Artigos de revistas sobre o tema "810/820"

Abstract The effect of the desorption-recombination temperature on the microstructure and magnetic properties of hydrogenation-disproportionation-desorption-recombination (HDDR) processed Nd-Fe-B powders was studied. The NdxB6.4Ga0.3Nb0.2Febal (x=12.5-13.5, at.%) casting alloys were pulverized after homogenizing annealing, and then subjected to HDDR treatment. During the HDDR process, desorption-recombination (DR) reaction was induced at two different temperature, 810°C and 820°C. The higher Nd content resulted in enhanced coercivity of the HDDR powder, and which was attributed to the thicker and more uniform Nd-rich phase along grain boundaries. But this uniform Nd-rich phase induced faster grain growth. The remanence of the powder DR-treated at 820°C is higher than that DR-treated at 810°C. In addition, it was also confirmed that higher DR temperature is much more effective to improve squareness.

Samples collected at the Chornoliska culture site near the village of Subotiv, Cherkasy region during the 1994–1995 Ukrainian-German expedition were radiocarbon dated in Kiev. The foundation of the Subotiv settlement dates to 1300–1200 cal BC. A skeleton found in one of the buildings at this site is dated at the end of the early period (between 1120 and 1040 cal BC). In the youngest part (a small town) of the Subotiv settlement, we found the remains of a “building sacrifice"—the skeleton of a teenager. The average calibrated date for this skeleton is 834–807 cal BC, whereas the timber from the rampart dates between 902–810 cal BC. Thus, the rampart was apparently built between 834–807 cal BC. Among the objects found on the site were Arzhan-type bone arrowheads. Such arrowheads, when found in Eastern Europe, are believed to indicate the military expansion of Proto-Scythian nomads. The Sargary settlement in western Kazakhstan dates to 960–820 cal BC, the Arzhan arrow in Siberia to 960–850 cal BC. We assume that the Chornogorivka complexes in eastern Eurasia date to the earlier time period (960–820) than those in western Eurasia (834–807). The time of the Chornogorivka expansion on the territory of Ukraine is therefore within the range 834 to 820 BC.

En la Biblioteca de Focio de Constantinopla (ca. 810/820-después de 893) hay dos pasajes concernientes a los contenidos de los sucesos de Alejandro Magno en el Breviario histórico de Cefalión (68, 34a10-11; 161, 104b13-14) que se contradicen entre sí, pues en uno parece referir al libro noveno, mientras que en el otro, al octavo. A su vez, la crítica y los traductores generalmente han preferido la adscripción a aquél. En este trabajo se aboga por un cambio textual del sintagma ἐν ᾗ (Bibl., 68, 34a10) que haga coincidir la información de ambos pasajes. Con ello se logra dar nueva luz a un documento perdido de la literatura griega.

The subsolidus phase relationships of the high-Tc 2223 superconductor in the (Bi, Pb)–Sr–Ca–Cu–O (BSCCO) system have been examined at 810–820 °C. All experiments were carried out at ambient pressure in a 7.5% O2 (92.5% Ar) atmosphere. Eleven phases were found to exist in equilibrium with the 2223 phase. These 11 phases include CuO and 10 oxide solid solutions. From among these phases, a total of 48 five-phase combinations including the 2223 and 2212 phases were investigated experimentally, and 16 equilibrium assemblages were found which define a multicomponent compositional space corresponding to the 2223 + 2212 solid-state compatibility region. The subsolidus data form a partial basis for future investigation of the Pb-2223 primary phase field.

Indonesia is a mega-diversity country with numerous endemic plants distributed throughout its regions. An Indonesias’ island with the unique and the highest endemic plant species due to being located in the Wallace area is Sulawesi Island. Hopea celebica, an endemic species to Sulawesi Island, is currently categorized as endangered by IUCN. Here, we selected the ISSR primers suitable for the genetic study of H. celebica from Luwu and Konawe provenances and investigated their genetic diversity. Ten ISSR primers were employed in primer screening, and fifty H. celebicaindividuals were genetically analyzed for their genetic diversity. The selected ISSR primers for genetic diversity analysis were UBC 810, UBC 813, UBC 814, UBC 820, UBC 822, UBC 823, and UBC 827. The evaluated H. celebica individuals have high genetic diversity, and this information will be beneficial for designing H. celebica breeding and conservation strategies

The kinetic regularities of the process of structural modification of highly dispersed powders of saponite-containing material after mechanical dispersion have been studied. As information criteria characterizing the restructuring of the crystal lattice of minerals, changes are used that occur with the specific surface of powders at different grinding times and the exothermic thermal effect (enthalpy change) in the temperature range of 810 – 820 °С. It has been determined that during mechanical grinding of a saponite-containing material for more than 20 minutes, intensive modification of saponite occurs, associated with its structural changes, leading to the formation of serpentine. It has been established that the traditionally used criterion for evaluating the process of mechanical grinding of raw materials by the specific surface of the powder in this case is not a sufficient information parameter when optimizing structural changes in experimental samples. The dominant parameter of this process is the enthalpy factor, which characterizes the thermal effect of the structural modification.

El objetivo de esta investigación es la aplicación del método del ahorro, para la obtención de rutas óptimas de distribución de una pyme, dedicada a la venta al por menor de bienes de consumo, localizada en el municipio de Yuriria Guanajuato. El método del ahorro consiste en cuatro etapas: determinar la demanda de los clientes, localización geográfica de los clientes, construcción de una matriz de costos utilizando la fórmula de la distancia euclidiana, construcción de matriz de ahorro e identificación de rutas factibles basado en los ahorros y la capacidad del transporte, garantizando la disminución de gastos de reparto. El método se resolvió a través de una hoja de cálculo en Excel, obteniendo como resultado lo siguiente, la ruta número 1 está compuesta por los clientes 3 y 5, la capacidad de esta ruta es de 820 kilogramos, la ruta número 2 está compuesta por los clientes 1, 4 y 7, la capacidad de esta ruta tiene un valor de 981 kilogramos y por último la ruta número 3 está compuesta por los clientes 2 y 6, cuya capacidad es de 810 kilogramos.

Abstract. Polar stratospheric clouds (PSCs) play an important role in the spatial and temporal evolution of trace gases inside the polar vortex due to different processes, such as chlorine activation and NOy redistribution. As there are still uncertainties in the representation of PSCs in model simulations, detailed observations of PSCs and information on their type – nitric acid trihydrate (NAT), supercooled ternary solution (STS), and ice – are desirable. The measurements inside PSCs made by the CRISTA-NF (CRyogenic Infrared Spectrometers and Telescope for the Atmosphere – New Frontiers) airborne infrared limb sounder during the RECONCILE (Reconciliation of essential process parameters for an enhanced predictability of Arctic stratospheric ozone loss and its climate interactions) aircraft campaign showed a spectral peak at about 816 cm−1. This peak is shifted compared with the known peak at about 820 cm−1, which is recognised as being caused by the emission of radiation by small NAT particles. To investigate the reason for this spectral difference, we performed a large set of radiative transfer simulations of infrared limb emission spectra in the presence of various PSCs (NAT, STS, ice, and mixtures) for the airborne viewing geometry of CRISTA-NF. NAT particles can cause different spectral features in the 810–820 cm−1 region. The simulation results show that the appearance of the feature changes with an increasing median radius of the NAT particle size distribution, from a peak at 820 cm−1 to a shifted peak and, finally, to a step-like feature in the spectrum, caused by the increasing contribution of scattering to the total extinction. Based on the appearance of the spectral feature, we defined different colour indices to detect PSCs containing NAT particles and to subgroup them into three size regimes under the assumption of spherical particles: small NAT (≤ 1.0 µm), medium NAT (1.5–4.0 µm), and large NAT (≥ 3.5 µm). Furthermore, we developed a method to detect the bottom altitude of a cloud by using the cloud index (CI), a colour ratio indicating the optical thickness, and the vertical gradient of the CI. Finally, we applied the methods to observations of the CRISTA-NF instrument during one local flight of the RECONCILE aircraft campaign and found STS and medium-sized NAT.

AbstractWithin the scope of this ex vivo study, the cut efficiency was investigated with eight diode laser wavelengths in the range from 400 to 1500 nm. Incisions on porcine gingiva samples were generated in CW-mode at a power range of 0.5–4 W using a bare fiber (∅ = 320 μm) in contact and non-contact mode at a cut speed of 2 mm/s. Cut depths, cut widths, and thermal damages were recorded based on histological sections and were evaluated via measurement masks. Moreover, with respect to the controllability of a therapeutic measure, an efficiency factor was defined. At powers above 2 W, for 445 nm, the maximum cut depth was 820 μm and 344 μm for 810 nm, respectively. At all wavelength and power ranges, the cut width averaged 125 μm. At minimum output power (0.5 W), the spatial expansion of the thermal damage in the tissue surface layer corresponds in the blue/green wavelength range from the very beginning of the laser impact to the fiber core diameter. It could be shown that increases in the diode laser power output do not correlate to the same extent with the incision depth nor with thermal damage to tissue.

Purpose:The effect of crushed ice ingestion as a precooling method on 40-km cycling time trial (CTT) performance was investigated.Methods:Seven trained male subjects underwent a familiarization trial and two experimental CTT which were preceded by 30 min of either crushed ice ingestion (ICE) or tap water (CON) consumption amounting to 6.8 g⋅kg-1 body mass. The CTT required athletes to complete 1200 kJ of work on a wind-braked cycle ergometer. During the CTT, gastrointestinal (Tgi) and skin (Tsk) temperatures, cycling time, power output, heart rate (HR), blood lactate (BLa), ratings of perceived exertion (RPE) and thermal sensation (RPTS) were measured at set intervals of work.Results:Precooling lowered the Tgi after ICE significantly more than CON (36.74 ± 0.67°C vs 37.27 ± 0.24°C, P < .05). This difference remained evident until 200 kJ of work was completed on the bike (37.43 ± 0.42°C vs 37.64 ± 0.21°C). No significant differences existed between conditions at any time point for Tsk, RPE or HR (P > .05). The CTT completion time was 6.5% faster in ICE when compared with CON (ICE: 5011 ± 810 s, CON: 5359 ± 820 s, P < .05).Conclusions:Crushed ice ingestion was effective in lowering Tgi and improving subsequent 40-km cycling time trial performance. The mechanisms for this enhanced exercise performance remain to be clarified.

