Approximately 10% of primary hyperparathyroidism cases are hereditary, due to germline mutations in certain genes. Although clinically relevant, a systematized genetic diagnosis is missing due to a lack of firm evidence regarding individuals to test and which genes to evaluate. Germline variants were observed in 9/40 patients (22.5%): 2 previously unknown pathogenic/likely pathogenic variants of CDKN1B (related to MEN4), 1 novel variant of uncertain significance of CDKN2C, 4 variants of CASR (3 pathogenic/likely pathogenic variants and 1 variant of uncertain significance), and 2 novel variants of uncertain significance of TRPV6. Familial segregation studies allowed diagnosis and early treatment of PHPT in first-degree relatives of probands. The observed prevalence of germline variants in the Mediterranean cohort under study was remarkable and slightly higher than that seen in other populations. Genetic screening for suspected familial hyperparathyroidism allows the early diagnosis and treatment of PHPT and other related comorbidities. We recommend genetic testing for patients with primary hyperparathyroidism who present with high-risk features. Volume 14 - 2023 | https://doi.org/10.3389/fendo.2023.1244361 Background: Approximately 10% of primary hyperparathyroidism cases are hereditary due to germline mutations in certain genes a systematized genetic diagnosis is missing due to a lack of firm evidence regarding individuals to test and which genes to evaluate and TRPV6) was performed in 40 patients from the Mediterranean area with suspected familial hyperparathyroidism (≤45 years of age We aimed to determine the prevalence of germline variants in these patients to clinically characterize the probands and their relatives and to compare disease severity in carriers versus those with a negative genetic test Results: Germline variants were observed in 9/40 patients (22.5%): 2 previously unknown pathogenic/likely pathogenic variants of CDKN1B (related to MEN4) 1 novel variant of uncertain significance of CDKN2C 4 variants of CASR (3 pathogenic/likely pathogenic variants and 1 variant of uncertain significance) and 2 novel variants of uncertain significance of TRPV6 Familial segregation studies allowed diagnosis and early treatment of PHPT in first-degree relatives of probands Conclusion: The observed prevalence of germline variants in the Mediterranean cohort under study was remarkable and slightly higher than that seen in other populations Genetic screening for suspected familial hyperparathyroidism allows the early diagnosis and treatment of PHPT and other related comorbidities We recommend genetic testing for patients with primary hyperparathyroidism who present with high-risk features it appears that FHPT is underdiagnosed and underreported in the literature likely due to the limited number of genetic studies performed in clinical practice and an insufficient understanding of these conditions none of these were carried out among the Spanish population and only a few involved people living in the Mediterranean area The aim of this study was to perform genetic screening of patients with PHPT who presented some risk features in order to: 1) Determine the prevalence of germline mutations in the analysed genes in our cohort 2) Clinically characterize carriers of variants and their first-degree relatives 3) Compare disease severity in carriers of variants with respect to those without a genetic alteration found and compare the prevalence of germline variants in our population with those in other cohorts An ambispective observational study was conducted We collected data from patients diagnosed with PHPT who also exhibited some risk factors for FHPT The diagnosis of PHPT was established by inappropriately non-suppressed or high parathyroid hormone levels (PTH) (reference value [RV] 12.32-41.99 pmol/L) with normal or elevated albumin-corrected serum calcium levels (RV 2.1-2.55 mmol/L) Patients were included in the study when at least one inclusion criterion was met: 1) Age at onset of PHPT ≤ 45 years 2) High-risk parathyroid histology (parathyroid carcinoma or biopsy-documented MGD defined as having two or more glands affected by either adenomas or hyperplasia) 3) Recurrent or persistent PHPT (established by presenting corrected serum calcium levels ≥ 2.62 mmol/L three months after parathyroid surgery) 4) Family history of PHPT in at least one first-degree relative 5) Other tumour/s related to syndromic FHPT (gastro-entero-pancreatic neuroendocrine tumours Having a known mutation in any of the genes under study as well as having a first-degree relative with a known mutation in any of them Patients who met the inclusion criteria and agreed to participate were interviewed to obtain detailed medical and family histories between February and July 2020 Baseline data were recorded for each patient preoperative and postoperative biochemical and hormonal findings (PTH and calcium creatinine clearance ratio (CCCR calculated using a 24-hour urinary calcium collection and one blood sample) at diagnosis when available We reviewed