Bright carbonate deposits as evidence of aqueous alteration on (1) Ceres.

The typically dark surface of the dwarf planet Ceres is punctuated by areas of much higher albedo, most prominently in the Occator crater. These small bright areas have been tentatively interpreted as containing a large amount of hydrated magnesium sulfate, in contrast to the average surface, which is a mixture of low-albedo materials and magnesium phyllosilicates, ammoniated phyllosilicates and carbonates. Here we report high spatial and spectral resolution near-infrared observations of the bright areas in the Occator crater on Ceres. Spectra of these bright areas are consistent with a large amount of sodium carbonate, constituting the most concentrated known extraterrestrial occurrence of carbonate on kilometre-wide scales in the Solar System. The carbonates are mixed with a dark component and small amounts of phyllosilicates, as well as ammonium carbonate or ammonium chloride. Some of these compounds have also been detected in the plume of Saturn's sixth-largest moon Enceladus. The compounds are endogenous and we propose that they are the solid residue of crystallization of brines and entrained altered solids that reached the surface from below. The heat source may have been transient (triggered by impact heating). Alternatively, internal temperatures may be above the eutectic temperature of subsurface brines, in which case fluids may exist at depth on Ceres today.

Exposed water ice on the nucleus of comet 67P/Churyumov-Gerasimenko.

Although water vapour is the main species observed in the coma of comet 67P/Churyumov-Gerasimenko and water is the major constituent of cometary nuclei, limited evidence for exposed water-ice regions on the surface of the nucleus has been found so far. The absence of large regions of exposed water ice seems a common finding on the surfaces of many of the comets observed so far. The nucleus of 67P/Churyumov-Gerasimenko appears to be fairly uniformly coated with dark, dehydrated, refractory and organic-rich material. Here we report the identification at infrared wavelengths of water ice on two debris falls in the Imhotep region of the nucleus. The ice has been exposed on the walls of elevated structures and at the base of the walls. A quantitative derivation of the abundance of ice in these regions indicates the presence of millimetre-sized pure water-ice grains, considerably larger than in all previous observations. Although micrometre-sized water-ice grains are the usual result of vapour recondensation in ice-free layers, the occurrence of millimetre-sized grains of pure ice as observed in the Imhotep debris falls is best explained by grain growth by vapour diffusion in ice-rich layers, or by sintering. As a consequence of these processes, the nucleus can develop an extended and complex coating in which the outer dehydrated crust is superimposed on layers enriched in water ice. The stratigraphy observed on 67P/Churyumov-Gerasimenko is therefore the result of evolutionary processes affecting the uppermost metres of the nucleus and does not necessarily require a global layering to have occurred at the time of the comet's formation.

Ammoniated phyllosilicates with a likely outer Solar System origin on (1) Ceres.

Studies of the dwarf planet (1) Ceres using ground-based and orbiting telescopes have concluded that its closest meteoritic analogues are the volatile-rich CI and CM carbonaceous chondrites. Water in clay minerals, ammoniated phyllosilicates, or a mixture of Mg(OH)2 (brucite), Mg2CO3 and iron-rich serpentine have all been proposed to exist on the surface. In particular, brucite has been suggested from analysis of the mid-infrared spectrum of Ceres. But the lack of spectral data across telluric absorption bands in the wavelength region 2.5 to 2.9 micrometres--where the OH stretching vibration and the H2O bending overtone are found--has precluded definitive identifications. In addition, water vapour around Ceres has recently been reported, possibly originating from localized sources. Here we report spectra of Ceres from 0.4 to 5 micrometres acquired at distances from ~82,000 to 4,300 kilometres from the surface. Our measurements indicate widespread ammoniated phyllosilicates across the surface, but no detectable water ice. Ammonia, accreted either as organic matter or as ice, may have reacted with phyllosilicates on Ceres during differentiation. This suggests that material from the outer Solar System was incorporated into Ceres, either during its formation at great heliocentric distance or by incorporation of material transported into the main asteroid belt.

Olivine in an unexpected location on Vesta's surface.