Ptolemy Chennus is a poorly known Roman author who wrote in Greek and lived in the late 1st — beginning of 2nd century ad. His works are enumerated in the corresponding article from the Byzantine encyclopedia Suda: a collection of Paradoxical stories, a historical drama Sphinx, and an epic entitled Anthomerus; his only extant work is the Novel History, probably another title of Ptolemy’s aforementioned paradoxographical collection, which has been preserved as an epitome in the Bibliotheca of Patriarch Photius (c. 810/820–893). By his professional pursuits, apparently initiated in his native Alexandria, Ptolemy is defined as grammaticus, i.e. classical scholar, and the classics in his time were centered primarily on Homer; the tendency to thwart this great authority is evident throughout the Novel History which is teeming with a mass of blatantly unorthodox versions of various mythological stories going back to Homer. It is this unorthodoxy that the compiler of the epitome finds attractive, though unfortunately a mere summary forestalls the possibility to savour the presumed stylistic complexity of the work, as well as to form a well-grounded judgement on how serious was its author’s attitude to the fibs he tells, or on how close these fanciful rehashes came to a deliberate parody; still, it almost seems certain that the original text was truly rich in playfulness, irony, and burgeoning imagination. The publication presents the first full Russian translation of the work, accompanied with sufficiently detailed commentary, paying special attention to Eustathius’ of Thessalonica (c. 1115–1195/6) Commentaria to Homeric poems, the only literary source where some few parallels to the wildly unconventional data provided by Ptolemy may be found.

Often Lake Rukwa characteristics have been misreported in literature giving different volumes and surface areas at similar water surface elevations. This study aimed at establishing reliable lake characteristics elevation-area-storage equations for Lake Rukwa by utilising all available data and information to define the bathymetry and derive characteristic equations. A procedure was developed that combines historical lake extents, spot heights from topographical maps and surveyed lake bathymetry to define refined bathymetry to levels it has never reached. It combined spot heights around the lake and selected 13,934 surveyed points (from 107,938 available) within the lake confined by the 820 m land contour boundary and define topographical raster image, which was used to extract lake volumes and surface areas between the lowest point (778 m) and 820 m boundary. Change-point analysis was used to detect segmentation of the elevation-area and elevation-volume relationships, which were fitted to a shifted power model. Contours generated from a refined bathymetry raster indicated Lake Rukwa to comprise two north and south lake basins, which are separated by a ridge lying at an altitude of 794.3 m. The north and south lakes consist respectively of five (5) and three (3) deeper depressions (pools) paralleling the northwest- southeast Konongo Scarp, which are disconnected below altitudes 792 m (north) and 789.4 m (south). Characteristic elevation-area and elevation-volume equations are segmented for lake below ridge altitude (794.3 m) whereas single relationships prevail for a single Lake Rukwa. Comparison of lake volumes estimated by refined and old equations indicated underestimation of lake stored volumes between 782.2 m and 805.65 m altitudes and overestimation thereafter by the old equations although the under/over-estimation remained within 10% between 801 m and 812 m. Old elevation-area equations underestimate lake surface area of up to 796.8 m, thereafter overestimate the lake area up to an altitude of 804.85 m and above this altitude underestimation re-appear. The old equations under/over-estimation, however, remains within 11% for altitudes between 794.3 m and 810 m. The refined equations indicate surface areas of north and south lakes at ridge altitude to be 2,554.4 and 837.1 km2 , respectively forming a 3,391.5 km2 lake while at its highest recorded historical elevation of 804.69 m, Lake Rukwa is 183 km long and 17-51 km wide occupying an area of 5,614.7 km2 (north: 4,409.8 km2; south: 1,204.9 km2) and containing 58.243 km3 of water (north: 44.318 km3; south: 13.925 km3). The developed characteristic equations can be used for water management studies of Lake Rukwa.

The main aim of this study was to determine the optimum line of triticale (X Triticosecale Wittmack) and best location for cultivating. The experimental design used in this study was randomized complete block design with two replications. In this study 29 lines of triticale were applied to assess some agronomic character (Plant Height (cm), No. of Days from Seeding to 50% Anthesis, No. of Days from Seeding to Physiological maturity, No. of Days from 50% Anthesis to Physiological maturity, No. of Fertile Tiller/Plant ), yield character (Grain Yield (t/ha), Biological Yield (t/ha) and Harvest Index). Plowing methods were used twice for the area of the study in each region. In Qlyasan region sowing started on 21 December and on 25 December in Halabja region. A total of 29 triticale lines developed from the hybridized winter triticale lines were used with a set name of 41ITYN and was taken from The International Maize and Wheat Improvement Center (CIMMYT). The 29 triticale lines consisted of (802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829 and 830). The result illustrated that ) the maximum plant height, No. of Days from Seeding to 50% Anthess, No. of Days from Seeding to Physiological maturity, No. of Days from 50% Anthesis to Physiological maturity and No. of Fertile Tiller/Plant was observed in lines (804, 809, 830, 827 and 807). The highest agronomic character was observed under cultivation of triticale in the Halabja location. The maximum Grain Yield (t/ha), Biological Yield (t/ha) and Harvest Index was observed in lines (802, 828 and 827). Cultivation of the plant in Halabja region also gave the highest yield.

The synthesis of complexes based on diethylenetriaminepenta-acetategermanate(IV) acid and a number of exo-ligands was carried out. Their composition, thermal stability, method of coordination of diethylenetriaminepentaacetic acid (H5Dtpa) and protonation of exo-ligands (isoniazid Ind, diphenylguanidine Dphg, piracetam Pam, imidazole Im, cytosine Ctz, 1,10-phenanthroline Phen, 2,2´-bipyridine Bipy), were established. The structural scheme and molecular formula of the obtained compounds were proposed (HL)[Ge(OH)(HDtpa)]·nH2O, де L = Ind, n = 0 (1), Dphg, n = 8 (2), Pam, n = 4 (3), Im, n = 2 (4), Ctz, n = 2 (5), Phen, n = 5 (6), Bipy, n = 4 (7). Based on the elemental analysis of the synthesis products 1–7, it was determined that they exhibit a molar ratio of Ge:N = 1:6 (1, 2, 5), Ge:N = 1:5 (3, 4, 6, 7), therefore, Ge:Dtpa:Ind (Dphg, Pam, Im, Ctz, Phen, Bipy) = 1:1:1. The thermal decomposition of complexes 2–7 begins with an endothermic effect in the temperature range of 80–180 °C, during which a certain amount of crystallization water molecules is removed. The relatively high temperature of its removal is due to the formation of a broad system of intermolecular and intramolecular hydrogen bonds, which is characteristic of various metal complexonates. Thus, in the new compounds, the structure of the octahedral polyhedron of Germanium remains the same as in the original complex acid: the Ge atom is coordinated by two Nitrogen atoms and three Oxygen atoms of three Dtpa acetate groups. The coordination number of Germanium is complemented to 6 by the hydroxo-ligand. All carboxyl groups of the ligand are deprotonated, as evidenced by the presence of bands νas(COO⁻) at 1630–1690 cm⁻¹ and νs(COO⁻) at 1380–1420 cm⁻¹. The presence of Ge-N and Ge-O bonds in the synthesized complexes is confirmed by the bands of valence vibrations of these bonds in the range of 640–650 cm⁻¹ and 590–620 cm⁻¹, respectively. Particularly noteworthy is the band of deformation vibrations of the Ge-O-N group at 810–820 cm⁻¹. In complexes 1–7, a splitting of bands in the 3000 cm⁻¹ region (valence vibrations of the C-H bond) is observed, indicating that all nitrogen atoms in their molecules are coordinated or protonated. The obtained compounds are of interest as promising agents for biomedical applications.

Background:The TNF-α inhibitor adalimumab is a biological disease modifying anti-rheumatic drug (bDMARD) that has been used in different rheumatic diseases with a resistant course. ABP-501 is a biosimilar product (BP) of adalimumab, recently approved by the FDA and EMA. To our knowledge, there is no study assess the efficacy and safety of these two molecules on pediatric patients.Objectives:We aimed to compare the efficacy and safety of the original and biosimilar adalimumab (ABP-501) molecules in childhood rheumatic diseases.Methods:This non-interventional, retrospective, single-centre analysis carried out in Umraniye Training and Resrach Hospital, Pediatric Rheumatology Clinic, Istanbul, Turkey. The study group consisted of patients who were followed due to chronic rheumatic disease between January 1, 2016 and June 1, 2020, and received reference or biosimilar adalimumab therapy for at least three months. Demographic and clinical data of patients were collected at baseline, 3rd, 6th, and 12th months of treatment. Disease activity assessment was made with JADAS-27 in JIA patients, with SUN criteria in uveitis patients, and with Behçet’s Disease Activity Index in BD patients. Efficacy and safety of treatments were compared between reference and biosimilar adalimumab groups.Results:A total of 89 patients (65 with original and 24 with biosimilar molecule) treated with adalimumab, were included in the study. There were 45 female and 44 male in the study, and the median age at the initiation of the adalimumab was 166 months (min-max: 36-231). Of the 89 patients evaluated, the primary diagnoses of 62 were juvenile idiopathic arthritis, 13 were idiopathic uveitis, eight were Behçet’s disease, three were Blau syndrome, two were chronic recurrent multifocal osteomyelitis and one was Vogt-Koyanagi-Harada syndrome. 63 of the patients were biologic-naïve, and 13 were switched from etanercept, 11 from infliximab, and two from other bDMARDs. The median exposure time of adalimumab was 16 months (min-max:3-70) in RP and 14.5 months (min-max: 3-23) in BP. All patients had active disease before treatment. In the group treated with RP, inactive disease was achieved in 60%, 76.6% and 87.2% of the patients at the 3rd, 6th and 12th months, respectively. Also, inactive disease was achieved in 62.5%, 78.2% and 78.2% of the patients at the 3rd, 6th and 12th months in the group treated with BP, respectively. There was no statistically significant difference in efficacy between the groups at the 3rd, 6th and 12th months (p=0.83, 0.07 and 0.32). Serious adverse events were seen in one patient in each groups (lymphoma in RP group, tuberculous meningitis in BP group). Non-serious adverse events were observed in eight patients (12.3%) in the RP group and in two patients (8.3%) in the BP group, without statistically significant difference between groups (p=0.86).Conclusion:No significant difference was observed between the biosimilar adalimumab ABP-501 and RP adalimumab in terms of efficacy and safety.References:[1]Renton, William D et al. Pediatr Rheumatol Online J. 2019;17(1):67.[2]Lovell DJ, Ruperto N, Goodman S, et al. N Engl J Med. 2008;359(8):810-820.[3]Kingsbury, Daniel J et al. Clin Rheumatol 2014;33(10):1433-41.Disclosure of Interests:None declared