the preoperative imaging results of the parathyroid glands Written informed consent was obtained from all patients and the study was approved by the institutional Ethics Committee of Institut d’Investigació i Innovació Parc Taulí I3PT The sequence variant analysis pipeline was validated in the Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathologists (CAP)-accredited Blueprint Genetics diagnostic laboratory The series of selected quality criteria included the variant call quality score and integrative genomics viewer visual analysis This algorithm was established based on the outcome of internal validation performed in the CLIA and CAP-accredited Blueprint Genetics diagnostic laboratory CNV analysis was performed bioinformatically from next-generation sequencing data using a bioinformatics pipeline; one component was a CNV kit and the other involved in-house developed proprietary technology CNVs were confirmed by digital polymerase chain reaction The CNV analysis pipeline was validated in the CLIA and CAP-accredited Blueprint Genetics diagnostic laboratories Sanger sequencing of the candidate variants was performed on the patient and family member samples to confirm the presence of the variant and the pattern of inheritance Variants were classified into five categories according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines (31): benign We reported all the variants classified as P genetic counselling of the proband and cascade genetic testing were offered to all at-risk family members loss of heterozygosity and CNV in tumours and immunohistochemistry studies were performed Results corresponding to quantitative variables were presented as the mean ± standard deviation Data associated with qualitative characteristics were reported as percentages The normality of quantitative variables was assessed using the Shapiro-Wilk normality test The significance of the difference between two means was assessed using Student’s T-test for normal variables and the Wilcoxon rank sum test for non-normal variables The significance of the difference between more than two means was assessed using the Kruskal-Wallis test for non-normal variables The significance of the difference between percentages was assessed using Pearson’s chi-square test Differences were considered statistically significant at P < 0.05 Calculations were performed using R Commander version 4.0.5 The clinical characteristics of the 40 participants (27 females and 13 males) are displayed in Table 1 The mean age at diagnosis of primary hyperparathyroidism was 51 ± 15.8 years The circumstances leading to diagnosis of PHPT were diverse: 30% incidental findings of hypercalcemia and other clinical features in the remaining patients Thirty-two patients (80%) underwent surgery with mean highest PTH levels of 50.28 (12.32-41.99) pmol/L (RV 1.06-6.89) mean albumin adjusted serum calcium of 3.03 ± 0.5 mmol/L and mean nadir phosphate levels of 0.84 ± 0.39 mmol/L The inclusion criteria were as follows: 15 subjects were under 45 years of age at diagnosis of PHPT; 28 cases met the histology criteria (one parathyroid carcinoma and five MGD); four patients presented with recurrence of PHPT after surgery; two cases were included because of family history of PHPT; and seven patients presented tumours that could be related to familial syndrome 32% of the patients met two or more inclusion criteria Table 1 Clinical variables of the 40 participants Genetic sequencing of the targeted panel identified five pathogenic/likely pathogenic germline variants in five of the 40 participants (three in CASR and two in CDKN1B) (12.5%) and four variants of uncertain significance (one in CDKN2C, one in CASR, and two in TRPV6) (10%). There was one frameshift variant, one nonsense variant, and seven missense variants. Table 2 summarizes the genetic and clinical characteristics of patients with germline variants Table 2 Genetic and clinical characteristics of patients displaying germline variants in any of the genes included in the panel Four patients carried heterozygous missense variants of the CASR gene (ID15 Two of the CASR variant carriers had CCCR < 0.01 Figure 2 Pedigree of probands with detection of germline variant of CASR or TRPV6 genes and their relatives Family members are indicated by generation (Roman numerals) and individuals (Arabic numerals) affected family member (inappropriately non-suppressed or high parathyroid hormone levels with normal or elevated serum calcium levels); Filled spot history of nephrolithiasis or severe vitamin D deficiency; Slashed symbol They were offered clinical and analytical follow-up although to date none of them required parathyroid surgery segregation was observed in all but one sibling p.