A global inventory of photovoltaic solar energy generating units.

Photovoltaic (PV) solar energy generating capacity has grown by 41 per cent per year since 20091. Energy system projections that mitigate climate change and aid universal energy access show a nearly ten-fold increase in PV solar energy generating capacity by 20402,3. Geospatial data describing the energy system are required to manage generation intermittency, mitigate climate change risks, and identify trade-offs with biodiversity, conservation and land protection priorities caused by the land-use and land-cover change necessary for PV deployment. Currently available inventories of solar generating capacity cannot fully address these needs1-9. Here we provide a global inventory of commercial-, industrial- and utility-scale PV installations (that is, PV generating stations in excess of 10 kilowatts nameplate capacity) by using a longitudinal corpus of remote sensing imagery, machine learning and a large cloud computation infrastructure. We locate and verify 68,661 facilities, an increase of 432 per cent (in number of facilities) on previously available asset-level data. With the help of a hand-labelled test set, we estimate global installed generating capacity to be 423 gigawatts (-75/+77 gigawatts) at the end of 2018. Enrichment of our dataset with estimates of facility installation date, historic land-cover classification and proximity to vulnerable areas allows us to show that most of the PV solar energy facilities are sited on cropland, followed by aridlands and grassland. Our inventory could aid PV delivery aligned with the Sustainable Development Goals.

Distinct tumor-infiltrating lymphocyte landscapes are associated with clinical outcomes in localized non-small-cell lung cancer.

BACKGROUND: Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. PATIENTS AND METHODS: Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. RESULTS: While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. CONCLUSIONS: Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.

Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression-free survival in recurrent small cell neuroendocrine carcinoma of the cervix.

OBJECTIVES: To assess if the combination of topotecan, paclitaxel, and bevacizumab (TPB) was active in recurrent SCCC and to compare the survival of patients with SCCC who received TPB to a group of women with SCCC who did not receive this regimen. METHODS: We retrospectively analyzed women with recurrent SCCC who received chemotherapy as primary therapy. Women treated with TPB for first recurrence were compared to women treated with non-TPB chemotherapy. RESULTS: Thirteen patients received TPB, and 21 received non-TPB chemotherapy, most commonly platinum with or without a taxane. Median progression-free survival (PFS) was 7.8months for TPB and 4.0months for non-TPB regimens (hazard ratio [HR] 0.21, 95% CI 0.09-0.54, P=0.001). Median overall survival (OS) was 9.7months for TPB and 9.4months for non-TPB regimens (HR 0.53, 95% CI 0.23-1.22, P=0.13). Eight women (62%) who received TPB versus four (19%) who received non-TPB regimens were on treatment for >6months (P=0.02), and four patients (31%) in the TPB group versus two (10%) in the non-TPB group were on treatment for >12months (P=0.17). In the TPB group, three patients (23%) had complete response, two (15%) had complete response outside the brain with progression in the brain, 3 (23%) had a partial response, 2 (15%) had stable disease, and 3 (23%) had progressive disease. CONCLUSIONS: These findings indicate that TPB for recurrent SCCC significantly improved PFS over non-TPB regimens, and trends towards improved OS. Furthermore, a significant number of patients had a durable clinical benefit.

L-dopa: selective toxicity for melanoma cells in vitro.

In a study of the effect of L-dopa, an intermediate in the biosynthesis of the pigment melanin, on the growth of human and murine melanoma cells a highly selective inhibition of growth was observed for pigmented cell lines (S91A and human melanoma) as compared to the nonpigmented control cells (amelanotic melanoma S91B, mouse fibroblast L929, and Chinese hamster ovary). There was a correlation between toxicity and the extent of incorporation of radioactively labeled L-dopa by each line.

ZEB1 induces LOXL2-mediated collagen stabilization and deposition in the extracellular matrix to drive lung cancer invasion and metastasis.