ABSTRACTIn earlier studies with pigs the P-adrenergic agonist Ro 16·8714 ((3-AG) enhanced the efficiency of nitrogen (N) retention. Therefore effects of Ro 16·8714 were studied on growth rate, body composition, N, fat and energy retention in pigs fed isoenergetically, but given different amounts of protein (112 or 138 g/kg diet) without (groups LP and NP) or with 60 mg Ro 16·8714 per kg diet (groups LPP and NPP) from 60 to 100 kg live weight. Weight gain (898, 927, 855 and 810 g/day in NP, NPp, LP and LPp) decreased, whereas food: gain ratio (2·94, 2·82, 3·04 and 3·24 kg/kg in NP, NPP, LP and LPP) was increased by low protein intake (P < 0·05) and both weight gain and food conversion were modified by the interaction (P × P) of protein intake and Ro 16·8714 (P < 0·05). Killing-out proportion (820, 830, 830 and 830 g/kg in groups NP, NPp, LP and LPP) was modified by protein intake and Ro 16·8714 (P < 0·05). Carcass growth rate (760, 814, 748 and 723 g/day in NP, NPP, LP and LPP) was modified by protein intake and by P × p (P < 0·05), while non-carcass growth rate (90, 77, 76 and 56 g/day in NP, NPP, LP and LPP) was changed by protein intake and by Ro 16·8714 (P < 0·05). Compared with NP, weights of kidneys (−0·025 kg), small intestine (−0·26 kg) and large intestine (−0·17 kg) were decreased by low protein feeding, and weights of heart, spleen and stomach decreased in response to Ro 16·8714 (-002, -0·02 and -0·06 kg; P < 0·05) while both low protein intake and Ro 16·8714 reduced liver weight (−0·12 and −0·23 kg, respectively; P < 0·05) and blood volume obtained at slaughter (-0·12 and -0·23 kg; P < 0·05). Carcass N (1813, 1970, 1786 and 1825 g in NP NPp, LP and LPP) increased in response to Ro 16-8714, but was reduced by low protein intake (P < 0·05), while noncarcass N (330, 309, 312 and 285 g in NP, NPp, LP and LPP) was decreased by both low protein intake and Ro 16-8714 (P < 0·01). Carcass and non-carcass fat (22·1, 19·9, 23·4 and 23·0 kg, respectively 1·51, 1·41, 1·59 and 1·68 kg in NP, NPp, LP and LPP) increased with low protein feeding (P < 0·05), but were not significantly influenced by Ro 16·8714. The efficiency of N retention (295, 363, 321 and 327 g/kg N retained: N intake in NP, NPp, LP and LPP) was enhanced by Ro 16·8714 (P > 0·05) whereas the efficiency of energy retention was not influenced by Ro 16·8714 and protein intake. In conclusion, an adequate intake of protein is necessary for optimum expression of many, but not all, effects of the P-adrenergic agonist Ro 16·8714.

AbstractMetamorphic rocks of undoubted crustal origin have been described in recent years, principally from Mediterranean collision zones that have been subjected to PT conditions along very low geothermal gradients (∼ 7°C/km) and have reached pressures up to 30 kbar. MgAl-rich metapelites develop particularly diagnostic high-pressure minerals and mineral assemblages that have been and are being studied experimentally in model systems involving the components K2O, MgO, Al2O3, TiO2, SiO2, P2O5, and H2O up to pressures of 50 kbar and temperatures of 1000°C.In the present review the following synthetic phases and phase assemblages are discussed, emphasizing their water-pressure-temperature stability fields (approximated in parentheses here), their reaction relationships, and their known or potential occurrences in metamorphic rocks. Sudoite (0 to ∼ 12 kbar, 150? to 380°C) occurs in very low-grade metapelites. Mg-carpholite (∼ 7 to ∼ 45 kbar, ∼ 200 to 600°C) is found in subducted metabauxites, metapelites, and related quartz veins. Mg-chloritoid (18 to 45 kbar?; 400 to 760°C) has not been found in nature as pure or nearly pure end-member; it requires silica-deficient environments. Yoderite, known in nature only from a single talc-kyanite schist occurrence, has only a small stability field (9 to 18 kbar?, 700 to 870°C?), cannot coexist with quartz, but may be stabilized by Fe3+. Pyrope (∼ 15 to at least 50 kbar, ∼ 700°C to melting), with or without relic coesite inclusions, occurs spectacularly in quartzites. Mg-staurolite (∼ 14 to some 90 kbar?, 700 to 1000°C), recently discovered as inclusions in pyrope, requires silica-deficiency. MgMgAl-pumpellyite is a new synthetic phase in which Mg totally replaces Ca of normal pumpellyite; because of its very high-pressure, low-temperature stability (∼ 37 to at least 55 kbar, < 400 to 780°C) it may not form within our globe. Ellenbergerite, the new high-pressure mineral forming inclusions in pyrope, apparently exhibits a rather composition-dependent stability with Ti-ellenbergerite, requiring higher pressures (> 20 kbar) than P-bearing, Ti-free members; a pure hydrous Mg-phosphate with ellenbergerite structure was synthesized at 10 kbar. Phengites, the widespread MgSi-substituted muscovites, require increasingly high water pressures (up to ∼ 20 kbar) for higher degrees of substitution, but the Al-celadonite end-member is not stable under any conditions; the compositions of phengites coexisting with limiting assemblages such as phlogopite, K-feldspar, and an SiO2 phase are useful geobarometers. The common assemblage Mg-chlorite + Al2SiO5 (mainly kyanite) has an extensive stability field ranging from near zero to 31 kbar at temperatures varying from some 320 to ∼ 760°C depending on pressure. The whiteschist assemblage talc + kyanite (6 to ∼ 45 kbar, 550 to 810°C) plays an important role in collision zone metamorphism as it forms from the greenschist assemblage chlorite + quartz at low grades but is also known to break down into pyrope + coesite at the highest grade observed thus far. The assemblage talc-phengite (11 to at least 35 kbar, 300? to 820°C depending on pressure), on the other hand, is well known from subducted metapelites. At pressures of 15–20 kbar and temperatures of 400–650°C a very K,Mg-rich, siliceous fluid forms as a consequence of the mutual reaction of the minerals K-feldspar and phlogopite (biotite) which are very common in crustal rocks including granites. Such fluids are bound to cause metasomatism in neighbouring mantle rocks which, upon subsequent increase of temperature, produce post-collisional ultrapotassic, lamproitic melts.

Abstract. This paper presents an update and extension of HYDE, the History Database of the Global Environment (HYDE version 3.2). HYDE is an internally consistent combination of historical population estimates and allocation algorithms with time-dependent weighting maps for land use. Categories include cropland, with new distinctions for irrigated and rain-fed crops (other than rice) and irrigated and rain-fed rice. Grazing lands are also provided, divided into more intensively used pasture and less intensively used rangeland, and further specified with respect to conversion of natural vegetation to facilitate global change modellers. Population is represented by maps of total, urban, rural population, population density and built-up area. The period covered is 10 000 before Common Era (BCE) to 2015 Common Era (CE). All data can be downloaded from https://doi.org/10.17026/dans-25g-gez3. We estimate that global population increased from 4.4 million people (we also estimate a lower range < 0.01 and an upper range of 8.9 million) in 10 000 BCE to 7.257 billion in 2015 CE, resulting in a global population density increase from 0.03 persons (or capita, in short cap) km−2 (range 0–0.07) to almost 56 cap km−2 respectively. The urban built-up area evolved from almost zero to roughly 58 Mha in 2015 CE, still only less than 0.5 % of the total land surface of the globe. Cropland occupied approximately less than 1 % of the global land area (13 037 Mha, excluding Antarctica) for a long time period until 1 CE, quite similar to the grazing land area. In the following centuries the share of global cropland slowly grew to 2.2 % in 1700 CE (ca. 293 Mha, uncertainty range 220–367 Mha), 4.4 % in 1850 CE (578 Mha, range 522–637 Mha) and 12.2 % in 2015 CE (ca. 1591 Mha, range 1572–1604 Mha). Cropland can be further divided into rain-fed and irrigated land, and these categories can be further separated into rice and non-rice. Rain-fed croplands were much more common, with 2.2 % in 1700 CE (289 Mha, range 217–361 Mha), 4.2 % (549 Mha, range 496–606 Mha) in 1850 CE and 10.1 % (1316 Mha, range 1298–1325 Mha) in 2015 CE, while irrigated croplands used less than 0.05 % (4.3 Mha, range 3.1–5.5 Mha), 0.2 % (28 Mha, range 25–31 Mha) and 2.1 % (277 Mha, range 273–278 Mha) in 1700, 1850 and 2015 CE, respectively. We estimate the irrigated rice area (paddy) to be 0.1 % (13 Mha, range 9–16 Mha) in 1700 CE, 0.2 % (28 Mha, range 26–31 Mha) in 1850 CE and 0.9 % (118 Mha, range 117–120 Mha) in 2015 CE. The estimates for land used for grazing are much more uncertain. We estimate that the share of grazing land grew from 5.1 % in 1700 CE (667 Mha, range 507–820 Mha) to 9.6 % in 1850 CE (1192 Mha, range 1068–1304 Mha) and 24.9 % in 2015 CE (3241 Mha, range 3211–3270 Mha). To aid the modelling community we have divided land used for grazing into more intensively used pasture, less intensively used converted rangeland and less or unmanaged natural unconverted rangeland. Pasture occupied 1.1 % in 1700 CE (145 Mha, range 79–175 Mha), 1.9 % in 1850 CE (253 Mha, range 218–287 Mha) and 6.0 % (787 Mha, range 779–795 Mha) in 2015 CE, while rangelands usually occupied more space due to their occurrence in more arid regions and thus lower yields to sustain livestock. We estimate converted rangeland at 0.6 % in 1700 CE (82 Mha range 66–93 Mha), 1 % in 1850 CE (129 Mha range 118–136 Mha) and 2.4 % in 2015 CE (310 Mha range 306–312 Mha), while the unconverted natural rangelands occupied approximately 3.4 % in 1700 CE (437 Mha, range 334–533 Mha), 6.2 % in 1850 CE (810 Mha, range 733–881 Mha) and 16.5 % in 2015 CE (2145 Mha, range 2126–2164 Mha).

