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Multisystem inflammatory syndrome (MIS) is a severe complication described in a minority of patients with COVID-19. Myocarditis has been reported in patients with COVID-19, including MIS. In this study, we compared the clinical characteristics and cardiac magnetic resonance (CMR) findings of COVID-19 myocarditis in patients with and without MIS. In the 330 patients with COVID-19 who were referred for CMR at our institution between July 24, 2020, to March 31, 2021, 40 patients were identified as having myocarditis, MIS myocarditis (n = 21) and non-MIS myocarditis (n = 19). MIS myocarditis was characterized by global myocardial inflammation/edema with significantly elevated native T1, whereas only regional inflammation, and edema were noted in the non-MIS group. Distinct late gadolinium enhancement (LGE) patterns—inferior myocardial involvement in non-MIS myocarditis and septal involvement in MIS myocarditis—were identified. The LGE burden was comparable between the 2 groups (5.9% vs 6.6%, MIS vs non-MIS group, p = 0.83). Myocarditis was diagnosed more frequently by CMR in the MIS group (70% vs 6.3%, MIS vs non-MIS, p

Supplementary Figure 2 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 3 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 1 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 4 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Figure 1 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 2 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Peer reviewed: True, Acknowledgements: We would like to thank all the participants, clinicians and other healthcare professionals who have contributed to the KARMA cohort., Funder: CHU de Quebec, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Quebec Breast Cancer Foundation, Funder: Ontario Research Fund, Funder: the Märit and Hans Rausing’s Initiative Against Breast Cancer, BACKGROUND: The multifactorial Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) breast cancer risk prediction model has been recently extended to consider all established breast cancer risk factors. We assessed the clinical validity of the model in a large independent prospective cohort. METHODS: We validated BOADICEA (V.6) in the Swedish KARolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) cohort including 66 415 women of European ancestry (median age 54 years, IQR 45-63; 816 incident breast cancers) without previous cancer diagnosis. We calculated 5-year risks on the basis of questionnaire-based risk factors, pedigree-structured first-degree family history, mammographic density (BI-RADS), a validated breast cancer polygenic risk score (PRS) based on 313-SNPs, and pathogenic variant status in 8 breast cancer susceptibility genes: BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51C, RAD51D and BARD1. Calibration was assessed by comparing observed and expected risks in deciles of predicted risk and the calibration slope. The discriminatory ability was assessed using the area under the curve (AUC). RESULTS: Among the individual model components, the PRS contributed most to breast cancer risk stratification. BOADICEA was well calibrated in predicting the risks for low-risk and high-risk women when all, or subsets of risk factors are included in the risk prediction. Discrimination was maximised when all risk factors are considered (AUC=0.70, 95% CI: 0.66 to 0.73; expected-to-observed ratio=0.88, 95% CI: 0.75 to 1.04; calibration slope=0.97, 95% CI: 0.95 to 0.99). The full multifactorial model classified 3.6% women as high risk (5-year risk ≥3%) and 11.1% as very low risk (5-year risk

This paper presents an approach to educate secondary school students in the province of Ontario about the credibility of online content. The critical focus here is on integrating computer technology into the teaching of the topic; how to introduce the material in classroom settings with respect to the current curriculum is also outlined. Contrast with an existing proposal for digital literacy developed by historians at Stanford University is provided at the outset. In all, the value of appealing to the current digital experiences of students, when revealing the potential for misinformation, is the critical message. Exploration of social media environments popular with youth and opportunities for game-based quizzes for interactive engagement are both advocated.