Olivine is a major component of the mantle of differentiated bodies, including Earth. Howardite, eucrite and diogenite (HED) meteorites represent regolith, basaltic-crust, lower-crust and possibly ultramafic-mantle samples of asteroid Vesta, which is the lone surviving, large, differentiated, basaltic rocky protoplanet in the Solar System. Only a few of these meteorites, the orthopyroxene-rich diogenites, contain olivine, typically with a concentration of less than 25 per cent by volume. Olivine was tentatively identified on Vesta, on the basis of spectral and colour data, but other observations did not confirm its presence. Here we report that olivine is indeed present locally on Vesta's surface but that, unexpectedly, it has not been found within the deep, south-pole basins, which are thought to be excavated mantle rocks. Instead, it occurs as near-surface materials in the northern hemisphere. Unlike the meteorites, the olivine-rich (more than 50 per cent by volume) material is not associated with diogenite but seems to be mixed with howardite, the most common surface material. Olivine is exposed in crater walls and in ejecta scattered diffusely over a broad area. The size of the olivine exposures and the absence of associated diogenite favour a mantle source, but the exposures are located far from the deep impact basins. The amount and distribution of observed olivine-rich material suggest a complex evolutionary history for Vesta.

REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma.

BACKGROUND: In the randomized phase II REGOMA trial, regorafenib showed promising activity in patients with recurrent glioblastoma. We conducted a large, multicenter, prospective, observational study to confirm the REGOMA data in a real-world setting. PATIENTS AND METHODS: The major inclusion criteria were histologically confirmed diagnosis of glioblastoma according to the World Health Organization (WHO) 2016 classification and relapse after radiotherapy with concurrent/adjuvant temozolomide treatment, good performance status [Eastern Cooperative Oncology Group performance status (ECOG PS 0-1)] and good liver function. Regorafenib was administered at the standard dose of 160 mg/day for 3 weeks on/1 week off. Brain magnetic resonance imaging was carried out within 14 days before starting regorafenib and every 8-12 weeks. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate, disease control rate (DCR), safety and health-related quality of life. The Response Assessment in Neuro-Oncology (RANO) criteria were used for response evaluation and Common Terminology Criteria for Adverse Events (CTCAE) version 5 for assessment of adverse events (AEs). RESULTS: From September 2020 to October 2022, 190 patients with recurrent glioblastoma were enrolled from 30 cancer centers in Italy: their median age was 58.5 years [interquartile range (IQR) 53-67 years], 68% were male and 85 (44.7%) were in optimal clinical condition (ECOG PS 0). The number of patients taking steroids at baseline was 113 (60%); the second surgery was carried out in 39 (20.5%). O6-methylguanine-DNA methyltransferase (MGMT) was methylated in 80 patients (50.3%) and 147 (92.4%) of the patients analyzed had isocitrate dehydrogenase (IDH) wild type. The median follow-up period was 20 months (IQR 15.6-25.5 months). The median OS was 7.9 months ([95% confidence interval (CI) 6.5-9.2 months] and the median PFS was 2.6 months (95% CI 2.3-2.9 months). Radiological response was partial response and stable disease in 13 (7.3%) and 26 (14.6%) patients, respectively, with a DCR of 21.9%. The median number of regorafenib cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 drug-related adverse events were reported in 22.6% of patients. A dose reduction due to AEs was required in 36% of patients. No deaths were considered as treatment-related AEs. CONCLUSIONS: This large, real-world observational study showed similar OS with better tolerability of regorafenib in patients with relapsed glioblastoma compared with the REGOMA study.

Candidemia in Neurosurgical Intensive Care Unit: preliminary analysis of the effect of topical Nystatin prophylaxis and adequate source control on patients with early tracheostomy intubation.