Эндофуллерены, содержащие один или несколько атомов металла внутри углеродного каркаса (металлофуллерены), представляют большой практический интерес в связи с возможностью создания на их основе эффективных контрастирующих агентов для магнитно-резонансной томографии (МРТ), антиоксидантных и противораковых средств. Данные соединения могут быть также использованы в спинтронике для создания наноразмерных электронных устройств. В настоящей работе в рамках теории функционала плотности произведен расчет структурных, электронных и термодинамических характеристик эндофуллеренов металлов подгруппы скандия с числом инкапсулированных атомов от одного до семи в газовой фазе. Описаны стабильные структуры с симметриямиCs, C2, C3 и Ci, соответствующие позициям, занимаемым атомами металла внутри каркаса фуллерена. Установлен теоретический предел числа атомов металла, при котором структура эндофуллерена сохраняет устойчивость – шесть атомов для скандия, четыре для иттрия и три для лантана. 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RESUMEN:El objetivo del artículo es aproximarnos a la controvertida biografía del comisario Manuel Brabo Portillo. El trabajo está basado en fuentes primarias y secundarias. El método utilizado es empírico. En el imaginario del mundo sindicalista revolucionario, Brabo Portillo era el policía más odiado, la reencarnación de la cara más turbia del Estado. Fue, así mismo, un espía alemán relacionado con el hundimiento de barcos españoles, el asesinato del empresario e ingeniero Barret y el primer jefe de los terroristas vinculados a la patronal barcelonesa. La conflictividad que afectó a España en el período de la Primera Guerra Mundial es fundamental para entender los orígenes del terrorismo vinculado al pistolerismo, que marcó la historia político social española del primer tercio del siglo XX.PALABRAS CLAVE: Brabo Portillo, pistolerismo, espionaje, sindicalismo, Primera Guerra Mundial.ABSTRACT:The objective of the article is an approach to the controversial biography of Police Chief Manuel Brabo Portillo. The work is based on primary and secondary sources. The method used is empirical. In the imagery of the revolutionary syndicalist world, Brabo Portillo was the most hated policeman, the reincarnation of the murkiest face of the state. He was also a German spy connected with the sinking of Spanish ships, the murder of businessman and engineer Josep Barret and the first head of the terrorists linked to Barcelona employers. 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Palaeomagnetic studies in the Malani Igneous Suite (ca. 770–750 Ma) of the Marwar Crustal Block, NW India, provide essential constraints on palaeogeographic reconstructions of the Rodinia Supercontinent. The Malani Igneous Suite is intrusive into megacrystic granite and granite-gneissic enclaves of the Marwar Crustal Block. A crustal-scale NE–SW ductile transpressional shear zone with a southeasterly dip known as the Phulad Shear Zone (820–810 Ma) separates this Marwar Crustal Block from the rocks farther east. The pre-shearing tectonic evolution of the Marwar Crustal Block is poorly understood. Three phases of ductile deformations (D1, D2, and D3, with associated fabrics S1, S2, and S3) were identified in the Marwar Crustal Block. The D1 deformation is restricted to enclave gneisses. The megacrystic granite was emplaced syn-tectonically during D2 deformation. The S2 magmatic foliation (NNW–SSE) in the megacrystic granite is oblique to the Phulad Shear Zone. The D3 deformation in the megacrystic granite is synchronous with the Phulad Shear Zone mylonites. Another porphyritic granite (Phulad granite, ca. 820 Ma) emplaced syn-tectonically during D3 deformation along and across the Phulad Shear Zone. U-Pb zircon dates in the Marwar Crustal Block document ca. 890 Ma and ca. 860 Ma magmatic dates. U-Pb-Th monazite dates in the Marwar Crustal Block show a strong peak at ca. 820 Ma. By integrating critical field relations, deformational patterns, and geochronology, we argue that the Marwar Crustal Block shows distinct geological evolution prior to its accretion with the remaining parts of India. We propose that the accretion of the Marwar Crustal Block must be younger than ca. 860 Ma and culminate during ca. 820–810 Ma to form the Greater India landmass along the Phulad Shear Zone.

ABSTRACTThe interactions between Ni and Ni/In/Ni thin-films and GaAs were studied by SEM, SAM and AES. The presence of a molten phase was observed for both contacts after annealing at 820°C for 3 minutes. This behavior was rationalized in terms of the presence of a ternary eutectic reaction in the gallium-nickel-arsenic system. DTA confirmed the existence of the reaction:at 810°C. In the case of Ni/In/Ni, melting was thought to occur because of the segregation of indium metal to the contact surface and the subsequent melting of the nearly ternary interfacial region. Upon further cooling the formation of NiGa, NiAs, InxGa1−xAs and an unspecified compound Ni-In was believed to occur. The contact was shown to be either sintered or alloyed, depending upon processing conditions.

This research aims to find out the names of educators during the Abbasid Dynasty and to find out who the caliphs were during. The historical method consists of data collection, source criticism, interpretation and finally historiography. The research approaches used in this research are a geographic approach, a sociological approach, an educational approach and historical education. The results of this research are that the educators presented by the researchers were 14 people, namely: 1) Imam Abu Hanifah Rahimahullah (80-150 H/700-767 M), 2) Imam Malik Rahimahullah (93 -179 H/712-796 M), 3) Imam Syafi’i Rahimahullah (150-204 H/767-820 M), 4) Imam Ahmad Rahimahullah (164-241 H/781-856 M), 5) Imam Ad-Darimi Rahimahullah (181-255 H/798-869 M), 6) Imam Al-Bukhari Rahimahullah (194-256 H/810-871 M), 7) Imam At-Tarmidzi Rahimahullah (200-279 H/816-892 M), 8) Imam Abu Daud Rahimahullah (202-275 H/818-889 M), 9) Imam Muslim Rahimahullah (204-261 H/820-875 M), 10) Imam Ibnu Majah Rahimahullah (209-273 H/825-887 M), 11) Imam An-Nasaai Rahimahullah (215-303 H/830-906 M), 12) Abu Ja’far Muhammad bin Jarir Ath-Thabari Rahimahullah (224-310 H/839-923 M), 13) Imam Daarud Ad-Qudni Rahimahullah (306-385 H/919-995 M), dan 14) Imam Al-Baihaqi Rahimahullah (384-458 H/995-1.066 M).

Neoproterozoic igneous rocks are widely distributed in the Dunhuang-Alxa Block, northwest China, and record geodynamic processes caused by the assembly and break-up of Rodinia. In this study, we present new petrological, geochemical, and zircon U-Pb-Hf isotope data for the Langshan gabbros in the northeastern Alxa Block. Langshan gabbros (827−819 Ma) have depleted whole-rock Nd (+3.2 to +4.9) and zircon Hf (+4 to +21) isotopic compositions and weak enrichments in large-ion lithophile elements. These rocks were probably derived by partial melting of a depleted mantle wedge metasomatized by fluids released from a subducted slab in a back-arc basin environment. Geochemical and zircon Hf isotope data for early Neoproterozoic igneous rocks are consistent with the presence of a long-lived (ca. 930−810 Ma) retreating subduction zone along the northern margin of the Dunhuang-Alxa Block, indicating it was located at the northern margin of Rodinia. Some mantle plume-related magmatism, including A1-type silicic volcanic rocks in the Langshan Group and Jinchuan ultramafic-mafic intrusions, occurred in the interior of the Dunhuang-Alxa Block, which was similar to early Neoproterozoic plume-related magmatism (ca. 850−820 Ma) in the interior of northern Rodinia. The temporal link between subduction and extension suggests that this retreating subduction zone along the northern margin of Rodinia, in combination with a mantle plume beneath its interior, resulted in lithospheric extension and break-up of Rodinia during ca. 850−810 Ma.