IMPORTANCEEsophageal cancer is among the most lethal type of cancers worldwide. However, risk factors contributing to more than tenfold increase in esophageal cancer in the last 50 years remain underexplored.OBJECTIVEThis study aimed to examine the associations between sleep behaviors and esophageal cancer overall, by histology, and according to genetic predispositions.DESIGNA prospective cohort study.SETTINGA population-based study.PARTICIPANTSA total of 410,428 participants aged 37-73 years at enrollment between 2006 and 2010 in the UK Biobank were followed up until March 31st, 2016 for England and Wales and October 31st, 2015 for Scotland.MAIN OUTCOME AND MEASUREThe risk of incident esophageal cancer.RESULTSDuring 2,799,342 person-years of follow-up, 410 incident esophageal cancer cases (294 adenocarcinomas) were diagnosed. Evening chronotype, sleep 9 h/day, daytime napping, and daytime sleepiness were significantly associated with increased risk of esophageal cancer in age-adjusted models and had aPlikelihood ratio test≤0.20 after multivariable adjustment. Compared with the group without these high-risk behaviors, participants with one high-risk behavior had a 41% (HR=1.41, 95%CI: 1.13, 1.77) increased risk of esophageal cancer, and those with two or more behaviors showed a 79% higher risk (HR=1.79, 95%CI: 1.32, 2.42) (PtrendPtrendPtrend=0.340). The elevated risks for esophageal adenocarcinoma were similar within strata of PRS quintiles (Pinteraction=0.791).CONCLUSION AND RELEVANCEUnhealthy sleep behaviors were associated with an increased risk of esophageal cancer, primarily adenocarcinoma, independent of genetic risk. Sleep behaviors may serve as modifiable factors for the prevention of esophageal cancer, particularly esophageal adenocarcinomas.Key PointsQuestionAre sleep behaviors associated with the risk of esophageal cancer?FindingsIn this prospective cohort study that included 410,428 participants in the UK Biobank, evening chronotype, sleep 9 h/day, daytime napping, and sleepiness were associated with increased risk of esophageal cancer. A greater number of these unhealthy sleep behaviors was associated with a higher risk of esophageal cancer. The elevated risks were primarily observed for esophageal adenocarcinoma and were independent of genetic risk.MeaningSleep behaviors may serve as modifiable factors for the esophageal cancer prevention, particularly esophageal adenocarcinoma, independent of genetic risk.

With improved management of patients with acute myocardial infarctions (MI), the prevalence in heart failure (HF) post-MI is expected to rise. Currently, the only successful treatments for HF are total heart transplantation and left ventricular (LV) assist devices, but their uses are limited by the availability of donor hearts and invasiveness of the procedure. In the last decade, advancements have been made towards developing injectable hydrogels for the purpose of cardiac repair. Injections of hydrogels alone have been shown to attenuate the decline in cardiac function and LV remodeling typically seen after MI in both large and small animals models. One of these hydrogels was previously developed by our lab and derived from decellularized porcine ventricular myocardium. The goal of this thesis was study to the mechanisms by which injections of the myocardial matrix hydrogel improve cardiac repair post-MI and improve upon its cardioreparative effects. To better understand how this myocardial matrix is able to induce the beneficial effects observed post-MI, a whole transcriptome microarray was performed on infarct tissue collected from matrix or saline injected infarcts. We showed through pathway analysis that the effects of the injection were dividable into several tissue level phenotypes. To better understand these in vivo phenomena, we wanted to recapitulate the observations by cell culture in vitro with the myocardial matrix. Several cell behaviors relevant to the infarct milieu were studied, including cardiac progenitor cell migration, cardiomyocyte apoptosis, cardiac fibroblast metallomatrix proteinase (MMP) production, and macrophage polarization. We demonstrated that the form of the matrix that is presented to the cells have a dramatic effect on the cellular response, whether through the 3D hydrogel or as soluble peptides released during degradation. In addition, different fractions of the degradation products also have different bioactivity. Results from these in vitro experiments suggested that the bioactivity of the myocardial matrix and its degradation products seemed to be essential to its cardioreparative effects post-MI; thus, we investigated whether this could be enhanced by prolonging the degradation rate of the hydrogel. Through these studies, we provided the first steps towards elucidating the mechanism of actions of the myocardial matrix, by defining the tissue level changes that it induces in infarcted myocardium and identifying the bioactivity in both the hydrogel form and degradation products.

The pedal ganglion of the nudibranch gastropod Tritonia diomedea has been the focus of neurophysiological studies for more than 50 yr. These investigations have examined the neural basis of behaviors as diverse as swimming, crawling, reflex withdrawals, orientation to water flow, orientation to the earth’s magnetic field, and learning. Despite this sustained research focus, most studies have confined themselves to the layer of neurons that are visible on the ganglion surface, leaving many neurons, which reside in deeper layers, largely unknown and thus unstudied. To facilitate work on such neurons, the present study used serial-section light microscopy to generate a detailed pictorial atlas of the pedal ganglion. One pedal ganglion was sectioned horizontally at 2-µm intervals and another vertically at 5-µm intervals. The resulting images were examined separately or combined into stacks to generate movie tours through the ganglion. These were also used to generate 3D reconstructions of individual neurons and rotating movies of digitally desheathed whole ganglia to reveal all surface neurons. A complete neuron count of the horizontally sectioned ganglion yielded 1,885 neurons. Real and virtual sections from the image stacks were used to reveal the morphology of individual neurons, as well as the major axon bundles traveling within the ganglion to and between its several nerves and connectives. Extensive supplemental data are provided, as well as a link to the Dryad Data Repository site, where the complete sets of high-resolution serial-section images can be downloaded.NEW & NOTEWORTHY Because of the large size and relatively low numbers of their neurons, gastropod mollusks are widely used for investigations of the neural basis of behavior. Most studies, however, focus on the neurons visible on the ganglion surface, leaving the majority, located out of sight below the surface, unexamined. The present light microscopy study generates the first detailed visual atlas of all neurons of the highly studied Tritonia pedal ganglion.