(Glu59Lys) was classified as VUS for the time being according to the ACMG criteria (PM1 (supporting) Case ID21 was included in the study because he had one daughter with PHPT His imaging localization studies were negative but treatment with cinacalcet was initiated (30 mg once daily) and calcium plasma levels decreased from 3.12 to 2.74 mmol/L (RV 2.1-2.55) The proband’s daughter declined to undergo a genetic test We analysed the clinical and biochemical features of the study participants according to their genetic test results (see Table 3) The median age at PHPT diagnosis of subjects with a positive genetic test result was not significantly different from that of patients with negative genetic results Mean PTH and calcium serum levels pre-surgery of patients carrying genetic variants were higher than those with a negative genetic study but the difference was not statistically significant Serum phosphate levels were statistically similar between both groups The only statistically significant difference found between the two groups was the CCCR which was lower in the group of patients with a positive genetic test (0.01 vs 0.02 Table 3 Characteristics of patients based on genetic test outcomes in a comparison of different characteristics of the participants according to the genetic results the only statistically significant difference was in CCCR There were no statistically significant differences in the mean age of the group carrying LP or P variants compared to that of subjects with a negative genetic study (54.2 vs Calcium and PTH concentrations were somewhat higher in the group of patients with a positive genetic test but without statistically significant differences from the group with a negative test we did not find a trait that was clearly more frequent in patients in whom we found germline variants Although the differences were not statistically significant the group of patients carrying a genetic variant had a greater tendency to present more than one inclusion criterion 28.6% in patients with a negative genetic study) This suggests that having more than one risk characteristic may increase the possibility of positive genetic screening it should be noted that our sample was small and that this is a descriptive study so it is difficult to draw firm conclusions Studies with a larger number of patients would be necessary to corroborate this hypothesis of the four CASR variant carriers we reported one had severe hypercalcemia requiring hospitalization (ID15) and three had bone damage (osteoporosis) The presence of osteoporosis more strongly suggests the acquisition of autonomy of one or more parathyroid glands Further research is required to determine the actual prevalence of these mutations and the extent of their phenotypic impact Variants in the TRPV6 gene have also been associated with nephrolithiasis and chronic pancreatitis when inherited in an autosomal recessive manner. However, most studies investigating the genotypic and phenotypic effects of TRPV6 were conducted in mice (45, 46) two cases (ID4 and ID30) were diagnosed with primary hyperparathyroidism in young adulthood and carried a single TRPV6 variant there have been no reports of adults with dominant inheritance of TRPV6 involvement that presented with PHPT we report these variants to expand the understanding of this gene their clinical significance remains unclear and should be interpreted with caution Further research is necessary to determine the clinical implications of TRPV6 variants inherited in a dominant manner A potential strategy could be to perform whole exome sequencing (WES) or whole genome sequencing (WGS) to study patients with inconclusive genetic test results This approach may help to uncover a second variant that was not detected by a gene panel and may reveal novel genes associated with FHPT variants in CDC73 were not found in 11 patients with these tumours included in our cohort we did not conduct functional analysis; therefore we could not confirm whether the variants caused the characteristics observed in the patients particularly in the case of those classified as VUS the genetic testing we conducted was limited to gene panel sequencing we found a remarkable prevalence of genetic variants among the genes studied in the at-risk population This is consistent with the hypothesis that FPHP is probably an underdiagnosed entity owing to non-standardized genetic screening genetic testing allowed the early diagnosis and treatment of PHPT and other related comorbidities of probands and their first-degree relatives We suggest genetic testing in patients with PHPT who present any of the risk characteristics considered in the inclusion criteria of our study WES strategy is replacing gene panel studies in clinical laboratories we propose a filtering procedure using the aforementioned customized gene panel updated as a first-tier virtual panel for patients with suspected FHPT The datasets presented in this study can be found in online repositories The names of the repository/repositories and accession number(s) can be found in the article/supplementary material The studies were conducted in accordance with the local legislation and institutional requirements The participants provided their written informed consent to participate in this study Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article NB performed and interpreted genetic data and wrote and edited the