The North China Craton records multiple metamorphic events related to supercontinent assembly during the Paleoproterozoic, forming Columbia, and again during the late Paleozoic, forming Pangea. Here we show that the Paleoproterozoic high-pressure granulites (HPGs) formed from enriched mid-ocean ridge basalt protoliths and record a clockwise pressure-temperature-time (P−T−t) path with prograde metamorphism at 7.8−10.0 kbar and 780−820 °C, peak granulite-facies metamorphism at 12−12.3 kbar and ∼860−880 °C, and retrograde metamorphism at 8.7−9.1 kbar and 850−855 °C. Subduction initiated prior to 1.90 Ga, with final collision and orogeny at 1.88 Ga, followed by post-collision/exhumation at 1.80 Ga, defining a prolonged exhumation period (∼90 m.y.) that occurred at a slow velocity of ∼0.16 ± 0.08 mm/y. Late Paleozoic HPGs are normal mid-ocean ridge basalt type and record a near clockwise P−T−t path, with peak/post-peak amphibolite-facies metamorphism at 11.0−12.5 kbar and 860−890 °C, isothermal decompression to 7.2−7.5 kbar and 810−820 °C, and retrogression to 5.5−7.2 kbar and 805−850 °C. Subduction initiated earlier than ca. 340 Ma, exhumation and uplift initiated at 335−309 Ma and continued to 297−287 Ma. The exhumation was short-lived (∼50 m.y.) and relatively fast (0.38 ± 0.14 mm/y). When compared to granulite-facies metamorphism documented in many Paleoproterozoic HPGs, late Paleozoic HPGs appear to commonly form with an initial period of steep subduction leading to eclogite-facies metamorphism, with subsequent exhumation to middle/lower levels of the crust. Our results further reveal that the exhumation velocity for supercontinent collision was facilitated and duration shortened through time, and that the exhumation mechanism might have been controlled by subduction angle, compression pressure, and temperature.

A field experiment was conducted to assess performance of newly developed five mid late and late sugarcane cultivars, i.e. Co 0121, Co 0123, Co 0124 and Co 0241 along with CoS 767(standard) with two row spacing (75 and 90 cm) under three fertility levels, i.e. 75, 100 (N150 P21.8 K41.5) and 125% of recommended dose of fertilizers (RDF) with plant-ratoon system. Varieties Co 0121 and Co 0241 recorded the maximum and significantly higher cane yield (69.1 and 67.2 tonnes/ha) and commercial cane sugar (10.22 and 9.00 tonnes/ha) in plant and ratoon crop, respectively. In ratoon crop number of millable canes (NMC) and cane yield increased substantially by 10.5 and 10.3 per cent, respectively with 75 cm row spacing. Closer spacing fetched maximum net return (` 24 810 and ` 47 820) with benefit: cost ratio of 1.42 and 2.27 with plant as well as ratoon crop, respectively. Fertility level of 125% RDF, being at par with 100% RDF registered improvement in yield attributes and produced increased cane yield and CCS both from plant as well as ratoon crop over 75% RDF. Except varieties, the quality parameters did not undergo significant variation due to change in row spacing and fertility treatments. Cultivar×fertility level interactions indicated that varieties Co 0121 and Co 0241 were equally productive at normal fertility level of 100% RDF.

Digital marketing has been recognized as a crucial aspect of attracting students for enrollment. Therefore, the aim of this research is to examine the influence of digital marketing strategies on student enrollment decisions and to identify the most effective digital marketing strategy for driving student enrollment in tertiary education. This research utilized a descriptive quantitative research approach with a stratified random sampling technique and employed a modified survey questionnaire as the primary method of data collection. The data obtained from the survey questionnaire were analyzed and interpreted using a Four-point Likert scale, which measures interval data. The findings of the study revealed that utilizing “university webinar platforms” significantly influences student enrollment decisions in tertiary education. Moreover, it was also revealed that utilizing “social media presence and retargeting campaigns”, and “mobile-friendly website and educational apps” increases the awareness of students on the university programs and services being offered by learning institutions. As a result, these digital marketing strategies increase the students’ interest in university programs influencing significantly their enrollment decisions. It came to light that there is a statistically significant relationship between digital marketing strategies, namely, social media presence and retargeting campaigns (r=.963, p=.008), mobile-friendly website and educational apps (r=.821, p=.089), video content strategy (r=.820, p=.089), SEO-enhanced content on web pages (r=.810, p=.097), and university webinar platforms (r=.760, p=.136) on the student enrollment decisions in tertiary education.

The publication presents a commented Russian translation of Proclus’ fragments associated with his Abridged Grammatical Chrestomathy (Πρόκλου χρηστομαθείας γραμματικῆς ἐκλογαί), which has been preserved as an epitome in the Bibliotheca of Patriarch Photius (c. 810/820–893). These fragments contain a biography of Homerus (Vita Homeri) along with six summaries of the poems included in the so-called Epic Cycle, comprising the following titles: Cypria, Ethiopis, The Little Iliad, The Sack of Ilion, The Returns, and Telegony. In the past, all these texts were ascribed to the renowned Neoplatonist philosopher Proclus Lycius (412–485), known not only by his commentaries on several of Plato’s dialogues, but by his purely philological works as well, for example his scholia to Hesiod’s Opera et dies, not to mention his own poetical compositions, the philosophically biased mythological hymns. Even today, a number of scholars are still inclined to support this attribution, though it appears that it was most likely written by an otherwise unknown philosopher’s namesake, to wit a grammarian from the Alexandrian school, who lived in the first half of the 2th century ad. The translation is based on the most recent edition of the text of the fragments prepared by Martin L. West (2003a and 2003b), who supplements Proclus’ summaries of the poems belonging to the Epic Cycle with some passages from Apollodorus’ Mythological Library and suggests, moreover, quite a number of apt conjectures compared with the textus receptus of Proclus’ fragments collated from the manuscripts by Albert Severyns, whose own edition (1963) has not as yet lost its relevance.

Background We conducted Mendelian randomization analyses investigating the linear associations of genetically proxied inhibition of different coagulation factors with risk of common cardiovascular diseases. Methods and Results Genetic instruments proxying coagulation factor inhibition were identified from genome‐wide association studies for activated partial thromboplastin time and prothrombin time in BioBank Japan (up to 58 110 participants). Instruments were identified for 9 coagulation factors (fibrinogen alpha, beta, and gamma chain; and factors II, V, VII, X, XI, and XII). Age‐ and sex‐adjusted estimates for associations of the instruments with the outcomes were derived from UK Biobank and the FinnGen, CARDIoGRAMplusC4D (Coronary Artery Disease Genome‐wide Replication and Meta‐analysis), and MEGASTROKE consortia with numbers of incident and prevalent cases of 820 to 60 810. Genetically proxied inhibition of fibrinogen alpha, beta, and gamma chain, factor II, and factor XI were associated with reduced risk of venous thromboembolism ( P <0.001). With the exception of fibrinogen beta and factor II, inhibition of these factors was also associated with reduced risk of any ischemic stroke and cardioembolic stroke ( P ≤0.002). Genetically proxied inhibition of fibrinogen beta and gamma were associated with reduced large‐artery stroke risk ( P =0.001). There were suggestive protective associations of genetically proxied inhibition of factors V, VII, and X with ischemic stroke ( P <0.05), and suggestive adverse associations of genetically proxied inhibition of factors II and XII with subarachnoid hemorrhage. Conclusions This study supports targeting fibrinogen and factor XI for reducing venous thromboembolism and ischemic stroke risk, and showed suggestive evidence that inhibition of factors V, VII, and X might reduce ischemic stroke risk.

Abstract Background While emerging studies suggest that the COVID-19 pandemic caused disruptions in routine healthcare utilization, the full impact of the pandemic on healthcare utilization among diverse group of patients with type 2 diabetes is unclear. The purpose of this study is to examine trends in healthcare utilization, including in-person and telehealth visits, among U.S. veterans with type 2 diabetes before, during and after the onset of the COVID-19 pandemic, by demographics, pre-pandemic glycemic control, and geographic region. Methods We longitudinally examined healthcare utilization in a large national cohort of veterans with new diabetes diagnoses between January 1, 2008 and December 31, 2018. The analytic sample was 733,006 veterans with recently-diagnosed diabetes, at least 1 encounter with veterans administration between March 2018–2020, and followed through March 2021. Monthly rates of glycohemoglobin (HbA1c) measurements, in-person and telehealth outpatient visits, and prescription fills for diabetes and hypertension medications were compared before and after March 2020 using interrupted time-series design. Log-linear regression model was used for statistical analysis. Secular trends were modeled with penalized cubic splines. Results In the initial 3 months after the pandemic onset, we observed large reductions in monthly rates of HbA1c measurements, from 130 (95%CI,110–140) to 50 (95%CI,30–80) per 1000 veterans, and in-person outpatient visits, from 1830 (95%CI,1640–2040) to 810 (95%CI,710–930) per 1000 veterans. However, monthly rates of telehealth visits doubled between March 2020–2021 from 330 (95%CI,310–350) to 770 (95%CI,720–820) per 1000 veterans. This pattern of increases in telehealth utilization varied by community type, with lowest increase in rural areas, and by race/ethnicity, with highest increase among non-hispanic Black veterans. Combined in-person and telehealth outpatient visits rebounded to pre-pandemic levels after 3 months. Despite notable changes in HbA1c measurements and visits during that initial window, we observed no changes in prescription fills rates. Conclusions Healthcare utilization among veterans with diabetes was substantially disrupted at the onset of the pandemic, but rebounded after 3 months. There was disparity in uptake of telehealth visits by geography and race/ethnicity.