INTRODUCTION: The present study represents a preliminary evaluation of the impact of topical nystatin prophylaxis administration and adequate CVC management on reducing the chance of developing candidemia in neurosurgical intensive care unit (NICU) patients. MATERIALS AND METHODS: We conducted a case-control study at the nine bed NICU of the Policlinico "Umberto I" teaching hospital in Rome, Italy, during the period from January 2011 to July 2012. We compared eight patients with culture proven Candida bloodstream infection (CBSI) with a control group of 19 patients who did not have evidence of CBSI. RESULTS: When the CBSI group was compared with the control group, the former were more likely than controls to not have received nystatin prophylaxis and adequate catheter care (p= 0,008). When CBSI group was matched with patients with no adequate source control and nystatin prophylaxis, average NICU stay (71.13 days vs 19.0 days) was significant (mean difference = -52.12 days, 95% CI -97.11 to -7.14, p= 0.028). The same was true for mean time of glucocorticoid exposure (mean difference = -10.5 days, 95% CI -17.35 to -3.65, p<0.01). Binary logistic regression analysis demonstrated no significant association between topical nystatin prophylaxis (p= 0.99), length of NICU stay (p= 0.99), time of glucocorticoid exposure (p= 0.99) and candidemia. CONCLUSION: Topical prophylaxis with nystatin and adequate source control proved to be effective in preventing invasive candidiasis in patients admitted to the NICU.

Zooplankton as an indicator of the status of contamination of the Mediterranean Sea and temporal trends.

Zooplankton has been intensively used as bioindicators of water pollution at global level, however, only few comprehensive studies have been conducted from the Mediterranean Sea and manly dated back to the 1970s. To redress the urgent need for updated data, this study provides information on the presence and levels of contaminants in zooplankton from the Tyrrhenian Sea. Although banned, both PCBs (46.9 ± 37.2 ng g-1) and DDT (8.9 ± 10.7 ng g-1) are still present and widespread, but their contamination appears to be a local problem and to be declining over the past 50 years. Zooplankton accumulates high levels of certain TEs, including Zn (400 ± 388 ppm) and Pb (35.3 ± 45.5 ppm), but shows intermediate concentrations of other TEs, including Cd (1.6 ± 0.9 ppm) and Hg (0.1 ± 0.1 ppm), comparing with both strongly polluted and more pristine marine habitats, which may reflect a general improvement.

Unique expression pattern of human nicotinamide mononucleotide adenylyltransferase isozymes in red blood cells.

Nicotinamide mononucleotide adenylyltransferase (NMNAT) catalyzes the formation of nicotinamide adenine dinucleotide (NAD). In humans, three isozymes have been identified: NMNAT1, which is widely expressed in all tissues, NMNAT2 and NMNAT3, which show a tissue-specific expression and whose mRNA levels are generally lower compared to NMNAT1. In the present study we determined the individual NMNAT isozymes activity in human red blood cells (RBCs) by using a biochemical discrimination assay based on the distinctive catalytic properties of the three proteins. We found that isozyme 3 predominates over isozyme 1, whereas isozyme 2 is absent. This high prevalence of NMNAT3 is cell-aging independent and was also confirmed by analyzing the mRNA and protein levels. RBC represent the first human cell type with a remarkable predominance of NMNAT3, and this unique expression pattern is discussed in light of the catalytic properties of the isozymes and in consideration of the biochemical microenvironment of RBC.

NAD(P) biosynthesis enzymes as potential targets for selective drug design.

NAD(P) biosynthetic pathways can be considered a generous source of enzymatic targets for drug development. Key reactions for NAD(P) biosynthesis in all organisms, common to both de novo and salvage routes, are catalyzed by NMN/NaMN adenylyltransferase (NMNAT), NAD synthetase (NADS), and NAD kinase (NADK). These reactions represent a three-step pathway, present in the vast majority of living organisms, which is responsible for the generation of both NAD and NADP cellular pools. The validation of these enzymes as drug targets is based on their essentiality and conservation among a large variety of pathogenic microorganisms, as well as on their differential structural features or their differential metabolic contribution to NAD(P) homeostasis between microbial and human cell types. This review describes the structural and functional properties of eubacterial and human enzymes endowed with NMNAT, NADS, and NADK activities, as well as with nicotinamide phosphoribosyltransferase (NamPRT) and nicotinamide riboside kinase (NRK) activities, highlighting the species-related differences, with emphasis on their relevance for drug design. In addition, since the overall NMNAT activity in humans is accounted by multiple isozymes differentially involved in the metabolic activation of antineoplastic compounds, their individual diagnostic value for early therapy optimization is outlined. The involvement of human NMNAT in neurodegenerative disorders and its role in neuroprotection is also discussed.

