grahanichikitsaadhyaywhile describing sampraptiof Grahani Dosha. The basic principle of treatment is mainly nidana parivarjana, shodhana, and shamana chikitsa. Vamanaand Virechana are mentioned for urdhva gatiand adho gatiof doshasalong with pathaya-pathayaof amalpitta.

Yeasts from temperate forests.

Yeasts are ubiquitous in temperate forests. While this broad habitat is well-defined, the yeasts inhabiting it and their life cycles, niches, and contributions to ecosystem functioning are less understood. Yeasts are present on nearly all sampled substrates in temperate forests worldwide. They associate with soils, macroorganisms, and other habitats and no doubt contribute to broader ecosystem-wide processes. Researchers have gathered information leading to hypotheses about yeasts' niches and their life cycles based on physiological observations in the laboratory as well as genomic analyses, but the challenge remains to test these hypotheses in the forests themselves. Here, we summarize the habitat and global patterns of yeast diversity, give some information on a handful of well-studied temperate forest yeast genera, discuss the various strategies to isolate forest yeasts, and explain temperate forest yeasts' contributions to biotechnology. We close with a summary of the many future directions and outstanding questions facing researchers in temperate forest yeast ecology. Yeasts present an exciting opportunity to better understand the hidden world of microbial ecology in this threatened and global habitat.

General Overview of Yeast and Yeast Cell as a Novel Model for Investigations

Biological scientists have been looking for a suitable experimental organism which can provide better understanding of biomolecular mechanisms involved in the physiological processes and observations can be readily interpolated. It can be easily procured, cost effective, and better maintained in laboratory conditions. Yeast is practically omnipresent in most of the biomes and exhibits higher genetic diversity in comparison to most of the angiosperms or chordates. These eukaryotes have very simple and short life cycle exhibiting budding, and sexual reproduction. Mostly, there are no ethical issues related to this organism being used as experimental model. Its small genome is the prime factor that makes easy manipulations in the field of molecular genetics, genomics, evolutionary genomics, senescence, cell cycle, biomedical genetics, and biotechnology. This experimental model opens new horizons in the direction of functional genomics that may be helpful in encoding metabolic mechanisms and ecological diversities.

2 Play to Prepare with Technology-Enhanced Simulation

Traditional simulation training within medical education has been well established for several decades and involves playing out emergency situations in a role-play format. This type of simulation training is typically located at hospitals and medical centres and requires considerable organization, costs, in-person attendance and allocated time away from clinical commitments. Technological transformation within healthcare education is growing and, in particular, there has been an increase in mobile applications (apps) to aid medical education. Coupling the two together has allowed ‘gamification’ to emerge and grow in popularity as a powerful tool to enhance learning retention.The aim of this innovation project was to create a technology-enhanced simulation app for mobile devices to train in Advanced Life Support (ALS) for cardiopulmonary arrest, using game mechanics.A technology-enhanced simulation mobile app called ‘SimPL’ has been created to facilitate technology-enhanced learning on mobile devices. It allows the user to run physiological observations on a simulated patient. This has gained popularity on the Apple and Google Play Store amongst healthcare professionals. We now want to build on this and start by simulating ALS for cardiopulmonary arrest. A minimum viable demo that healthcare professionals can use to run an ALS scenario is being developed. The aim is to allow healthcare professionals to run through an interactive ALS scenario and give the user flexibility to make any decision they want regarding intervention and see how the patient responds to it. It provides real-time, haptic and constructive performance feedback to the intervention being carried out.The use of technology-enhanced simulation for healthcare education is a novel area and with the fast acceleration of game mechanics development, there is scope for medical education to be delivered in this way. The technology-enhanced simulation app will be launched on the Apple and Google Play Store to all healthcare professionals around the world. Feedback will be gathered from users to allow further developments of the product. The overall outcome is to produce a network of mobile apps to deliver medical education in an interactive, engaging and easily accessible way to help clinicians prepare for emergency medical situations anytime, anywhere.

Evaluating the 35°C wet-bulb temperature adaptability threshold for young, healthy subjects (PSU HEAT Project).

A wet-bulb temperature of 35°C has been theorized to be the limit to human adaptability to extreme heat, a growing concern in the face of continued and predicted accelerated climate change. Although this theorized threshold is based in physiological principles, it has not been tested using empirical data. This study examined the critical wet-bulb temperature (Twb,crit) at which heat stress becomes uncompensable in young, healthy adults performing tasks at modest metabolic rates mimicking basic activities of daily life. Across six experimentally determined environmental limits, no subject's Twb,crit reached the 35°C limit and all means were significantly lower than the theoretical 35°C threshold. Mean Twb,crit values were relatively constant across 36°C -40°C humid environments and averaged 30.55 ± 0.98°C but progressively decreased (higher deviation from 35°C) in hotter, dry ambient environments. Twb,crit was significantly associated with mean skin temperature (and a faster warming rate of the skin) due to larger increases in dry heat gain in the hot-dry environments. As sweat rates did not significantly differ among experimental environments, evaporative cooling was outpaced by dry heat gain in hot-dry conditions, causing larger deviations from the theoretical 35°C adaptability threshold. In summary, a wet-bulb temperature threshold cannot be applied to human adaptability across all climatic conditions and where appropriate (high humidity), that threshold is well below 35°C.NEW & NOTEWORTHY This study is the first to use empirical physiological observations to examine the well-publicized theoretical 35°C wet-bulb temperature limit for human to extreme environments. We find that uncompensable heat stress in humid environments occurs in young, healthy adults at wet-bulb temperatures significantly lower than 35°C. In addition, uncompensable heat stress occurs at widely different wet-bulb temperatures as a function of ambient vapor pressure.