manuscript and RP participated in editing the manuscript All authors approved the final version of the manuscript to be published The study was financed with research funds from the Endocrinology and Nutrition Department Institut d’Investigació i Innovació Parc Taulí (I3PT) The authors thank the staff of our hospital for suggestions and guidance and the Blueprint Genetic laboratory for 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of each article we publish Metrics details The NASA MESSENGER mission explored the innermost planet of the solar system and obtained a rich data set of range measurements for the determination of Mercury’s ephemeris Here we use these precise data collected over 7 years to estimate parameters related to general relativity and the evolution of the Sun These results confirm the validity of the strong equivalence principle with a significantly refined uncertainty of the Nordtvedt parameter η = (−6.6 ± 7.2) × 10−5 By assuming a metric theory of gravitation we retrieved the post-Newtonian parameter β = 1 + (−1.6 ± 1.8) × 10−5 and the Sun’s gravitational oblateness \({{J}}_{2 \odot }\) = (2.246 ± 0.022) × 10−7 we obtain an estimate of the time variation of the Sun gravitational parameter \(\dot{{G} {{M}}_ \odot} {\mathrm{/}}{{G}}{{M}}_ \odot\) = (−6.13 ± 1.47) × 10−14 which is consistent with the expected solar mass loss due to the solar wind and interior processes This measurement allows us to constrain \(\left| {{\dot{ G}}} \right|{\mathrm{/}}{{G}}\) to be <4 × 10−14 per year The relativistic corrections to Mercury’s heliocentric acceleration can be formulated based on the parameterized post-Newtonian (PPN) parameters β and γ which respectively measure the nonlinearity in superposition of gravity and space-time curvature produced by a unit rest mass Both parameters are zero in the Newtonian formulation and equal to 1 in GR (Methods) which is known as the gravitomagnetic Einstein–Lense–Thirring (ELT) effect is related to the distortion of space-time induced by the rotation of the Sun The relationship between these coefficients is: which implies that the PPN parameters α1 and α2 are equal to 0 The contribution of the SEP to the gravitational-to-inertial mass ratio depends on the self-gravitational energy (ΩB) and the rest energy of the body (mIc2) where mG and mI are the gravitational and inertial masses The Nordtvedt parameter η must be zero to validate the SEP the test mass used in the experiment needs to be sufficiently large so that the self-gravitational force is not negligible tests at the scale of the solar or planetary system are suitable to prove the SEP The study of Mercury’s orbit with a long-duration data set also gives a unique opportunity to detect the time variation of the gravitational constant G The estimation of \(\dot{{G}}/{{G}}\) is not strongly correlated with other relativistic and solar parameters because its effect is quadratic in time Mercury’s orbit is perturbed by the combined effect of secular changes in G and M⊙ as follows: we focused on the radio science data of the NASA Mercury Surface and Ranging (MESSENGER) mission to investigate the interior structure and evolution of the Sun (GM⊙ and \(\dot { {M}}_ \odot {\mathrm{/}}{ {M}}_ \odot\)) and theory of gravitation (β Our results show improved estimates of the solar gravitational oblateness and the mass loss rate that are consistent with helioseismology and heliophysics theoretical studies The accurate measurement of the time variation of the solar gravitational parameter enabled us to constrain \(\left| \dot { {G}} \right|/{ {G}}\) to be lower than 4.0 × 10−14 per year we determined the Nordtvedt parameter η with a refined uncertainty that demonstrates that there are no violations of the SEP at the level of ~6–7 × 10−5 These data are range-rate (or Doppler) observables that measure the relative velocity in the line-of-sight between the spacecraft and a Deep Space Network (DSN) Earth station and range observables of the relative distance between the spacecraft and the DSN station Parallel and independent investigations so far have been conducted to exclusively determine either Mercury’s geophysics or its ephemeris The estimation of Mercury’s gravity field relied on the assumption of planet’s orbits and GMs the ephemeris work processed spacecraft range measurements only by using a pre-converged MESSENGER trajectory Although both methods have successfully been used for interplanetary orbit determination their piecemeal combination is not the best approach in the case of Mercury Systematic errors in the MESSENGER orbits directly enter the range data and are then absorbed into Mercury’s estimated position since the spacecraft trajectory is not adjusted in the ephemeris solution a mismodeling of Mercury’s ephemeris leads to imperfect geophysical solutions We numerically integrate the spacecraft and planet orbits simultaneously in order to provide a comprehensive solution that includes geophysical and relativity results together with their associated covariances Here we focus on the results that provide new