Background: Healthcare providers are influenced by prevailing social norms. Addressing their underlying values on female genital mutilation (FGM) as well as their knowledge and skills in person-centred care could enable them to be effective change agents in the prevention of FGM. However, there is limited evidence on what works to achieve this. Objective: To test the effectiveness of an intervention involving person-centered communication (PCC) for FGM prevention in antenatal care (ANC) settings in Guinea, Kenya, and Somalia. Methods: A cluster randomized implementation study was conducted between August 2020 and September 2021. Sixty ANC clinics were randomized to the intervention and control arms in each country. ANC providers from the intervention arm received training to build their knowledge of FGM, question their FGM-related values and attitudes, and conduct FGM prevention counseling using a PCC approach. Data were collected at baseline, three months, and six months using tablets and were analyzed using multilevel regression models. Results: Over six months, 222 ANC providers (n=105 intervention; n=117 control) were followed up from 163 clinics. In month six, 1,630 new clients (n=820 intervention; n=810 control) were interviewed after their ANC clinic visit. ANC providers in the intervention arm were more likely than providers in the control arm to apply the PCC approach (p<0.001), communicate effectively about FGM prevention (p<0.05), and have higher FGM knowledge scores (p=0.005). Provider attitudes against FGM were consistently high in both arms across all time points. After the ANC clinic visit, a higher proportion of ANC clients in the intervention arm than in the control arm reported a change in their support for FGM (52% vs. 29%, p<0.001), were strongly opposed to FGM (61% vs. 47%, p<0.001), reported that they did not intend to cut their daughters (84% vs. 70%, p<0.001), and wanted to be actively engaged in FGM prevention (83% vs. 66%, p<0.001). Conclusion: This study provides robust evidence that training primary care providers to challenge their FGM-related values and attitudes and build their interpersonal communication skills using a person-centered approach is effective for strengthening FGM prevention in the health sector. Study impact and recommendations: This is the first randomized controlled trial to provide evidence on the effectiveness of a social norm change approach for FGM prevention in the health sector. The strength of the evidence should inform the scale-up of this approach to ensure effective delivery of FGM prevention services at the primary care level.

Abstract The last four caldera-forming ignimbrites in the central San Juan caldera cluster, Colorado, erupted 1400 km3 in ≤80 kyr and alternated between zoned crystal-poor rhyolite to crystal-rich dacite and unzoned, crystal-rich dacite. The zoned 150 km3 Rat Creek Tuff (26·91 Ma), unzoned 250 km3 Cebolla Creek Tuff, and zoned 500 km3 Nelson Mountain Tuff (26·90 Ma) formed the nested San Luis caldera complex with slightly offset calderas, and the unzoned 500 km3 Snowshoe Mountain Tuff (26·87 Ma) formed the Creede caldera to the south. The Rat Creek Tuff, Nelson Mountain Tuff, and Snowshoe Mountain Tuff have similar mineral assemblages of plagioclase, sanidine, quartz, biotite, hornblende, clinopyroxene, Fe–Ti oxides, and accessory zircon, titanite, and apatite. The Cebolla Creek Tuff differs from the other three ignimbrites with more abundant hornblende and a lack of quartz and sanidine. Trace element compositions of interstitial glass are unique to each ignimbrite, correlating with mineral assemblages and inferred crystallization depths. Glass, feldspar, hornblende, and clinopyroxene thermobarometry calculations provide evidence for vertically extensive crustal magma reservoirs with a common magmatic zone at ∼435–470 MPa (∼16–17 km) showing a transition into shallow pre-eruptive reservoirs between ∼110 and 340 MPa (∼4–13 km), similar to the estimated magma reservoir architecture of the Altiplano Puna Volcanic Complex. The upper portions of the eruptible parts of the magma reservoirs of the Rat Creek Tuff (215 ± 50 MPa, ∼810–820 °C), Cebolla Creek Tuff (340 ± 20 MPa, ∼860–880 °C), Nelson Mountain Tuff (215 ± 20 MPa, ∼745–800 °C), and Snowshoe Mountain Tuff (110 ± 40 MPa, 825 ± 10 °C) occupied shallow levels in the crust similar to other magma reservoirs of the central San Juan caldera cluster. Trace element modelling correlates with a deep crystallization signature in the unzoned Cebolla Creek Tuff and Snowshoe Mountain Tuff, typified by a flat trend in Ba versus Sr whole-rock and glass chemistry. The zoned Rat Creek Tuff and Nelson Mountain Tuff are typified by a steep trend in Ba versus Sr chemistry interpreted as a shallower crystallization signature. Similarly, the unzoned Cebolla Creek Tuff and Snowshoe Mountain Tuff have flatter slopes in FeO versus An space of plagioclase chemistry interpreted as more abundant deep plagioclase crystallization and a difficulty in physically mixing with Fe-rich mafic recharge magma owing to higher viscosity. The zoned Rat Creek Tuff and Nelson Mountain Tuff have higher slopes in FeO versus An space of plagioclase chemistry interpreted as more abundant shallow plagioclase crystallization and more feasible mixing with Fe-rich mafic recharge magma owing to lower viscosity. The eruption of the Rat Creek Tuff was probably triggered by mafic injection, but the other three ignimbrites lack mingling textures in pumice, suggesting that other mechanisms were important in causing such large eruptions. After a prolonged period of mantle-derived magma injection and crustal heating (∼25 000 km3 Conejos Formation erupted during ∼35–29 Ma), the San Juan magmatic body became a robust and versatile producer of diverse eruptible magmas in short time periods during its Oligocene ignimbrite flare-up.