Lung cancer is the leading cause of cancer-related deaths, primarily due to distant metastatic disease. Metastatic lung cancer cells can undergo an epithelial-to-mesenchymal transition (EMT) regulated by various transcription factors, including a double-negative feedback loop between the microRNA-200 (miR-200) family and ZEB1, but the precise mechanisms by which ZEB1-dependent EMT promotes malignancy remain largely undefined. Although the cell-intrinsic effects of EMT are important for tumor progression, the reciprocal dynamic crosstalk between mesenchymal cancer cells and the extracellular matrix (ECM) is equally critical in regulating invasion and metastasis. Investigating the collaborative effect of EMT and ECM in the metastatic process reveals increased collagen deposition in metastatic tumor tissues as a direct consequence of amplified collagen gene expression in ZEB1-activated mesenchymal lung cancer cells. In addition, collagen fibers in metastatic lung tumors exhibit greater linearity and organization as a result of collagen crosslinking by the lysyl oxidase (LOX) family of enzymes. Expression of the LOX and LOXL2 isoforms is directly regulated by miR-200 and ZEB1, respectively, and their upregulation in metastatic tumors and mesenchymal cell lines is coordinated to that of collagen. Functionally, LOXL2, as opposed to LOX, is the principal isoform that crosslinks and stabilizes insoluble collagen deposition in tumor tissues. In turn, focal adhesion formation and FAK/SRC signaling is activated in mesenchymal tumor cells by crosslinked collagen in the ECM. Our study is the first to validate direct regulation of LOX and LOXL2 by the miR-200/ZEB1 axis, defines a novel mechanism driving tumor metastasis, delineates collagen as a prognostic marker, and identifies LOXL2 as a potential therapeutic target against tumor progression.

The miR-200 family and the miR-183~96~182 cluster target Foxf2 to inhibit invasion and metastasis in lung cancers.

Metastatic lung cancer is one of the most lethal forms of cancer and molecular pathways driving metastasis are still not clearly elucidated. Metastatic cancer cells undergo an epithelial-mesenchymal transition (EMT) where they lose their epithelial properties and acquire a migratory and invasive phenotype. Here we identify that the expression of microRNAs from the miR-200 family and the miR-183~96~182 cluster are significantly co-repressed in non-small cell lung cancer cell lines and primary tumors from multiple TCGA dataset with high EMT scores. Ectopic expression of the miR-183~96~182 cluster inhibited cancer cell migration and invasion, whereas its expression was tightly modulated by miR-200. We identified Foxf2 as a common, novel and direct target of both these microRNA families. Foxf2 expression tightly correlates with the transcription factor Zeb1 and is elevated in mesenchymal-like metastatic lung cancer cells. Foxf2 expression induced robust EMT, migration, invasion and metastasis in lung cancer cells, whereas Foxf2 inhibition significantly repressed these phenotypes. We also demonstrated that Foxf2 transcriptionally represses E-cadherin and miR-200, independent of Zeb1, to form a double-negative feedback loop. We, therefore, identified a novel mechanism whereby the miR-200 family and the miR-183~96~182 cluster inhibit lung cancer invasion and metastasis by targeting Foxf2.

Inhibition of beta-glucosidase by imidazoles.

Over 25 nitrogen-containing heterocycles were tested as inhibitors of sweet almond beta-glucosidase (EC 3.2.1.21). Among the most potent of these are some imidazole derivatives. The pH dependence indicates that the unprotonated inhibitor binds most tightly to the catalytically active species of the enzyme. This is analogous to the situation with 1-deoxynojirimycin where the permanently cationic species, N,N-dimethyl-1-deoxynojirimycin, binds at least two orders of magnitude less tightly to the enzyme than does the unprotonated 1-deoxynojirimycin. The binding of imidazole derivatives show a general tendency of increasing affinity with increasing basicity (beta approximately 0.4). One derivative which shows a significant positive deviation from this correlation (- log Ki vs. pKa) is 4-phenylimidazole. 4-Phenylimidazole is one of the most potent reversible inhibitors of beta-glucosidase with a pH-independent Ki = 0.8 microM. It is also fairly specific for beta-glucosidase, binding at least three orders of magnitude less tightly to any of the other exoglycosidases tested. This inhibitor combines, in a mono-molecular species, the binding affinities of benzene, which binds at the hydrophobic aglycone binding site, and imidazole, which binds at the sugar binding site of beta-glucosidase. The binding energy of 4-phenylimidazole can be attributed to the sum of the intrinsic binding energies of the phenyl and imidazole moieties. Thus, there is no significant entropic advantage of combining the component parts of phenylimidazole in a single species. This indicates that there is no significant uncompensated entropy loss upon binding of either benzene or imidazole to the enzyme. Nevertheless, the additivity of binding energy, even in the absence of an entropic advantage, results in the most powerful known inhibitor of the enzyme.

Phosphonate inhibitors of glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase.

