The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells

CLN1 disease (OMIM # 256730) is an early childhood ceroid-lipofuscinosis associated with mutated CLN1, whose product Palmitoyl-Protein Thioesterase 1 (PPT1) is a lysosomal enzyme involved in the removal of palmitate residues from S-acylated proteins. In neurons, PPT1 expression is also linked to synaptic compartments. The aim of this study was to unravel molecular signatures connected to CLN1. We utilized SH-SY5Y neuroblastoma cells overexpressing wild type CLN1 (SH-p. wtCLN1) and five selected CLN1 patients' mutations. The cellular distribution of wtPPT1 was consistent with regular processing of endogenous protein, partially detected inside Lysosomal Associated Membrane Protein 2 (LAMP2) positive vesicles, while the mutants displayed more diffuse cytoplasmic pattern. Transcriptomic profiling revealed 802 differentially expressed genes (DEGs) in SH-p. wtCLN1 (as compared to empty-vector transfected cells), whereas the number of DEGs detected in the two mutants (p. L222P and p. M57Nfs * 45) was significantly lower. Bioinformatic scrutiny linked DEGs with neurite formation and neuronal transmission. Specifically, neuritogenesis and proliferation of neuronal processes were predicted to be hampered in the wtCLN1 overexpressing cell line, and these findings were corroborated by morphological investigations. Palmitoylation survey identified 113 palmitoylated protein-encoding genes in SH-p. wtCLN1, including 25 ones simultaneously assigned to axonal growth and synaptic compartments. A remarkable decrease in the expression of palmitoylated proteins, functionally related to axonal elongation (GAP43, CRMP1 and NEFM) and of the synaptic marker SNAP25, specifically in SH-p. wtCLN1 cells was confirmed by immunoblotting. Subsequent, bioinformatic network survey of DEGs assigned to the synaptic annotations linked 81 DEGs, including 23 ones encoding for palmitoylated proteins. Results obtained in this experimental setting outlined two affected functional modules (connected to the axonal and synaptic compartments), which can be associated with an altered gene dosage of wtCLN1. Moreover, these modules were interrelated with the pathological effects associated with loss of PPT1 function, similarly as observed in the Ppt1 knockout mice and patients with CLN1 disease.Peer reviewe

Presoaking ACL Grafts in Vancomycin Decreases the Frequency of Postoperative Septic Arthritis : A Cohort Study of 29,659 Patients, Systematic Review, and Meta-analysis From the SANTI Study Group

Presoaking anterior cruciate ligament (ACL) grafts in vancomycin has been reported to reduce the occurrence of septic arthritis (SA). However, strong recommendations for its universal use have been precluded by concerns regarding the fragility of previous meta-analyses. The primary objective was to investigate whether presoaking ACL grafts in vancomycin was associated with a reduction in the rate of SA in a large series of patients. The secondary objective was to perform an updated systematic review and meta-analysis to determine the efficacy of vancomycin in reducing the rate of SA. Cohort study and systematic review; Level of evidence, 3. A retrospective analysis of patients who underwent primary ACL reconstruction (ACLR) at our institution was undertaken. Rates of postoperative SA were determined and analyzed according to whether patients had received grafts presoaked in vancomycin. A systematic review of the literature and meta-analysis was performed. Odds ratios (ORs) for the risk of SA were calculated according to the inverse variance approach. Results were presented using forest plots, funnel plots, and the fragility index. A total of 5300 patients underwent primary ACLR during the study period. The rate of SA was 0.34% (11/3228) in the control group and 0.05% (1/2072) in the presoaked group. There was a 5-fold greater risk of SA in patients who did not receive grafts presoaked in vancomycin (OR, 5.13 [95% CI, 1.16-48.30]; P =.04). Overall, 11 studies were included in the systematic review (29,659 ACLR procedures). The meta-analysis demonstrated a significantly greater risk of SA in those patients who did not receive grafts presoaked in vancomycin (OR, 14.39 [95% CI, 5.90-35.10]; fragility index = 23). This finding held true for the subpopulation receiving hamstring tendon grafts (fragility index = 16), but only a trend was demonstrated for bone-patellar tendon-bone grafts. The meta-analysis demonstrated that presoaking ACL grafts in vancomycin was associated with significant reductions in the rates of SA when all graft types were analyzed together. This finding held true specifically for hamstring tendon autografts. The fragility index of these findings allows for a strong recommendation for the universal use of vancomycin presoaking. However, it should be noted that only a trend toward reduced SA rates was demonstrated with presoaking bone-patellar tendon-bone autografts in vancomycin

Variations in the amount of water ice on Ceres' surface suggest a seasonal water cycle.