Iron is an essential element for almost all living organisms as it participates in a wide variety of metabolic processes. Disorders of iron metabolism are among the most prevalent human diseases, ranging from anemia to hemochromatosis. Excessive iron accumulations in major organs of iron overload patients can lead to high mortality. Hepcidin, a HAMP-encoded liver hormone, is the master regulator of iron homeostasis. By binding to the sole iron exporter ferroportin and causing internalization and degradation of the complex, hepcidin inhibits cellular iron efflux, thereby lowers plasma iron levels. Inappropriately suppressed/low hepcidin production is central to iron overload. Transmembrane protease serine-6 (TMPRSS6), a type II transmembrane serine protease primarily expressed in liver, downregulates hepcidin expression through BMP-SMAD pathway. TMPRSS6 deficiencies have been shown to cause hepcidin overexpression in both TMPRSS6-mutant mice and in patients with iron-refractory iron deficiency anemia (IRIDA). Therefore, TMPRSS6 is a viable therapeutic target for iron overload disorders. Here we report the generation of an anti-TMPRSS6 antibody through a hybridoma campaign using a DNA-based immunization approach, followed by humanization and sequence optimization. Lead antibody, hzMWTx-003 selectively binds human TMPRSS6 with low nanomolar affinity (KD: 7.6nM), and is cross-reactive to rodent (mouse and rat) and monkey (cynomolgus and rhesus) TMPRSS6. Single-dose injection of hzMWTx-003 was able to significantly elevate serum hepcidin and liver HAMP RNA levels in wildtype mice, resulting in significantly reduced serum iron level. The Hbb th3/+ mouse model of β-thalassemia, like its human counterpart, is characterized by iron overload, ineffective erythropoiesis and splenomegaly. Treatment of Hbb th3/+mice with MWTx-003 effectively increased hepcidin expression at both protein and RNA levels, leading to significantly reduced serum iron and liver non-heme iron content. MWTx-003 also dramatically improved anemia and ineffective erythropoiesis, and alleviated splenomegaly in these mice. CMC development of hzMWTx-003 confirms outstanding biophysical properties. Preliminary studies in cynomolgus monkey using GLP-grade material demonstrated good pharmacokinetics of hzMWTx-003 and expected pharmacodynamic response where reduction of serum iron could be sustained for 21 days after single dose administration. A single dose toxicology study in cynomolgus monkey revealed no safety concerns, and no production of anti-idiotype antibodies was detected. In summary, anti-TMPRSS6 antibody MWTx-003 represents a promising therapy for iron overload disorders such as β-thalassemia, and potentially other diseases where iron restriction is beneficial. Disclosures Chen: Mabwell Therapeutics Inc: Current Employment. Wang: Mabwell Therapeutics Inc: Current Employment. Zheng: Mabwell (Shanghai) Bioscience Co. Ltd: Current Employment. Huang: Mabwell Therapeutics Inc: Current Employment. Mao: Mabwell (Shanghai) Bioscience Co. Ltd.: Current Employment. Ouyang: Mabwell (Shanghai) Bioscience Co. Ltd.: Current Employment. Du: Mabwell Therapeutics Inc: Current Employment.