Several bisphosphonates were examined as inhibitors of yeast GPD (glyceraldehyde-3-phosphate dehydrogenase, EC 1.2.1.12) and PGK (phosphoglycerate kinase, EC 2.7.2.3). The phosphonomethyl analog of 2-deoxy-1,3-bisphosphoglycerate (i.e., 2-oxo-1,5-bisphosphonopentane, 2-oxo-PC5P) is a good inhibitor of PGK (Ki = 0.2 +/- 0.08 mM at pH 8.5, 27 degrees C) and a poor inhibitor of GPD (Ki = 20 +/- 1 mM, pH 8.5). The shorter, butane, analog (2-oxo-PC4P) binds more tightly to PGK (Ki = 84 +/- 6 microM), and about equally well to GPD, as does 2-oxo-PC5P. The 2-oxo-bisphosphonates bind to PGK more tightly (by approx. 4 kJ/mol) than do the corresponding non-carbonyl analogues (1,4-bisphosphonobutane and 1,5-bisphosphonopentane).

Selective toxicity of 6-hydroxydopa for melanoma cells.

The growth inhibitory effect of 6-hydroxydopa, a cytotoxic analog of L-dopa, was studied in melanotic and amelanotic Cloudman melanoma, mouse fibroblast L929 and Chinese hamster ovary cells. A marked sensitivity of pigmented cells to 6-hydroxydopa was observed with a 10-fold increase in sensitivity of pigmented cells. Sensitivity correlated with the capacity of cells to incorporate radiolabeled exogenous L-dopa. The drug affected primarily DNA and RNA synthesis with greater inhibition observed in pigmented cells than the nonpigmented control cells. The mechanism of action may involve interaction with the melanocyte specific enzyme, tyrosinase, as a false substrate.

The liver converts the antihypertensive hormone of the kidney. The renohepatic axis.

The antihypertensive neutral renomedullary lipid, derived from the renal papilla, causes a vasodepressor effect when injected into a peripheral vein, such as the inferior vena cava, after a lag period of 1 to 2 minutes. The blood pressure tracing is skewed (cuplike effect). The lag period is significantly reduced after injection of the antihypertensive lipid into the portal vein. The vasodepressor configuration (cuplike) is the same whether the lipid is injected into the vena cava or portal vein. Removal of the liver from the circulation prevents the depressor effect. Thus, passage through the liver is essential for antihypertensive lipid activity. Renoportal shunting of blood potentiates the antihypertensive function of the kidney after unclipping in the one-kidney, one clip hypertensive rat. Lack of a hepatic circulation prevents the antihypertensive function of the kidney after unclipping. Antihypertensive neutral renomedullary lipid and the renal venous effluent after unclipping have the same biological behavior. We conclude that antihypertensive neutral renomedullary lipid is a promolecule, the putative prohormone of the renal papilla and its renomedullary interstitial cells. The liver converts the antihypertensive prohormone of the kidney to an active antihypertensive substance. A renohepatic axis of blood pressure control appears to exist.

Alkyl ether analogs of phosphatidylcholine are orally active in hypertensive rabbits.

1-0-alkyl ethers of phosphatidylcholine having an acetoyl in the second position were derived from fresh renal tissue. The main ether so derived had a 16:0 chain. The C16:0 alkyl ether was synthesized de novo. The renally derived and the synthetic ether exerted a similar and powerful antihypertensive action in hypertensive rabbits when given orally in divided doses. This action was prolonged, requiring more than 60 hours after the last input of the compound for recovery of the arterial pressure. As these ethers exerted their antihypertensive action, there was no evidence of adverse effects. Noteworthy was the failure of these depressor compounds to cause renin release. Diuresis-kaliuresis did not occur. A suggestion of sodium retention was noted.

Analogs of phosphatidylcholine: alpha-adrenergic antagonists from the renal medulla.

Antihypertensive polar renomedullary lipid (APRL), a conglomerate of 1-0-alkyl-2-acetoyl-glycero-3-phosphocholine analogs, ws tested in 4- to 6-week-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats using microcirculatory techniques. APRL (0.5 ug/ml), when added to the solution bathing the cremaster muscle, caused significant changes in the diameter, red blood cell velocity, and blood flow in both groups of rats, for arterioles and venules. Arteriolar changes in diameter were significantly greater (p less than 0.05) in SHR than in WKY. Micropipette application of APRL indicated a dose-dependent response for arterioles and venules in both groups. Moreover, the potent nature of this compound was demonstrated. Relative potency of APRL given intravenously was tested in 10- to 12-week-old SHR and WKY. The response curve was shifted significantly to the left for SHR (p less than 0.01). APRL interaction with known controllers of blood flow was tested in SHR. Blockade of cholinergic, beta-adrenergic, or histaminergic receptors did not inhibit APRL action. blockade of prostaglandin or bradykinin synthesis did not prevent depression of blood pressure by APRL. APRL (40 ug/kg) inhibited (p less than 0.001) the pressor response to norepinephrine (1-10 ug/kg) but not to angiotensin II (4 ug/kg). The present study provides direct evidence that APRL is a vasodilator with increased potency in SHR hypertension. The acute vascular response may be mediated by alpha-adrenergic antagonism.