NAD(+) and axon degeneration revisited: Nmnat1 cannot substitute for Wld(S) to delay Wallerian degeneration.

The slow Wallerian degeneration protein (Wld(S)), a fusion protein incorporating full-length nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), delays axon degeneration caused by injury, toxins and genetic mutation. Nmnat1 overexpression is reported to protect axons in vitro, but its effect in vivo and its potency remain unclear. We generated Nmnat1-overexpressing transgenic mice whose Nmnat activities closely match that of Wld(S) mice. Nmnat1 overexpression in five lines of transgenic mice failed to delay Wallerian degeneration in transected sciatic nerves in contrast to Wld(S) mice where nearly all axons were protected. Transected neurites in Nmnat1 transgenic dorsal root ganglion explant cultures also degenerated rapidly. The delay in vincristine-induced neurite degeneration following lentiviral overexpression of Nmnat1 was significantly less potent than for Wld(S), and lentiviral overexpressed enzyme-dead Wld(S) still displayed residual neurite protection. Thus, Nmnat1 is significantly weaker than Wld(S) at protecting axons against traumatic or toxic injury in vitro, and has no detectable effect in vivo. The full protective effect of Wld(S) requires more N-terminal sequences of the protein.

Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene.

Axons and their synapses distal to an injury undergo rapid Wallerian degeneration, but axons in the C57BL/WldS mouse are protected. The degenerative and protective mechanisms are unknown. We identified the protective gene, which encodes an N-terminal fragment of ubiquitination factor E4B (Ube4b) fused to nicotinamide mononucleotide adenylyltransferase (Nmnat), and showed that it confers a dose-dependent block of Wallerian degeneration. Transected distal axons survived for two weeks, and neuromuscular junctions were also protected. Surprisingly, the Wld protein was located predominantly in the nucleus, indicating an indirect protective mechanism. Nmnat enzyme activity, but not NAD+ content, was increased fourfold in WldS tissues. Thus, axon protection is likely to be mediated by altered ubiquitination or pyridine nucleotide metabolism.

Localized aliphatic organic material on the surface of Ceres.

Organic compounds occur in some chondritic meteorites, and their signatures on solar system bodies have been sought for decades. Spectral signatures of organics have not been unambiguously identified on the surfaces of asteroids, whereas they have been detected on cometary nuclei. Data returned by the Visible and InfraRed Mapping Spectrometer on board the Dawn spacecraft show a clear detection of an organic absorption feature at 3.4 micrometers on dwarf planet Ceres. This signature is characteristic of aliphatic organic matter and is mainly localized on a broad region of ~1000 square kilometers close to the ~50-kilometer Ernutet crater. The combined presence on Ceres of ammonia-bearing hydrated minerals, water ice, carbonates, salts, and organic material indicates a very complex chemical environment, suggesting favorable environments to prebiotic chemistry.

Structure of nicotinamide mononucleotide adenylyltransferase: a key enzyme in NAD(+) biosynthesis.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD(+)) is an essential cofactor involved in fundamental processes in cell metabolism. The enzyme nicotinamide mononucleotide adenylyltransferase (NMN AT) plays a key role in NAD(+) biosynthesis, catalysing the condensation of nicotinamide mononucleotide and ATP, and yielding NAD(+) and pyrophosphate. Given its vital role in cell life, the enzyme represents a possible target for the development of new antibacterial agents. RESULTS: The structure of NMN AT from Methanococcus jannaschii in complex with ATP has been solved by X-ray crystallography at 2.0 A resolution, using a combination of single isomorphous replacement and density modification techniques. The structure reveals a hexamer with 32 point group symmetry composed of alpha/beta topology subunits. The catalytic site is located in a deep cleft on the surface of each subunit, where one ATP molecule and one Mg(2+) are observed. A strictly conserved HXGH motif (in single-letter amino acid code) is involved in ATP binding and recognition. CONCLUSIONS: The structure of NMN AT closely resembles that of phosphopantetheine adenylyltransferase. Remarkably, in spite of the fact that the two enzymes share the same fold and hexameric assembly, a striking difference in their quaternary structure is observed. Moreover, on the basis of structural similarity including the HXGH motif, we identify NMN AT as a novel member of the newly proposed superfamily of nucleotidyltransferase alpha/beta phosphodiesterases. Our structural data suggest that the catalytic mechanism does not rely on the direct involvement of any protein residues and is likely to be carried out through optimal positioning of substrates and transition-state stabilisation, as is proposed for other members of the nucleotidyltransferase alpha/beta phosphodiesterase superfamily.