CXCR5 is a seven transmembrane protein coupled to protein G(i) expressed mainly on mature, resting B cells, follicular helper T cells (TFH), tonsillar B cells, and B cell lymphoma cells. CXCR5 is activated by its ligand CXCL13 and involved in cell migration. Dysregulated CXCL13 and/or CXCR5 expression and signaling have been associated with cancer promotion, as well as autoimmune and chronic inflammatory disorders. Overexpression of CXCL13 in autoimmune and lymphoproliferative disorders has been shown to correlate with disease progression. We therefore hypothesized that an antibody that selectively depletes CXCR5+ malignant B cells through antibody dependent cell-mediated cytotoxicity (ADCC) could be developed to treat B cell lymphomas. Here, we present preclinical data supporting the rationale for indication selection, biomarker identification, dose selection, and phase I clinical trial design. Using our single-cell screening platform technology, CelliGo™, we identified a panel of monoclonal antibodies against human CXCR5. We selected HFB2-4, which binds to CXCR5 expressing cells, blocks CXCL13-induced intracellular signaling and B cell migration, and induces ADCC of Raji B cell lymphoma cells at sub-nM concentrations. HFB2-4 demonstrates good PK behavior in mice and exhibits potent anti-tumor activity in a Raji xenograft murine model. HFB2-4 efficacy in this model is comparable to that of rituximab, despite a lower number of huCXCR5 receptors compared to CD20 on the surface of Raji cells. Our data shows that HFB2-4 holds promise as a therapeutic agent for B cell lymphoproliferative diseases by depleting CXCR5+ tumor B cells in refractory B cell lymphoma and lymphomas derived from severe Sjogren syndrome. Compared to the emerging treatments for refractory B cell lymphomas such as Antibody-Drug-Conjugates, bi-specific antibodies or cell therapies, HFB2-4 may represent a well-tolerated, efficacious, cost-efficient and easy to manufacture alternative. Citation Format: Ayrin Kok, Germain Margallducos, Stephanie Beq, Clarisse Monchecourt, Hombline Poullain, Muriel David, Carine George, Sami Ellouze, Mingjie Chen, Yun-Yueh Lu, Juying Li, Qian Zhang, Jean Wang, Francisco Adrian, Liang Schweizer, Nicola Beltraminelli. Dicovery and characterization of a novel anti-human CXCR5 antibody for the treatment of B cell lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1843.

Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation. WO 2014201206, 2014] of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynamic activity in a NaV1.7-dependent model of histamine-induced pruritus (i...

Understanding complex tissues requires single-cell deconstruction of gene regulation with precision and scale. Here we present a massively parallel droplet-based platform for mapping transposase-accessible chromatin in tens of thousands of single cells per sample (scATAC-seq). We obtain and analyze chromatin profiles of over 200,000 single cells in two primary human systems. In blood, scATAC-seq allows marker-free identification of cell type-specificcis- andtrans-regulatory elements, mapping of disease-associated enhancer activity, and reconstruction of trajectories of differentiation from progenitors to diverse and rare immune cell types. In basal cell carcinoma, scATAC-seq reveals regulatory landscapes of malignant, stromal, and immune cell types in the tumor microenvironment. Moreover, scATAC-seq of serial tumor biopsies before and after PD-1 blockade allows identification of chromatin regulators and differentiation trajectories of therapy-responsive intratumoral T cell subsets, revealing a shared regulatory program driving CD8+T cell exhaustion and CD4+T follicular helper cell development. We anticipate that droplet-based single-cell chromatin accessibility will provide a broadly applicable means of identifying regulatory factors and elements that underlie cell type and function.

Hallucinations - compelling perceptions of stimuli that aren't really there - occur in many psychiatric and neurological disorders, and are triggered by certain drugs of abuse. Despite their clinical importance, the neuronal mechanisms giving rise to hallucinations are poorly understood, in large part due to the absence of animal models in which they can be induced, confirmed to be endogenously generated, and objectively analyzed. In humans, amphetamine (AMPH) and related psychostimulants taken in large or repeated doses can induce hallucinations. Here we present evidence for such phenomena in the marine mollusk Tritonia diomedea. Animals injected with AMPH were found to sporadically launch spontaneous escape swims in the absence of eliciting stimuli. Deafferented isolated brains exposed to AMPH, where real stimuli could play no role, generated sporadic, spontaneous swim motor programs. A neurophysiological search of the swim network traced the origin of these drug-induced spontaneous motor programs to spontaneous bursts of firing in the S-cells, the CNS afferent neurons that normally inform the animal of skin contact with its predators and trigger the animal's escape swim. Further investigation identified AMPH-induced enhanced excitability and plateau potential properties in the S-cells. Taken together, these observations support an argument that Tritonia's spontaneous AMPH-induced swims are triggered by false perceptions of predator contact - i.e., hallucinations-and illuminate potential cellular mechanisms for such phenomena.