Medullipin system. Generation of medullipin II by isolated kidney-liver perfusion.

Perfusion of isolated normal rat kidneys with blood at elevated blood pressure (180-200 mm Hg) followed by perfusion of the renal perfusate through an isolated normal rat liver under venous pressure yielded in the plasma of the hepatic effluent a vasodepressor lipid having the chromatographic and biological characteristics of medullipin II. These findings support the view that medullipin II is the final product of the renohepatic axis of blood pressure control.

Antihypertensive action of medullipin I given by mouth.

Perfusion of normal rat kidneys with 5% human albumin in a balanced salt solution bubbled with oxygen yielded medullipin I (Med I) in the renal venous effluent. The presence of Med I in the renal venous effluent has been established by thin-layer chromatography, by the type of vasodepressor effect when injected intravenously as a bolus into the hypertensive rat, by inhibition of the vasodepressor effect of the renal venous effluent by Tween 20 and SKF 525A (proadifen, inhibitor of cytochrome P-450), and by removal of the liver from the circulation (a procedure that inhibits extracted Med I). Med I so derived lowered blood pressure of spontaneously hypertensive rats when injected into the stomach by an indwelling tube or when given by mouth. The lowering of blood pressure was attended by no change in cardiac output and no change in heart rate. Med I given by mouth to the spontaneously hypertensive rat is a vasodilator that suppresses sympathetic tone, acting in the same way as Med I extracted from renal papillae and given intravenously. Importantly, the antihypertensive action was demonstrated in the spontaneously hypertensive rat, a model of hypertension considered to mimic idiopathic or essential hypertension of humans. Med I is a promising therapeutic agent for hypertension.

Antihypertensive polar and neutral renopapillary lipids. Which is a hormone?

Two antihypertensive lipids can be derived from the renal papilla, the antihypertensive polar (APRL) and the antihypertensive neutral (ANRL) renomedullary lipid. The renal venous effluent of the unclipped kidney contains both ANRL and APRL. This effluent lowers the arterial pressure (AP) of the normal rat when infused i.v. As it lowers the AP the heart rate (HR) and sympathetic nerve activity (SNA) are depressed. ANRL infused i.v. also lowers HR and SNA as it depresses the AP. Conversely, APRL elevates HR and SNA as it lowers the AP. Thus, of the two lipids in the renal venous effluent after unclipping, ANRL appears to be dominant. APRL, however, in the renal venous effluent could potentiate the action of ANRL. The net effect of these observations is to support the view that ANRL is an antihypertensive hormone liberated by the kidney after unclipping. The renomedullary interstitial cells (RIC) degranulate after unclipping. ANRL can be derived from these cells. Thus, the RIC, cells known to exert an endocrine-type antihypertensive function, may well be the source of ANRL in the renal venous effluent after unclipping. The hormonal action of ANRL appears as a major cause of the lowering of the AP after unclipping. It is not known what factors modulate the RIC endocrine system. There is a suggestion that angiotensin may be one of these factors based on the ineffectiveness of these cells toward retarding hypertension when the circulating plasma angiotensin level is high, and their effectiveness when the circulating plasma angiotensin level is low.

Cardiovascular effects of antihypertensive polar and neutral renomedullary lipids.

Two antihypertensive lipids can be extracted from fresh renal medulla. One is polar (the antihypertensive polar renomedullary lipid, or APRL) and the other is nonpolar (the antihypertensive neutral renomedullary lipid, or ANRL). APRL and ANRL differ in their biologic activities: APRL in bolus intravenous injections causes a very rapid decline in the arterial pressure (AP) while ANRL, after a lag of 2 minutes, causes a slower decline in AP. APRL increases heart rate and sympathetic activity. ANRL decreases heart rate and sympathetic activity. ANRL appears to convert to APRL, under certain in vitro circumstances, suggesting that the structure of the two molecules is related. ANRL and APRL appear in the renal venous effluent after unclipping; biologically, ANRL seems dominant. The renal venous effluent of the unclipped isolated kidney lowers the HR and sympathetic activity of the normal rat. Unclipping degranulates the renomedullary interstitial cells (RIC). The antihypertensive effect of unclipping appears due to the secretion of ANRL and APRL by the kidney. It is concluded that ANRL seems to be the antihypertensive hormone of the RIC.