Distribution of phyllosilicates on the surface of Ceres.

The dwarf planet Ceres is known to host phyllosilicate minerals at its surface, but their distribution and origin have not previously been determined. We used the spectrometer onboard the Dawn spacecraft to map their spatial distribution on the basis of diagnostic absorption features in the visible and near-infrared spectral range (0.25 to 5.0 micrometers). We found that magnesium- and ammonium-bearing minerals are ubiquitous across the surface. Variations in the strength of the absorption features are spatially correlated and indicate considerable variability in the relative abundance of the phyllosilicates, although their composition is fairly uniform. These data, along with the distinctive spectral properties of Ceres relative to other asteroids and carbonaceous meteorites, indicate that the phyllosilicates were formed endogenously by a globally widespread and extensive alteration process.

Seasonal exposure of carbon dioxide ice on the nucleus of comet 67P/Churyumov-Gerasimenko.

Carbon dioxide (CO2) is one of the most abundant species in cometary nuclei, but because of its high volatility, CO2 ice is generally only found beneath the surface. We report the infrared spectroscopic identification of a CO2 ice-rich surface area located in the Anhur region of comet 67P/Churyumov-Gerasimenko. Spectral modeling shows that about 0.1% of the 80- by 60-meter area is CO2 ice. This exposed ice was observed a short time after the comet exited local winter; following the increased illumination, the CO2 ice completely disappeared over about 3 weeks. We estimate the mass of the sublimated CO2 ice and the depth of the eroded surface layer. We interpret the presence of CO2 ice as the result of the extreme seasonal changes induced by the rotation and orbit of the comet.

Variation of anatomic valve area during ejection in patients with valvular aortic stenosis evaluated by two-dimensional echocardiographic planimetry: comparison with traditional Doppler data.

OBJECTIVES: Flow variations can affect valve-area calculation in aortic stenosis and lead to inaccuracies in the evaluation of the stenosis. Knowing that transvalvular flow varies normally within one beat, we designed this study to assess the response of the valve to intrabeat variation of flow during systole. Results were compared with flow-derived measurements. BACKGROUND: Technological improvements now allow us to evaluate aortic valve area directly by short axis planimetry. This offers the possibility to perform serial planimetries during one ejection phase and analyze the intrabeat dynamic behavior of the stenotic-aortic valve and compare these measurements with flow-derived measurements. METHODS: Forty echocardiograms displaying different degrees of aortic stenosis were analyzed by frame-by-frame planimetry of the valve area from onset of opening to complete closure. Maximal-mean area, opening and closing rates and ejection times were obtained and compared with Doppler-derived data. RESULTS: Valve area varied during ejection. Stenotic valves opened and closed more slowly than normals and remained maximally open for a shorter period. Mean area by Doppler data corresponded more closely to maximal than to mean-planimetered area. Duration of flow was shorter than valve opening in severely stenotic valves. Discrepancies between Doppler-derived and two-dimensional (2D) measurements decreased in less stenotic valves. CONCLUSIONS: Our observations reveal striking differences between the dynamics of normal and stenotic valves. Surprisingly, Doppler-derived mean-valve area correlated better with maximal-anatomic area than with mean-anatomic area in patients with aortic stenosis. Discrepancies between duration of flow and valve opening could explain this phenomenon.

Meiotic Diploid Progeny and Meiotic Nondisjunction in SACCHAROMYCES CEREVISIAE.