The dwarf planet Ceres is known to host a considerable amount of water in its interior, and areas of water ice were detected by the Dawn spacecraft on its surface. Moreover, sporadic water and hydroxyl emissions have been observed from space telescopes. We report the detection of water ice in a mid-latitude crater and its unexpected variation with time. The Dawn spectrometer data show a change of water ice signatures over a period of 6 months, which is well modeled as ~2-km2 increase of water ice. The observed increase, coupled with Ceres' orbital parameters, points to an ongoing process that seems correlated with solar flux. The reported variation on Ceres' surface indicates that this body is chemically and physically active at the present time

Somatic mosaicism represents an underestimated event underlying collagen 6-related disorders

Background: Collagen VI-related disorders (COL6-RD) are a group of heterogenous muscular diseases due to mutations in the COL6A1, COL6A2 and COL6A3 genes, encoding for collagen VI, a critical component of the extracellular matrix. Ullrich congenital muscle disorder and Bethlem myopathy represent the ends of a clinical spectrum that includes intermediate phenotypes of variable severity. UCMD are caused by recessive loss of function mutations or de-novo dominant-negative mutations. The intermediate phenotype and BM are more commonly caused by dominantly acting mutations, and less commonly by recessive mutations. Recently parental mosaicism for dominant mutations in COL6 have been reported in four COL6-RD families and germinal mosaicism has been also identified in a family with recurrence of UCMD in two half-sibs. Methods and results: Here we report three unrelated patients affected by a COL6-RD who carried de novo mosaic mutations in COL6A genes. These mutations, missed by Sanger sequencing, were identified by next generation sequencing. Conclusions: This report highlights the importance of a complete diagnostic workup when clinical and histological finding are consistent with a COL6-RD and strengthen the impression that mosaicisms are underestimated events underlying COL6-RD. (C) 2017 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.Peer reviewe

Anterolateral Ligament Reconstruction Does Not Delay Functional Recovery, Rehabilitation, and Return to Sport After Anterior Cruciate Ligament Reconstruction: A Matched-Pair Analysis From the SANTI (Scientific ACL Network International) Study Group.

PurposeTo determine whether the addition of an anterolateral ligament reconstruction (ALLR) resulted in delayed functional recovery (based on the Knee Santy Athletic Return to Sport [K-STARTS] score) at 6 months after anterior cruciate ligament reconstruction (ACLR).MethodsA retrospective analysis of prospectively collected data from consecutive patients who underwent an ACLR between September 2017 and December 2020 was conducted. Patients who received an isolated hamstring autograft (isolated ACLR group) were propensity matched in a 1:1 ratio to patients who received a hamstring autograft ACLR combined with an ALLR (ACLR-ALLR group). Outcome measures included the Tegner Activity Scale and the K-STARTS test-a validated composite return-to-sports test (including the Anterior Cruciate Ligament-Return to Sport After Injury scale, Qualitative Assessment of Single-Leg Landing tool, limb symmetry index, and ability to change direction using the Modified Illinois Change of Direction Test).ResultsThe study included 111 matched pairs. At 6 months postoperatively, there were no significant differences between groups in the overall K-STARTS score (65.4 for isolated ACLR vs 61.2 for ACLR-ALLR, P = .087) or the Tegner Activity Scale score (3.7 for isolated ACLR vs 3.8 for ACLR-ALLR, P = .45). In addition, an evaluation of the subscales of the K-STARTS score revealed no disadvantage across the domains of neuromuscular control, limb symmetry index, agility, or psychological readiness to return to sport when an ALLR was performed.ConclusionsThe addition of ALLR at the time of ACLR does not delay functional recovery. Specifically, at 6 months postoperatively, there was no disadvantage in patients undergoing ALLR-ACLR, when compared with those undergoing isolated ACLR, with respect to neuromuscular control, limb symmetry indices (hop tests), agility, or psychological readiness to return to sport.Level of evidenceLevel III, retrospective comparative study

Removal of atmospheric features in near infrared spectra by means of principal component analysis and target transformation on Mars: I. Method

Acknowledgments We thank the Italian Institute of Astrophysics INAF for the financial support within the project PRIN-INAF 2011. We are thankful to OMEGA team and ESA staff for scientific, operational and technical supports.The aim of this work is to extract the surface contribution in the martian visible/near-infrared spectra removing the atmospheric components by means of Principal Component Analysis (PCA) and target transformation (TT). The developed technique is suitable for separating spectral components in a data set large enough to enable an effective usage of statistical methods, in support to the more common approaches to remove the gaseous component. In this context, a key role is played by the estimation, from the spectral population, of the covariance matrix that describes the statistical correlation of the signal among different points in the spectrum. As a general rule, the covariance matrix becomes more and more meaningful increasing the size of initial population, justifying therefore the importance of sizable datasets. Data collected by imaging spectrometers, such as the OMEGA (Observatoire pour la Minéralogie, l'Eau, les Glaces et l'Activité) instrument on board the ESA mission Mars Express (MEx), are particularly suitable for this purpose since it includes in the same session of observation a large number of spectra with different content of aerosols, gases and mineralogy. The methodology presented in this work has been first validated using a simulated dataset of spectra to evaluate its accuracy. Then, it has been applied to the analysis of OMEGA sessions over Nili Fossae and Mawrth Vallis regions, which have been already widely studied because of the presence of hydrated minerals. These minerals are key components of the surface to investigate the presence of liquid water flowing on the martian surface in the Noachian period. Moreover, since a correction for the atmospheric aerosols (dust) component is also applied to these observations, the present work is able to completely remove the atmospheric contribution from the analysed spectra. Once the surface reflectance, free from atmospheric contributions, has been obtained, the Modified Gaussian Model (MGM) has been applied to spectra showing the hydrated phase. Silicates and iron-bearing hydrated minerals have been identified by means of the electronic transitions of Fe2+ between 0.8 and 1.2 μm, while at longer wavelengths the hydrated mineralogy is identified by overtones of the OH group. Surface reflectance spectra, as derived through the method discussed in this paper, clearly show a lower level of the atmospheric residuals in the 1.9 hydration band, thus resulting in a better match with the MGM deconvolution parameters found for the laboratory spectra of martian hydrated mineral analogues and allowing a deeper investigation of this spectral range. <P /