information on the interior of the Sun and on gravitational theories The MESSENGER RF subsystem operated at X-band frequencies (7.2 GHz uplink 8.4 GHz downlink) and its two opposite-viewing phased-array antennas (PAAs) were used to conduct the range data campaigns (Methods) Data distribution throughout Mercury’s orbit Number of the analyzed measurements as function of the Mercury distance from the Sun in AU Colors indicate the noise level distribution during each phase bin of Mercury’s orbit The greater part of the data was collected close to Mercury’s perihelion and aphelion Both constrained and unconstrained solutions are consistent with Einstein’s theory of GR. GR predictions of β and η values are within 1-σ, as reported in Table 2 These results enable substantial enhancement of both β−1 and η estimates which are ~7 and ~5 times closer to 0 than LLR solutions The knowledge of the PPN parameter β in this study is now comparable to the Cassini solution of the PPN parameter a mean value of the total solar mass loss of −(0.9–1.1) × 10−13\({ {M}}_ \odot\) per year would be expected since the MESSENGER mission operated during ~2/3 of an entire solar cycle whose maximum occurred in proximity of the end of the mission Temporal distribution of the range biases with three Mercury’s ephemeris The measurement biases are required to fit the MESSENGER range data at the noise level with the JPL DE430 (purple) and D432 (blue) ephemerides and our integrated trajectory for Mercury (black) These biases were used to determine the quality of the ephemeris results all the adjusted parameters (Methods) are applied in a final iteration in which the range biases are adjusted instead of the Mercury’s initial state and \(\dot{{{ {G} { {M}}}}_ \odot} /{{G}}{{M}}_ \odot\) Large range biases suggest significant errors in the planet’s ephemeris The dynamical orbital equations of both Mercury and MESSENGER account for the Lense–Thirring effect due to the Sun’s gravitomagnetic field that leads to a secular precession of the heliocentric longitude of the ascending node and argument of pericenter The ELT effect on Mercury due to the solar gravitomagnetic field is not negligible and it may theoretically be used to measure the angular momentum of the Sun Mercury’s acceleration due to the ELT effect is: The ELT effect on Mercury’s orbit is mainly in the radial direction with a maximum acceleration of ~2 × 10−7 m s−2 assuming \({ {S}}_ \odot\) = 190 × 10−39 kg m2 s−1 the perturbation induced by the ELT precession is strongly anti-correlated with the effect due to \({ {J}}_{2 \odot }\) and the recovery of \({ {S}}_ \odot\) is unachievable with the estimation of Mercury’s ephemeris The Sun’s position correction (Eq. 9) entails an indirect term in the heliocentric acceleration of Mercury The partial derivative of Mercury’s heliocentric acceleration (aM) with respect to η which enables the estimation of this parameter by adjusting the planet ephemeris The time-varying gravitational parameter \(\dot{ {G} { {M}}_ \odot} /{ {G}}{ {M}}_ \odot\) is defined by the sum of the time-variations of the gravitational universal constant \(\dot G/G\) and the mass of the Sun \(\dot { {M}}_ \odot /{ {M}}_ \odot\) The additional term of Mercury’s heliocentric acceleration due to \(\dot{ {G} { {M}}_ \odot} /{ {G}}{ {M}}_ \odot\) is: where Δt is the difference between the current epoch and the reference epoch J2000 (1 January 2000 at 1200 UTC) and \({\mathbf{r}}_{{{M}} \odot }\) is the relative position vector between Mercury and the Sun This software is based on a batch least-squares scheme that allows the combination of all observations within one batch (arc) for the estimation of the parameters of interest The least-squares technique relies on an adjustment of model parameters to minimize the discrepancies between the computed observables and actual measurements (residuals) If the trajectory of the spacecraft alone is integrated the only parameters that can be estimated are related to MESSENGER’s dynamics around Mercury (e.g. The simultaneous numerical integration of the planet ephemeris allows the adjustment of other model parameters such as those from heliophysics and relativity that perturb the orbit of Mercury The MESSENGER orbital mission (2011–2015) was partitioned in 1499 1-day arcs Three additional ~10-day arcs cover the three Mercury flybys in 2008–2009 The range data were weighted according to the contribution of the solar plasma that varied through the mission as expressed by the Sun–Earth–Probe angle the Mercury’s ephemeris is continuously integrated from the Flyby 1 initial epoch (7 January 2008 at 0000 UTC) We generated partial derivatives of the following MESSENGER-related parameters: spacecraft initial states Mercury’s gravity field up to degree and order 100 in spherical harmonics and Mercury’s Love number k2 and orientation (pole’s right ascension and declination) We also computed partial derivatives of the following Mercury-related parameters: planet’s initial state \(\dot{ {G} { {M}}}_ \odot /{ {G}}{ {M}}_ \odot\) \({ {J}}_{{\it{2}}{\it{ \odot }}}\) and \({ {S}}_{\it{ \odot }}\) The individual normal equations of all these arcs were combined and inverted to yield the final estimates of the geophysical The orbit of the Earth is not integrated and adjusted in this study since the orbital accuracy of the Earth from the JPL DE432 ephemerides is comparable to the precision of the MESSENGER data The data processed in this paper include the three MESSENGER flybys around Mercury The three flybys occurred on 14 January 2008 MESSENGER was inserted in a highly eccentric and near-polar orbit about Mercury on 18 March 2011 The initial period was ~12 h and the orbital periapsis was at ~200-km altitude and ~60°N latitude Orbit-correction maneuvers (OCMs) were required to maintain the periapsis between 200 and 500 km for the first year of operations The third-body perturbation of the Sun combined with the high eccentricity of the orbit led to a significant drift of the periapsis altitude and latitude The mission was extended for a second year in March 2012 and one of them was used to reduce the orbital period to ~8 h A second extended mission (XM2) started in March 2013 and included a low-altitude campaign until Mercury impact on 28 April 2015 The fuel reserves enabled the spacecraft to maintain periapsis altitudes as low as 15–25 km for several weeks NASA’s DSN stations tracked the spacecraft during part of these passages from April to October 2014 leading to accurate measurements of Mercury’s gravity at altitudes between 25 and 100 km the closest approaches of MESSENGER were occulted by Mercury and were thus not visible from the Earth additional range-rate and range measurements were collected at low altitudes between 75 and 100 km The data included in this study were collected over ~900 days The greater part of the excluded data is because of high levels of plasma noise in proximity of superior solar conjunctions (SPE < 35°) Other arcs were also omitted because of the presence of OCMs or reaction wheel momentum desaturation maneuvers that imparted significant ΔVs leading to significant orbital errors The analysis of the range data to estimate Mercury’s ephemeris relies strongly on the accuracy of MESSENGER orbital reconstruction are very sensitive to the quality of the spacecraft orbits Uncompensated gravity anomalies of Mercury’s gravity field may affect significantly the range residuals leading to inaccurate ephemeris solutions To mitigate the effects of MESSENGER orbital errors in the determination of Mercury’s ephemeris both range-rate and range data have been analyzed in this study This data set includes two-way and three-way coherent range-rate and two-way coherent range measurements The difference between two- and three-way data is only related to the receiving station The signal is transmitted by the DSN station and sent coherently back to the same (two-way) or a different (three-way) station by the spacecraft deep space transponder (DST) The two-way configuration guarantees highly accurate data thanks to the H-masers at the DSN ground stations The three-way data require additional bias corrections due to the time delay between the oscillators at the transmitting and receiving stations The biases of the three-way range-rate data are adjusted in the solution to mitigate this error source Another source of range data error is given by station biases due to imperfect calibration The accurate measurement of the ranging signal round-trip delay is made through digital signal processors at the DSN stations by correlating the uplink and downlink carriers that are coherently related This calibration may lead to biases on the measured delay with a standard deviation of 1–3 m range station biases for each tracking pass may be estimated in orbit determination the estimation of the range station biases tends to absorb the uncompensated ephemeris mismodeling the range station biases are not estimated in this study of Mercury’s ephemeris Relativity: The Special and General Theory (Princeton University Press The relativity effect in planetary motions Erklarung der Perihelionbewegung der Merkur aus der allgemeinen Relativitatstheorie Solar quadrupole moment and purely relativistic gravitation contributions to Mercury’s perihelion advance Constraining the angular momentum of the Sun with planetary orbital motions and general relativity Post-Newtonian metric for a general class of scalar-tensor gravitational theories and observational consequences Torsion-balance tests of the weak equivalence principle New test of the equivalence principle from lunar laser ranging Progress in lunar laser ranging tests of relativistic gravity Lunar laser ranging tests of the equivalence principle Lunar laser ranging: recent results based on refined modelling Relativistic models for the BepiColombo radioscience experiment Noerdlinger, P. D. Solar mass loss, the astronomical unit, and the scale of the solar system. Preprint at https://arxiv.org/pdf/0801.3807.pdf (2008) The MESSENGER mission to Mercury: scientific objectives and implementation and ephemeris of Mercury from MESSENGER