Prior studies have found that functional networks can rapidly add neurons as they build short-term memories, yet little is known about the principles underlying this process. Using voltage-sensitive dye imaging, we found that short-term sensitization of Tritonia's swim motor program involves rapid expansion of the number of participating neurons. Tracking neurons across trials revealed that this involves the conversion of recently discovered variably participating neurons to reliable status. Further, we identify a candidate serotonergic cellular mechanism mediating this process. Our findings reveal a new mechanism for memory formation, involving recruitment of pre-positioned, variably committed neurons into memory networks. This represents a shift from the field's long-term focus on synaptic plasticity, toward a view that certain neurons have characteristics that predispose them to join networks with learning.

Sarcoidosis is an immunologic disease of unknown etiology that manifests most frequently within the lungs or associated lymph nodes. Sarcoidosis involving the breast is seen in

Because of its strong genetic validation, Na

Human genetic evidence has identified the voltage-gated sodium channel Na

Methamphetamine (MA), a highly abused amphetamine-like psychostimulant, has surged in popularity worldwide in the last decade. Repeated MA exposure has been shown to affect the alternative splice variant expression of large conductance Ca2+-activated K+ (BK) channels. It remains unclear whether MA affects BK channel activity. The present study investigated the effects of MA on BK channels in NG108-15 mouse neuroblastoma × rat glioma hybrid cells using whole-cell and cell-attached patch clamp techniques. In whole-cell recordings, the macroscopic K+ outward currents were inhibited by MA with an EC50 of 146 μM, but not affected by dopamine (DA). It implies that DA is not involved in the effects of MA on K+ outward currents. In cell-attached patches, MA significantly decreased BK channel activity. Moreover, MA significantly decreased the BK channel opener NS1619-evoked whole-cell K+ outward currents and BK channel activity. Finally, the effect of MA on membrane potential was examined by current-clamp configuration. MA caused membrane depolarization and application of NS1619 returned the depolarized potential to resting value. These findings suggest that MA might act as an inhibitor of BK channels, and thereby increase the neuronal excitability and enhance neurotransmitter release.

Human genetic evidence has identified the voltage-gated sodium channel NaV1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of NaV1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining NaV1.7 potency led to the identification of quinazoline 16 (AM-2099). Compound 16 demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine-induced scratching bouts in a mouse behavioral model following oral dosing.

Journal article A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P â ¤ 3 Ã 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 Ã 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype. EC Seventh Framework Programme - grant number HEALTH-F2-2009-223175 peer-reviewed

The majority of potent and selective hNaV1.7 inhibitors possess common pharmacophoric features that include a heteroaryl sulfonamide headgroup and a lipophilic aromatic tail group. Recently, reports of similar aromatic tail groups in combination with an acyl sulfonamide headgroup have emerged, with the acyl sulfonamide bestowing levels of selectivity over hNaV1.5 comparable to the heteroaryl sulfonamide. Beginning with commercially available carboxylic acids that met selected pharmacophoric requirements in the lipophilic tail, a parallel synthetic approach was applied to rapidly generate the derived acyl sulfonamides. A biaryl acyl sulfonamide hit from this library was elaborated, optimizing for potency and selectivity with attention to physicochemical properties. The resulting novel leads are potent, ligand and lipophilic efficient, and selective over hNaV1.5. Representative lead 36 demonstrates selectivity over other human NaV isoforms and good pharmacokinetics in rodents. The biaryl acyl sulfonamides reported herein may also offer ADME advantages over known heteroaryl sulfonamide inhibitors.

This study evaluated the outcome and process of a community-based aging intervention program for the elderly in Taiwan. The program included education on nutrition and dietary behavior and on physical activities. Outcome and process evaluations were conducted. The program may have had some effects on decreasing some dietary behavioral problems and increasing regular exercise, but the effect on health outcome was not proved. The strength of this program was its proper design, dosage, and implementation; the weaknesses included a low participation rate, low commitment and continuity, and selection bias for the nonparticipants who might be frailer than the actual participants.

Beladi and Chao (2006) and Barcena-Ruiz and Garzon (2006) considered the role of environmental policy on the decision whether to privatize a public firm in different market structures. This paper re-examines whether privatization improves (or deteriorates) the environment in a mixed duopolistic framework with differentiated product and pollution abatement. It is shown that, due to privatization, less attention is paid to pollution abatement by all the firms coupled with less environment taxes levied by the government in a differentiated duopoly, and the environment is more (less) damaged when the product is less (more) substitutable. When the product is highly substitutable, industry profits increase because this softens the intensity of the product market, but social welfare deteriorates accompanied with the path of privatization because the loss of consumer surplus and tax revenue exceeds the increases in profits, even if the environment is less damaged.