The TRP superfamily of channels (nomenclature as agreed by NC-IUPHAR [176, 1072]), whose founder member is the Drosophila Trp channel, exists in mammals as six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. TRP subunits contain six putative TM domains and assemble as homo- or hetero-tetramers to form cation selective channels with diverse modes of activation and varied permeation properties (reviewed by [730]). Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and in a number of books [401, 686, 1155, 256]. The established, or potential, involvement of TRP channels in disease [1126] is reviewed in [448, 685], [688] and [464], together with a special edition of Biochemica et Biophysica Acta on the subject [685]. Additional disease related reviews, for pain [633], stroke [1135], sensation and inflammation [988], itch [130], and airway disease [310, 1051], are available. The pharmacology of most TRP channels has been advanced in recent years. Broad spectrum agents are listed in the tables along with more selective, or recently recognised, ligands that are flagged by the inclusion of a primary reference. See Rubaiy (2019) for a review of pharmacological tools for TRPC1/C4/C5 channels [805]. Most TRP channels are regulated by phosphoinostides such as PtIns(4,5)P2 although the effects reported are often complex, occasionally contradictory, and likely to be dependent upon experimental conditions, such as intracellular ATP levels (reviewed by [1009, 689, 801]). Such regulation is generally not included in the tables.When thermosensitivity is mentioned, it refers specifically to a high Q10 of gating, often in the range of 10-30, but does not necessarily imply that the channel's function is to act as a 'hot' or 'cold' sensor. In general, the search for TRP activators has led to many claims for temperature sensing, mechanosensation, and lipid sensing. All proteins are of course sensitive to energies of binding, mechanical force, and temperature, but the issue is whether the proposed input is within a physiologically relevant range resulting in a response. TRPA (ankyrin) familyTRPA1 is the sole mammalian member of this group (reviewed by [293]). TRPA1 activation of sensory neurons contribute to nociception [414, 890, 602]. Pungent chemicals such as mustard oil (AITC), allicin, and cinnamaldehyde activate TRPA1 by modification of free thiol groups of cysteine side chains, especially those located in its amino terminus [575, 60, 365, 577]. Alkenals with α, β-unsaturated bonds, such as propenal (acrolein), butenal (crotylaldehyde), and 2-pentenal can react with free thiols via Michael addition and can activate TRPA1. However, potency appears to weaken as carbon chain length increases [26, 60]. Covalent modification leads to sustained activation of TRPA1. Chemicals including carvacrol, menthol, and local anesthetics reversibly activate TRPA1 by non-covalent binding [424, 511, 1081, 1080]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [425, 212]. The electron cryo-EM structure of TRPA1 [740] indicates that it is a 6-TM homotetramer. Each subunit of the channel contains two short ‘pore helices’ pointing into the ion selectivity filter, which is big enough to allow permeation of partially hydrated Ca2+ ions. TRPC (canonical) familyMembers of the TRPC subfamily (reviewed by [284, 778, 18, 4, 94, 446, 739, 70]) fall into the subgroups outlined below. TRPC2 is a pseudogene in humans. It is generally accepted that all TRPC channels are activated downstream of Gq/11-coupled receptors, or receptor tyrosine kinases (reviewed by [765, 953, 1072]). A comprehensive listing of G-protein coupled receptors that activate TRPC channels is given in [4]. Hetero-oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [18] and [447]. TRPC channels have frequently been proposed to act as store-operated channels (SOCs) (or compenents of mulimeric complexes that form SOCs), activated by depletion of intracellular calcium stores (reviewed by [741, 18, 770, 820, 1121, 157, 726, 64, 158]). However, the weight of the evidence is that they are not directly gated by conventional store-operated mechanisms, as established for Stim-gated Orai channels. TRPC channels are not mechanically gated in physiologically relevant ranges of force. All members of the TRPC family are blocked by 2-APB and SKF96365 [347, 346]. Activation of TRPC channels by lipids is discussed by [70]. Important progress has been recently made in TRPC pharmacology [805, 619, 436, 102, 851, 191, 291]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [295, 71, 885, 1031, 1025, 154, 103, 561, 913, 409]. TRPC1/C4/C5 subgroup TRPC1 alone may not form a functional ion channel [229]. TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La3+. TRPC2 is a pseudogene in humans, but in other mammals appears to be an ion channel localized to microvilli of the vomeronasal organ. It is required for normal sexual behavior in response to pheromones in mice. It may also function in the main olfactory epithelia in mice [1114, 723, 724, 1115, 539, 1168, 1109].TRPC3/C6/C7 subgroup All members are activated by diacylglycerol independent of protein kinase C stimulation [347].TRPM (melastatin) familyMembers of the TRPM subfamily (reviewed by [275, 346, 741, 1151]) fall into the five subgroups outlined below. TRPM1/M3 subgroupIn darkness, glutamate released by the photoreceptors and ON-bipolar cells binds to the metabotropic glutamate receptor 6 , leading to activation of Go . This results in the closure of TRPM1. When the photoreceptors are stimulated by light, glutamate release is reduced, and TRPM1 channels are more active, resulting in cell membrane depolarization. Human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function. TRPM1 is also found melanocytes. Isoforms of TRPM1 may present in melanocytes, melanoma, brain, and retina. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures [398, 708]. TRPM3 (reviewed by [714]) exists as multiple splice variants which differ significantly in their biophysical properties. TRPM3 is expressed in somatosensory neurons and may be important in development of heat hyperalgesia during inflammation (see review [941]). TRPM3 is frequently coexpressed with TRPA1 and TRPV1 in these neurons. TRPM3 is expressed in pancreatic beta cells as well as brain, pituitary gland, eye, kidney, and adipose tissue [713, 940]. TRPM3 may contribute to the detection of noxious heat [1017]. TRPM2TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells). The direct activators are calcium, adenosine diphosphate ribose (ADPR) [970] and cyclic ADPR (cADPR) [1118]. As for many ion channels, PI(4,5)P2 must also be present [1109]. Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [239]. Recent studies have reported structures of human (hs) TRPM2, which demonstrate two ADPR binding sites in hsTRPM2, one in the N-terminal MHR1/2 domain and the other in the C-terminal NUDT9-H domain. In addition, one Ca2+ binding site in the intracellular S2-S3 loop is revealed and proposed to mediate Ca2+ binding that induces conformational changes leading the ADPR-bound closed channel to open [387, 1027]. Meanwhile, a quadruple-residue motif (979FGQI982) was identified as the ion selectivity filter and a gate to control ion permeation in hsTRPM2 [1120]. TRPM2 is involved in warmth sensation [848], and contributes to several diseases [76]. TRPM2 interacts with extra synaptic NMDA receptors (NMDAR) and enhances NMDAR activity in ischemic stroke [1164]. Activation of TRPM2 in macrophages promotes atherosclerosis [1165, 1147]. Moreover, silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction [1028]. Recent studies have designed various compounds for their potential to selectively inhibit the TRPM2 channel, including ACA derivatives A23, and 2,3-dihydroquinazolin-4(1H)-one derivatives [1137, 1139]. TRPM4/5 subgroupTRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca2+ [1072]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium-activated cation (CAN) channels [327]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic-mediated inotropy [593]. Mutations are associated with conduction defects [404, 593, 879]. TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [993] and dendritic cell migration [52]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [537] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [513]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [246]. TRPM6/7 subgroupTRPM6 and 7 combine channel and enzymatic activities (‘chanzymes’) [172]. These channels have the unusual property of permeation by divalent (Ca2+, Mg2+, Zn2+) and monovalent cations, high single channel conductances, but overall extremely small inward conductance when expressed to the plasma membrane. They are inhibited by internal Mg2+ at ~0.6 mM, around the free level of Mg2+ in cells. Whether they contribute to Mg2+ homeostasis is a contentious issue. PIP2 is required for TRPM6 and TRPM7 activation [810, 1077]. When either gene is deleted in mice, the result is embryonic lethality [413, 1065]. The C-terminal kinase region of TRPM6 and TRPM7 is cleaved under unknown stimuli, and the kinase phosphorylates nuclear histones [479, 480]. TRPM7 is responsible for oxidant- induced Zn2+ release from intracellular vesicles [3] and contributes to intestinal mineral absorption essential for postnatal survival [622]. The putative metal transporter proteins CNNM1-4 interact with TRPM7 and regulate TRPM7 channel activity [40, 467]. TRPM8Is a channel activated by cooling and pharmacological agents evoking a ‘cool’ sensation and participates in the thermosensation of cold temperatures [63, 178, 224] reviewed by [1011, 562, 457, 649]. Direct chemical agonists include menthol and icilin[1086]. Besides, linalool can promote ERK phosphorylation in human dermal microvascular endothelial cells, down-regulate intracellular ATP levels, and activate TRPM8 [68]. Recent studies have found that TRPM8 has typical S4-S5 connectomes with clear selective filters and exowell rings [512], and have identified cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP2-dependent gated pathways [1111]. Moreover, the last 36 amino acids at the carboxyl terminal of TRPM8 are key protein sequences for TRPM8's temperature-sensitive function [194]. TRPM8 deficiency reduced the expression of S100A9 and increased the expression of HNF4α in the liver of mice, which reduced inflammation and fibrosis progression in mice with liver fibrosis, and helped to alleviate the symptoms of bile duct disease [556]. Channel deficiency also shortens the time of hypersensitivity reactions in migraine mouse models by promoting the recovery of normal sensitivity [12]. A cyclic peptide DeC‐1.2 was designed to inhibit ligand activation of TRPM8 but not cold activation, which can eliminate the side effects of cold dysalgesia in oxaliplatin-treated mice without changing body temperature [9]. Analysis of clinical data shows that TRPM8-specific blockers WS12 can reduce tumor growth in colorectal cancer xenografted mice by reducing transcription and activation of Wnt signaling regulators and β-catenin and its target oncogenes, such as C-Myc and Cyclin D1 [732]. TRPML (mucolipin) familyThe TRPML family [782, 1132, 775, 1084, 190] consists of three mammalian members (TRPML1-3). TRPML channels are probably restricted to intracellular vesicles and mutations in the gene (MCOLN1) encoding TRPML1 (mucolipin-1) cause the neurodegenerative disorder mucolipidosis type IV (MLIV) in man. TRPML1 is a cation selective ion channel that is important for sorting/transport of endosomes in the late endocytotic pathway and specifically, fission from late endosome-lysosome hybrid vesicles and lysosomal exocytosis [822]. TRPML2 and TRPML3 show increased channel activity in low luminal sodium and/or increased luminal pH, and are activated by similar small molecules [319, 147, 877]. A naturally occurring gain of function mutation in TRPML3 (i.e. A419P) results in the varitint waddler (Va) mouse phenotype (reviewed by [782, 690]). TRPP (polycystin) familyThe TRPP family (reviewed by [216, 214, 300, 1061, 374]) or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [1072]. It should also be noted that the nomenclature of PC2 was TRPP2 in old literature. However, PC2 has been uniformed to be called TRPP2 [345]. PKD2 family channels are clearly distinct from the PKD1 family, whose function is unknown. PKD1 and PKD2 form a hetero-oligomeric complex with a 1:3 ratio. [905]. Although still being sorted out, TRPP family members appear to be 6TM spanning nonselective cation channels. TRPV (vanilloid) familyMembers of the TRPV family (reviewed by [995]) can broadly be divided into the non-selective cation channels, TRPV1-4 and the more calcium selective channels TRPV5 and TRPV6. TRPV1-V4 subfamilyTRPV1 is involved in the development of thermal hyperalgesia following inflammation and may contribute to the detection of noxius heat (reviewed by [762, 882, 922]). Numerous splice variants of TRPV1 have been described, some of which modulate the activity of TRPV1, or act in a dominant negative manner when co-expressed with TRPV1 [844]. The pharmacology of TRPV1 channels is discussed in detail in [329] and [1015]. TRPV2 is probably not a thermosensor in man [736], but has recently been implicated in innate immunity [547]. Functional TRPV2 expression is described in placental trophoblast cells of mouse [204]. TRPV3 and TRPV4 are both thermosensitive. There are claims that TRPV4 is also mechanosensitive, but this has not been established to be within a physiological range in a native environment [127, 530]. TRPV5/V6 subfamily TRPV5 and TRPV6 are highly expressed in placenta, bone, and kidney. Under physiological conditions, TRPV5 and TRPV6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and kidney tubule epithelia (reviewed by [1057, 205, 651, 270]).TRPV6 is reported to play a key role in calcium transport in the mouse placenta [1056].