Abnormalities in chromosome number that occurred during meiosis were evaluated with a specially-constructed diploid strain of Saccharomyces cerevisiae. The strain is heterozygous for six markers of the right arm of chromosome V and heterozygous for cyh2 (resistance to cycloheximide) on chromosome VII.-Selection of meiotic spores on a medium containing cycloheximide and required nutrilites-except those for the markers of the right arm of chromosome V-allows the growth of aberrant clones belonging only to two classes: a) diploid clones, caused by failure of the second meiotic division, with a frequency of 0.54 x 10(-4) per viable spore; and b) diplo V, aneuploids derived from nondisjunctions in meiosis I or meiosis II, with a total spontaneous frequency of 0.95 x 10(-4) per viable spore. About two-thirds of the aneuploids originated during meiosis I, the rest during meiosis II. An investigation of these events in control meioses and after treatment with MMS, Benomyl and Amphotericin B suggests that this assay system is suitable for screening environmental mutagens for their effects on meiotic segregation.

No difference in emergence time and early cognitive function between sevoflurane-fentanyl and propofol-remifentanil in patients undergoing craniotomy for supratentorial intracranial surgery.

Balanced anesthesia with sevoflurane-fentanyl has been widely accepted as anesthetic management for neurosurgery. Propofol-remifentanil regimen has been successfully used in various surgical settings, but a comprehensive comparison of sevoflurane-fentanyl and propofol-remifentanil anesthesia in patients undergoing craniotomy for supratentorial intracranial surgery has not yet been done. The aim of this prospective, randomized, open-label clinical trial was to compare clinical properties of sevoflurane-fentanyl with propofol-remifentanil anesthesia in patients undergoing supratentorial intracranial surgery. The primary endpoint was to compare early postoperative recovery and cognitive functions within the two groups; we also evaluated hemodynamic events, vomiting, shivering, and pain. One hundred twenty patients (64 males; age 15-75 years) were randomized to either total intravenous anesthesia (group T) or sevoflurane anesthesia (group S). Emergence and extubation times and cognitive function (Short Orientation Memory Concentration Test [SOMCT]) were compared in the two groups. Brain swelling, incidence of hypotensive and hypertensive episodes, postoperative vomiting, shivering, and pain were also analyzed. The mean emergence time (12.2 +/- 4.9 minutes for group S versus 12.3 +/- 6.1 minutes for group T; P = 0.92) and extubation time (18.2 +/- 2.3 minutes for group S versus 18.3 +/- 2.1 minutes for group T; P = 0.80) were similar in the two groups. Average SOMCT scores, both 15 minutes after extubation (25.6 +/- 4.9 in group S versus 23.9 +/- 7.5 in group T; P = 0.14) and 45 minutes after extubation (27.3 +/- 2.2 in group S versus 26.0 +/- 5.1 in group T; P = 0.07) were also comparable. Brain swelling was present in seven and five patients in groups S and T, respectively (P = 0.76). Hypotension was present in 12% (group S) and 28% (group T) of patients (P = 0.02). Hypertension was present in 17% of patients in group S and 40% of patients in group T (P = 0.0046). Shivering was present in 18% and 25% of patients in groups T and S (P = 0.37). Our study demonstrates that there is no patient benefit of using total intravenous anesthesia with an ultra-short-acting opioid over the conventional balanced volatile technique in terms of recovery and cognitive functions.

Psychosocial outcome one year after heart surgery. A prospective study.

Ninety-nine of 118 patients receiving cardiac valve replacements (n = 55) or coronary artery bypass grafts (n = 44) were studied before surgery and again one year after surgery. Psychological, social, and physical variables were assessed. For the 19 subjects not returning for follow-up, medical data collected by their general practitioner were available. The physical results of surgery were good, with over 90% of the patients showing improvement. Mean scores for psychological distress and quality of life improved; however, a bad psychosocial adjustment was present in about 25% of patients at follow-up. Bad psychosocial adjustment was not correlated with surgical results. The preoperative variables most predictive of poor psychosocial outcome were high scores in the general hypochondriasis and irritability subscales of the illness Behaviour Questionnaire, bad psychological adjustment characterized by high anxiety, depression, and global scores on the Symptom Distress Checklist, and ischemic rather than valvular heart disease.