observations after three years in orbit Folkner, W. M. Planetary ephemeris DE432. Technical Report. Jet Propulsion Laboratory, Pasadena, CA, USA. https://naif.jpl.nasa.gov/pub/naif/generic_kernels/spk/planets/de432.pdf (2014) Development of planetary ephemerides EPM and their applications Numerical estimation of the sensitivity of INPOP planetary ephemerides to general relativity parameters The radio frequency subsystem and radio science on the MESSENGER mission Helioseismic determination of the solar gravitational quadrupole moment Precession of Mercury’s Perihelion from Ranging to the MESSENGER Spacecraft Relativistic effects and dark matter in the Solar system from observations of planets and spacecraft Testing theories of gravitation using 21-year timing of pulsar binary J1713+ 0747 A test of general relativity using radio links with the Cassini spacecraft Changes in the Sun’s mass and gravitational constant estimated using modern observations of planets and spacecraft Coupling the solar dynamo and the corona: wind properties and momentum losses during an activity cycle NASA’s Planetary Geodynamics Laboratory, Goddard Space Flight Center, Greenbelt, MD, USA. https://pgda.gsfc.nasa.gov (2017) Zuber, M.T. et al. From Copernicus to Newton to Einstein: toward a dynamical understanding of the Solar System. Planetary Science Vision 2050 Workshop. Preprint at https://www.hou.usra.edu/meetings/V2050/pdf/8074.pdf (2017) A confirmation of the general relativistic prediction of the Lense-Thirring effect Gravity probe B: final results of a space experiment to test general relativity A possible new test of general relativity with Juno Jupiter spin-pole precession rate and moment of inertia from Juno radio-science observations Report of the IAU working group on cartographic coordinates and rotational elements: 2009 Testing general relativity with the BepiColombo radio science experiment Future gravitational physics tests from ranging to the BepiColombo Mercury planetary orbiter The solar test of the equivalence principle Testing the strong equivalence principle with spacecraft ranging towards the nearby Lagrangian points Constraining the Nordtvedt parameter with the BepiColombo Radioscience experiment Download references This work was conducted at the NASA Goddard Space Flight Center. We are grateful to J.B. Nicholas (EST, Inc.), D.E. Pavlis (SGT, Inc.), and D.D. Rowlands (NASA, GSFC) for their help with the GEODYN II software. A.G. thanks L. Iorio (MIUR), and A. Milani, (University of Pisa) for ideas and discussions. The data used in this paper are available at http://pds-geosciences.wustl.edu/missions/messenger/rs.htm Center for Research and Exploration in Space Science and Technology performed radio tracking data processing and preliminary analysis of the MESSENGER orbits developed updated relativistic and solar modeling in the NASA GSFC orbit determination software (GEODYN II) contributed to the interpretation of the results The authors declare no competing financial interests Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41467-017-02558-1 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing newsletter — what matters in science headed by Guillermo Avanzini Alcibar (Bilbao 1989) has refurbished an abandoned farming-equipment storehouse in Ojacastro and turned it into a dwelling With just 40 square meters of space within it and an execution budged of 83,000 euros the wooden cottage was thought of as a livable piece of furniture taking up the plot delimited by existing stone walls A single room incorporates foldable furnishing and a pull-down bed The cooker and other electrical appliances also disappear into thick walls so it was replaced with another fishbone structure of laminated timber beams The intervention involved consolidating the old stone walls and saving the original tiles of the tiny construction maintaining the local morphology instead of raising the three-floor building originally envisioned which did not respect the scale of the Riojan village The sensitivity of the owners and the municipal council’s readiness to approve the project have together halted the degradation and ultimate destruction of this corner of town Adrián Martínez MuñozColaboradores CollaboratesEnrique Uyarra (Constructor Constructor) Sánchez (Carpintería Carpenter)Fotografía PhotographsGuillermo Avanzini Alcibar there arent any match using your search terms but a significantly lower crust density on Mars transforms our understanding of (inter)planetary science we're coming to the conclusion that it's not enough just to know the composition of the rocks We also need to know how the rocks have been reworked over time." These findings will help researchers learn more about what is going on under the surface of the Red Planet Aside from the information about the planet's density the researchers were also able to learn more about the makeup of the planet Articles may contain affiliate links which enable us to share in the revenue of any purchases made Registration on or use of this site constitutes acceptance of our Terms of Service