Nature, formation, and distribution of carbonates on Ceres

Different carbonates have been detected on Ceres, and their abundance and spatial distribution have been mapped using a visible and infrared mapping spectrometer (VIR), the Dawn imaging spectrometer. Carbonates are abundant and ubiquitous across the surface, but variations in the strength and position of infrared spectral absorptions indicate variations in the composition and amount of these minerals. Mg-Ca carbonates are detected all over the surface, but localized areas show Na carbonates, such as natrite (Na_2CO_3) and hydrated Na carbonates (for example, Na_2CO_3·H_2O). Their geological settings and accessory NH_4-bearing phases suggest the upwelling, excavation, and exposure of salts formed from Na-CO_3-NH_4-Cl brine solutions at multiple locations across the planet. The presence of the hydrated carbonates indicates that their formation/exposure on Ceres’ surface is geologically recent and dehydration to the anhydrous form (Na_2CO_3) is ongoing, implying a still-evolving body

Fresh emplacement of hydrated sodium chloride on Ceres from ascending salty fluids

The surface and internal structure of Ceres show evidence of a global process of aqueous alteration, indicating the existence of an ocean in the past. However, it is not clear whether part of this ocean is still present and whether residual fluids are still circulating in the dwarf planet. These fluids may be exposed in a geologically young surface, and the most promising site to verify the occurrence of present fluids on Ceres is Cerealia Facula dome, in Occator crater. This very young facula exhibits minerals that are relatively rare in our Solar System, the formation of which requires the presence of liquid water in combination with hydrothermal activity. Here we report the discovery of hydrated sodium chloride on Cerealia Facula. These newly identified chloride salts are concentrated on the top of the dome, close to a system of radial fractures. The spatial distribution of the hydrated phase suggests that chloride salts are the solid residue of deep brines that reached the surface only recently, or are still ascending. These salts are very efficient in maintaining Ceres's warm internal temperature and lowering the eutectic temperature of the brines, in which case ascending salty fluids may exist in Ceres today

Mineralogy of Occator crater on Ceres and insight into its evolution from the properties of carbonates, phyllosilicates, and chlorides

Occator Crater on dwarf planet Ceres hosts the so-called faculae, several areas with material 5 to 10 times the albedo of the average Ceres surface: Cerealia Facula, the brightest and largest, and several smaller faculae, Vinalia Faculae, located on the crater floor. The mineralogy of the whole crater is analyzed in this work. Spectral analysis is performed from data of the VIR instrument on board the Dawn spacecraft. We analyse spectral parameters of all main absorption bands, photometry, and continuum slope. Because most of the absorption features are located in a spectral range affected by thermal emission, we developed a procedure for thermal removal. Moreover, quantitative modeling of the measured spectra is performed with a radiative transfer model in order to retrieve abundance and grain size of the identified minerals. Unlike the average Ceres surface that contains a dark component, Mg-Ca-carbonate, Mg-phyllosilicates, and NH4-phyllosilicates, the faculae contain mainly Na-carbonate, Al-phyllosilicates, and NH4-chloride. The present work establishes unambiguously the presence of NH4-chloride thanks to the high-spatial resolution data. Vinalia and Cerealia Faculae show significant differences in the concentrations of these minerals, which have been analyzed. Moreover, heterogeneities are also found within Cerealia Facula that might reflect different deposition events of bright material. An interesting contrast in grain size is found between the center (10-60 μm) and the crater floor/peripheral part of the faculae (100-130 μm), pointing to different cooling time of the grains, respectively faster and slower, and thus to different times of emplacement. This implies the faculae formation is more recent than the crater impact event, consistent with other observations reported in this special issue. For some ejecta, we derived larger concentrations of minerals producing the absorption bands, and smaller grains with respect to the surrounding terrain. This may be related to heterogeneities in the material pre-existent to the impact event