The TRP superfamily of channels (nomenclature as agreed by NC-IUPHAR [176, 1072]), whose founder member is the Drosophila Trp channel, exists in mammals as six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. TRP subunits contain six putative TM domains and assemble as homo- or hetero-tetramers to form cation selective channels with diverse modes of activation and varied permeation properties (reviewed by [730]). Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and in a number of books [401, 686, 1155, 256]. The established, or potential, involvement of TRP channels in disease [1126] is reviewed in [448, 685], [688] and [464], together with a special edition of Biochemica et Biophysica Acta on the subject [685]. Additional disease related reviews, for pain [633], stroke [1135], sensation and inflammation [988], itch [130], and airway disease [310, 1051], are available. The pharmacology of most TRP channels has been advanced in recent years. Broad spectrum agents are listed in the tables along with more selective, or recently recognised, ligands that are flagged by the inclusion of a primary reference. See Rubaiy (2019) for a review of pharmacological tools for TRPC1/C4/C5 channels [805]. Most TRP channels are regulated by phosphoinostides such as PtIns(4,5)P2 although the effects reported are often complex, occasionally contradictory, and likely to be dependent upon experimental conditions, such as intracellular ATP levels (reviewed by [1009, 689, 801]). Such regulation is generally not included in the tables.When thermosensitivity is mentioned, it refers specifically to a high Q10 of gating, often in the range of 10-30, but does not necessarily imply that the channel's function is to act as a 'hot' or 'cold' sensor. In general, the search for TRP activators has led to many claims for temperature sensing, mechanosensation, and lipid sensing. All proteins are of course sensitive to energies of binding, mechanical force, and temperature, but the issue is whether the proposed input is within a physiologically relevant range resulting in a response. TRPA (ankyrin) familyTRPA1 is the sole mammalian member of this group (reviewed by [293]). TRPA1 activation of sensory neurons contribute to nociception [414, 890, 602]. Pungent chemicals such as mustard oil (AITC), allicin, and cinnamaldehyde activate TRPA1 by modification of free thiol groups of cysteine side chains, especially those located in its amino terminus [575, 60, 365, 577]. Alkenals with α, β-unsaturated bonds, such as propenal (acrolein), butenal (crotylaldehyde), and 2-pentenal can react with free thiols via Michael addition and can activate TRPA1. However, potency appears to weaken as carbon chain length increases [26, 60]. Covalent modification leads to sustained activation of TRPA1. Chemicals including carvacrol, menthol, and local anesthetics reversibly activate TRPA1 by non-covalent binding [424, 511, 1081, 1080]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [425, 212]. The electron cryo-EM structure of TRPA1 [740] indicates that it is a 6-TM homotetramer. Each subunit of the channel contains two short ‘pore helices’ pointing into the ion selectivity filter, which is big enough to allow permeation of partially hydrated Ca2+ ions. TRPC (canonical) familyMembers of the TRPC subfamily (reviewed by [284, 778, 18, 4, 94, 446, 739, 70]) fall into the subgroups outlined below. TRPC2 is a pseudogene in humans. It is generally accepted that all TRPC channels are activated downstream of Gq/11-coupled receptors, or receptor tyrosine kinases (reviewed by [765, 953, 1072]). A comprehensive listing of G-protein coupled receptors that activate TRPC channels is given in [4]. Hetero-oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [18] and [447]. TRPC channels have frequently been proposed to act as store-operated channels (SOCs) (or compenents of mulimeric complexes that form SOCs), activated by depletion of intracellular calcium stores (reviewed by [741, 18, 770, 820, 1121, 157, 726, 64, 158]). However, the weight of the evidence is that they are not directly gated by conventional store-operated mechanisms, as established for Stim-gated Orai channels. TRPC channels are not mechanically gated in physiologically relevant ranges of force. All members of the TRPC family are blocked by 2-APB and SKF96365 [347, 346]. Activation of TRPC channels by lipids is discussed by [70]. Important progress has been recently made in TRPC pharmacology [805, 619, 436, 102, 851, 191, 291]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [295, 71, 885, 1031, 1025, 154, 103, 561, 913, 409]. TRPC1/C4/C5 subgroup TRPC1 alone may not form a functional ion channel [229]. TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La3+. TRPC2 is a pseudogene in humans, but in other mammals appears to be an ion channel localized to microvilli of the vomeronasal organ. It is required for normal sexual behavior in response to pheromones in mice. It may also function in the main olfactory epithelia in mice [1114, 723, 724, 1115, 539, 1168, 1109].TRPC3/C6/C7 subgroup All members are activated by diacylglycerol independent of protein kinase C stimulation [347].TRPM (melastatin) familyMembers of the TRPM subfamily (reviewed by [275, 346, 741, 1151]) fall into the five subgroups outlined below. TRPM1/M3 subgroupIn darkness, glutamate released by the photoreceptors and ON-bipolar cells binds to the metabotropic glutamate receptor 6 , leading to activation of Go . This results in the closure of TRPM1. When the photoreceptors are stimulated by light, glutamate release is reduced, and TRPM1 channels are more active, resulting in cell membrane depolarization. Human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function. TRPM1 is also found melanocytes. Isoforms of TRPM1 may present in melanocytes, melanoma, brain, and retina. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures [398, 708]. TRPM3 (reviewed by [714]) exists as multiple splice variants which differ significantly in their biophysical properties. TRPM3 is expressed in somatosensory neurons and may be important in development of heat hyperalgesia during inflammation (see review [941]). TRPM3 is frequently coexpressed with TRPA1 and TRPV1 in these neurons. TRPM3 is expressed in pancreatic beta cells as well as brain, pituitary gland, eye, kidney, and adipose tissue [713, 940]. TRPM3 may contribute to the detection of noxious heat [1017]. TRPM2TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells). The direct activators are calcium, adenosine diphosphate ribose (ADPR) [970] and cyclic ADPR (cADPR) [1118]. As for many ion channels, PI(4,5)P2 must also be present [1109]. Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [239]. Recent studies have reported structures of human (hs) TRPM2, which demonstrate two ADPR binding sites in hsTRPM2, one in the N-terminal MHR1/2 domain and the other in the C-terminal NUDT9-H domain. In addition, one Ca2+ binding site in the intracellular S2-S3 loop is revealed and proposed to mediate Ca2+ binding that induces conformational changes leading the ADPR-bound closed channel to open [387, 1027]. Meanwhile, a quadruple-residue motif (979FGQI982) was identified as the ion selectivity filter and a gate to control ion permeation in hsTRPM2 [1120]. TRPM2 is involved in warmth sensation [848], and contributes to several diseases [76]. TRPM2 interacts with extra synaptic NMDA receptors (NMDAR) and enhances NMDAR activity in ischemic stroke [1164]. Activation of TRPM2 in macrophages promotes atherosclerosis [1165, 1147]. Moreover, silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction [1028]. Recent studies have designed various compounds for their potential to selectively inhibit the TRPM2 channel, including ACA derivatives A23, and 2,3-dihydroquinazolin-4(1H)-one derivatives [1137, 1139]. TRPM4/5 subgroupTRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca2+ [1072]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium-activated cation (CAN) channels [327]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic-mediated inotropy [593]. Mutations are associated with conduction defects [404, 593, 879]. TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [993] and dendritic cell migration [52]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [537] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [513]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [246]. TRPM6/7 subgroupTRPM6 and 7 combine channel and enzymatic activities (‘chanzymes’) [172]. These channels have the unusual property of permeation by divalent (Ca2+, Mg2+, Zn2+) and monovalent cations, high single channel conductances, but overall extremely small inward conductance when expressed to the plasma membrane. They are inhibited by internal Mg2+ at ~0.6 mM, around the free level of Mg2+ in cells. Whether they contribute to Mg2+ homeostasis is a contentious issue. PIP2 is required for TRPM6 and TRPM7 activation [810, 1077]. When either gene is deleted in mice, the result is embryonic lethality [413, 1065]. The C-terminal kinase region of TRPM6 and TRPM7 is cleaved under unknown stimuli, and the kinase phosphorylates nuclear histones [479, 480]. TRPM7 is responsible for oxidant- induced Zn2+ release from intracellular vesicles [3] and contributes to intestinal mineral absorption essential for postnatal survival [622]. The putative metal transporter proteins CNNM1-4 interact with TRPM7 and regulate TRPM7 channel activity [40, 467]. TRPM8Is a channel activated by cooling and pharmacological agents evoking a ‘cool’ sensation and participates in the thermosensation of cold temperatures [63, 178, 224] reviewed by [1011, 562, 457, 649]. Direct chemical agonists include menthol and icilin[1086]. Besides, linalool can promote ERK phosphorylation in human dermal microvascular endothelial cells, down-regulate intracellular ATP levels, and activate TRPM8 [68]. Recent studies have found that TRPM8 has typical S4-S5 connectomes with clear selective filters and exowell rings [512], and have identified cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP2-dependent gated pathways [1111]. Moreover, the last 36 amino acids at the carboxyl terminal of TRPM8 are key protein sequences for TRPM8's temperature-sensitive function [194]. TRPM8 deficiency reduced the expression of S100A9 and increased the expression of HNF4α in the liver of mice, which reduced inflammation and fibrosis progression in mice with liver fibrosis, and helped to alleviate the symptoms of bile duct disease [556]. Channel deficiency also shortens the time of hypersensitivity reactions in migraine mouse models by promoting the recovery of normal sensitivity [12]. A cyclic peptide DeC‐1.2 was designed to inhibit ligand activation of TRPM8 but not cold activation, which can eliminate the side effects of cold dysalgesia in oxaliplatin-treated mice without changing body temperature [9]. Analysis of clinical data shows that TRPM8-specific blockers WS12 can reduce tumor growth in colorectal cancer xenografted mice by reducing transcription and activation of Wnt signaling regulators and β-catenin and its target oncogenes, such as C-Myc and Cyclin D1 [732]. TRPML (mucolipin) familyThe TRPML family [782, 1132, 775, 1084, 190] consists of three mammalian members (TRPML1-3). TRPML channels are probably restricted to intracellular vesicles and mutations in the gene (MCOLN1) encoding TRPML1 (mucolipin-1) cause the neurodegenerative disorder mucolipidosis type IV (MLIV) in man. TRPML1 is a cation selective ion channel that is important for sorting/transport of endosomes in the late endocytotic pathway and specifically, fission from late endosome-lysosome hybrid vesicles and lysosomal exocytosis [822]. TRPML2 and TRPML3 show increased channel activity in low luminal sodium and/or increased luminal pH, and are activated by similar small molecules [319, 147, 877]. A naturally occurring gain of function mutation in TRPML3 (i.e. A419P) results in the varitint waddler (Va) mouse phenotype (reviewed by [782, 690]). TRPP (polycystin) familyThe TRPP family (reviewed by [216, 214, 300, 1061, 374]) or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [1072]. It should also be noted that the nomenclature of PC2 was TRPP2 in old literature. However, PC2 has been uniformed to be called TRPP2 [345]. PKD2 family channels are clearly distinct from the PKD1 family, whose function is unknown. PKD1 and PKD2 form a hetero-oligomeric complex with a 1:3 ratio. [905]. Although still being sorted out, TRPP family members appear to be 6TM spanning nonselective cation channels. TRPV (vanilloid) familyMembers of the TRPV family (reviewed by [995]) can broadly be divided into the non-selective cation channels, TRPV1-4 and the more calcium selective channels TRPV5 and TRPV6. TRPV1-V4 subfamilyTRPV1 is involved in the development of thermal hyperalgesia following inflammation and may contribute to the detection of noxius heat (reviewed by [762, 882, 922]). Numerous splice variants of TRPV1 have been described, some of which modulate the activity of TRPV1, or act in a dominant negative manner when co-expressed with TRPV1 [844]. The pharmacology of TRPV1 channels is discussed in detail in [329] and [1015]. TRPV2 is probably not a thermosensor in man [736], but has recently been implicated in innate immunity [547]. Functional TRPV2 expression is described in placental trophoblast cells of mouse [204]. TRPV3 and TRPV4 are both thermosensitive. There are claims that TRPV4 is also mechanosensitive, but this has not been established to be within a physiological range in a native environment [127, 530]. TRPV5/V6 subfamily TRPV5 and TRPV6 are highly expressed in placenta, bone, and kidney. Under physiological conditions, TRPV5 and TRPV6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and kidney tubule epithelia (reviewed by [1057, 205, 651, 270]).TRPV6 is reported to play a key role in calcium transport in the mouse placenta [1056].