Mathematical modelling of atrial and ventricular pressure–volume dynamics and their change with heart rate

This paper presents mathematical models that can simulate the cardiovascular system of a healthy sheep under normal resting conditions in which the heart rate changes significantly. The models include several new modelling features that are introduced progressively. The contraction of the cardiac chambers is modelled using a time-dependent muscle force with constant elasticity instead of time dependent elasticity. A new hypothesis about the mechanical contraction of the atria generates realistic pressure volume (PV) loops. The inter-ventricular interaction is modelled as well. Additionally, hysteresis is incorporated in the aortic valve to produce an end-systolic reverse (negative) flow. Most of the model parameter values are based on previous literature data while time periods of delay, atrial and ventricular contraction are derived using experimental data from 14 sheep. We provide new relationships between contraction time and delay as a function of heart period. The effects of different aspects of our modelling on the mean cardiac output, stroke volume, ejection time, ejection fraction and PV loops are studied. Model outputs are compared with published experimental results where possible, and are within a wide range of physiological observations.

Guest Editor's Memo: Genetics Moves To Center Stage

Our understanding of pulmonary hypertension (PH) has advanced steadily. Almost 100 years ago, light microscopy provided the earliest insights into a rare progressive and fatal disease, primary pulmonary hypertension (“PPH”). Pathologists described the histopathology of PPH, with terms like “plexogenic” and “microthromboembolic” PPH. Pathologists, who specialized in pulmonary vascular disease, identified two rare disorders, pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH), that mimicked PPH clinically, but were distinctly different under the microscope.By the middle of the 20th century, the introduction of pulmonary artery catheterization to the study of cardiovascular diseases produced a new level of understanding of PH based upon physiologic observations of intravascular pressures and flows, with an emphasis on mechanisms that caused constriction and relaxation of pulmonary arterioles. This era supported early efforts to treat sporadic PPH and familial PPH, now known as idiopathic and heritable pulmonary arterial hypertension (PAH) with vasodilators, eventually leading to treatments which targeted three pathways integral to vasoconstriction and vasodilation of pulmonary arterioles.Even as pathologic, physiologic, and treatment studies proceeded during the second half of the 20th century, the genetic era began. Investigators took advantage of scientific advances in genetics to discover heritable causes of PH. The first breakthrough occurred in 2000, when two research teams independently reported that mutations in the gene (BMPR2), encoding the bone morphogenetic protein type 2 receptor, caused familial PPH. Over the next two decades investigators linked DNA sequence variations in 16 additional genes to heritable forms of PAH, including PVOD and PCH. These discoveries shaped a new understanding of PAH.Investigators quickly determined that BMPR2 regulated the proliferation of vascular cells, not vasoconstriction. Recognition of the pivotal role of cellular proliferation and transforming growth factor β (TGF-β) signaling paved the way for a new approach to the treatment of PAH. In the Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PULSAR), sotatercept, a fusion protein that impairs activation of a TGFβ pro-proliferative pathway, produced a greater reduction in pulmonary vascular resistance than placebo. Now studies are underway to assess the efficacy and safety of sotatercept across a broad spectrum of PAH disease severity.We have entered a new era of understanding and treating PAH, as genetics moves to center stage. This issue of Advances in Pulmonary Hypertension was organized to serve as a valuable resource for the PH community. The first article, authored by Drs. Carrie Welch and Wendy Chung of Columbia University, provides a comprehensive overview of the genomics of pulmonary hypertension. With this foundation in place, the second article, authored by Rachel Sullivan, MD (Stanford University) and Eric Austin, MD (Vanderbilt University) reviews the relationships between specific gene sequence variations and PAH phenotypes that clinicians are likely to encounter.In recent years genetic counseling and genetic testing have become important affordable services for patients with PAH and their families. Sumathi Rachamadugu, MSc, MS and Melanie Emmerson, MS (Intermountain Healthcare) collaborated with Barbara Girerd, PhD (Université Paris-Saclay) and Hunter Best, PhD (University of Utah) to provide an in depth introduction pretest genetic counseling, genetic testing, and posttest genetic counseling for PAH patients and their families. The PH Professional network contribution by Athena Angelopoulos, MS and Rachel Farrell, MS (University of California San Francisco) complements the preceding article by providing additional details related to genetic counseling and testing for PAH patients and their families.Finally, Drs. Austin, Chung, and Yu, joined us for a roundtable discussion on the genetics of pulmonary hypertension. Participants shared their personal knowledge of the history of genetic research and discovery related to PH, their advice on discussing genetic aspects of PH with patients and families, their thoughts about involving genetic counselors and ordering genetic tests, as well as how genetic test results influence treatment decisions and how knowledge of molecular pathways informs the development of new medications to treat PAH.In closing, we thank the authors and everyone at PHA and Allen Press who worked so hard to produce this issue of Advances.