Secretion of medullipin I by the kidney involves the cytochrome P-450 enzyme system.

OBJECTIVE: To determine whether secretion of medullipin I by the kidney is dependent on the cytochrome P-450 enzyme system in Sprague-Dawley and spontaneously hypertensive rats (SHR). METHODS: Isolated kidneys from Sprague-Dawley rats were perfused with 5% human albumin gassed with 95% O2 and 5% CO2 at 185 mmHg. The resultant renal venous effluent was tested in the SHR for medullipin I-type vasodepressor activity. The kidneys were then treated with ketoconazole, and inhibitor of the cytochrome P-450 enzyme system. After rinsing with 50 ml saline, the last 10 ml of which was saved for a control test (see below), the kidneys were reperfused with 50 ml human albumin and the resultant renal venous effluent was tested for vasodepressor activity. One milliliter of the saline rinse was administered to the SHR and the preketoconazole renal venous effluent was administered after 15 min. The medullipin I-type vasodepression occurred. Thus, inhibition of vasodepression after ketoconazole treatment was not due to residual ketoconazole in the post-treatment renal venous effluent. RESULTS: Treatment of isolated kidneys with ketoconazole prevented secretion of medullipin I which had been induced by 5% human albumin. CONCLUSION: The cytochrome P-450 enzyme system is involved in two major metabolic steps of the medullipin system: synthesis of medullipin I by the kidney and conversion of medullipin I to medullipin II by the liver as shown previously.

Secretion of medullipin I by the kidney requires oxygen.

OBJECTIVE: To test the hypothesis that the secretion of medullipin I by the kidney involves an oxidative step. DESIGN: Medullipin I is secreted by kidney renomedullary interstitial cells and is converted to medullipin II by the liver. Medullipin I can be derived from the kidney in the renal venous effluent by perfusing normal rat kidneys with 95% O2- 5% CO2 at an elevated pressure (180 mmHg). To evaluate whether the secretion of medullipin I involves an oxidative step normal rat kidneys were perfused at an elevated pressure in the presence of O2, in the absence of O2 and after treatment of the kidneys with a powerful antioxidant. METHODS: Normal rat kidneys were perfused with 5% albumin bubbled with O2-CO2 at 180 mmHg. This was the control procedure for each of the three approaches. In approach (1), the kidneys were perfused with 5% albumin bubbled with N2. In approach (2), the kidneys were perfused with 'blood' treated with carbon monoxide. In approach (3), the kidneys were treated with the antioxidant butylated hydroxytoluene then perfused with 5% albumin bubbled with O2-CO2. Each perfusate was tested for medullipin I activity by rapid intravenous injection into the SHR. RESULTS: All three approaches, which exclude the action of molecular O2, prevented the secretion of medullipin I by the kidneys. CONCLUSION: The secretion of medullipin I by the kidneys involves an oxidative step.

The renal antihypertensive endocrine function: its relation to cytochrome P-450.

Unclipping the Goldblatt hypertensive rat lowers the blood pressure by cells in the renal papilla, the renomedullary interstitial cells (RIC), secreting a hormone that is part of a vasodilator system. A vasodilator, termed medullipin I, can be extracted from the renal papilla. Medullipin I and the renal venous effluent following unclipping have identical biologic properties. Medullipin I appears to be the agent secreted by the kidney following unclipping. Both medullipin I and the renal venous effluent must traverse the liver to be active. Medullipin I is converted in the liver to its active form, medullipin II. The blood pressure-lowering effect of both medullipin I and the renal venous effluent after unclipping are blocked by SKF 525A, the inhibitor of cytochrome P-450. The relation of the kidney to the liver was tested using the rate of decline of the blood pressure after unclipping as an index of the endocrine antihypertensive function of the kidney--acceleration of the decline being considered as increased function, decrease of the decline as decreased function. Five compounds: BW755C, phenobarbital, ketoconazole, eicosatetraynoic acid (ETYA) and butylated hydroxytoluene (BHT), and two manipulations: uretero-caval anastomosis (UCA) and removal of the liver from the circulation were used followed by unclipping. BW755C, inhibitor of both cyclo-oxygenase and lipoxygenase, potentiated the antihypertensive function to a maximum. It is reasoned that inhibition of the first two pathways of arachidonic acid metabolism potentiates the third pathway, the cytochrome P-450 pathway.(ABSTRACT TRUNCATED AT 250 WORDS)