Expanding the genetic and phenotypic spectrum of congenital myasthenic syndrome: new homozygous VAMP1 splicing variants in 2 novel individuals.

We report the cases of two Spanish pediatric patients with hypotonia, muscle weakness and feeding difficulties at birth. Whole-exome sequencing (WES) uncovered two new homozygous VAMP1 (Vesicle Associated Membrane Protein 1) splicing variants, NM_014231.5:c.129+5 G > A in the boy patient (P1) and c.341-24_341-16delinsAGAAAA in the girl patient (P2). This gene encodes the vesicle-associated membrane protein 1 (VAMP1) that is a component of a protein complex involved in the fusion of synaptic vesicles with the presynaptic membrane. VAMP1 has a highly variable C-terminus generated by alternative splicing that gives rise to three main isoforms (A, B and D), being VAMP1A the only isoform expressed in the nervous system. In order to assess the pathogenicity of these variants, expression experiments of RNA for VAMP1 were carried out. The c.129+5 G > A and c.341-24_341-16delinsAGAAAA variants induced aberrant splicing events resulting in the deletion of exon 2 (r.5_131del; p.Ser2TrpfsTer7) in the three isoforms in the first case, and the retention of the last 14 nucleotides of the 3' of intron 4 (r.340_341ins341-14_341-1; p.Ile114AsnfsTer77) in the VAMP1A isoform in the second case. Pathogenic VAMP1 variants have been associated with autosomal dominant spastic ataxia 1 (SPAX1) and with autosomal recessive presynaptic congenital myasthenic syndrome (CMS). Our patients share the clinical manifestations of CMS patients with two important differences: they do not show the typical electrophysiological pattern that suggests pathology of pre-synaptic neuromuscular junction, and their muscular biopsies present hypertrophic fibers type 1. In conclusion, our data expand both genetic and phenotypic spectrum associated with VAMP1 variants.

Towards Negative Emissions: Hydrothermal Carbonization of Biomass for Sustainable Carbon Materials.

The contemporary production of carbon materials heavily relies on fossil fuels, contributing significantly to the greenhouse effect. Biomass is a carbon-neutral resource whose organic carbon is formed from atmospheric CO2. Employing biomass as a precursor for synthetic carbon materials can fix atmospheric CO2 into solid materials, achieving negative carbon emissions. Hydrothermal carbonization (HTC) presents an attractive method for converting biomass into carbon materials, by which biomass can be transformed into materials with favorable properties in a distinct hydrothermal environment, and these carbon materials have made extensive progress in many fields. However, the HTC of biomass is a complex and interdisciplinary problem, involving simultaneously the physical properties of the underlying biomass and sub/supercritical water, the chemical mechanisms of hydrothermal synthesis, diverse applications of resulting carbon materials, and the sustainability of the entire technological routes. This review starts with the analysis of biomass composition and distinctive characteristics of the hydrothermal environment. Then, the factors influencing the HTC of biomass, the reaction mechanism, and the properties of resulting carbon materials are discussed in depth, especially the different formation mechanisms of primary and secondary hydrochars. Furthermore, the application and sustainability of biomass-derived carbon materials are summarized, and some insights into future directions are provided.

Cork-Derived Carbon Sheets for High-Performance Na-Ion Capacitors.

S-doped carbon sheets have been easily prepared by deconstructing the 3D cellular structure of a fully sustainable and renewable biomass material such as cork through a mild ball-milling process. S-doping of the material (>14 wt % S) has been achieved by using sulfur as an earth-abundant, cost-effective, and environmentally benign S-dopant. Such synthesized materials provide large Na storage capacities in the range of 300-550 mAh g-1 at 0.1 A g-1 and can handle large current densities of 10 A g-1, providing 55-140 mAh g-1. Their increased packing density compared to the 3D pristine structure allows them to also provide good volumetric capacities in the range of 285-522 mAh cm-3 at 0.1 A g-1 and 53-133 mAh cm-3 at 10 A g-1. In addition, highly porous carbon sheets (SBET > 2700 m2 g-1) have been produced from the same carbon precursor by rationally designing the chemical activation approach. These materials are able to provide good anion storage capacities/capacitances of up to 100-114 mAh g-1/163-196 F g-1. A sodium-ion capacitor assembled with the optimized S-doped carbon sheets and the highly porous carbon sheets with mass matching ratios provided the best energy/power characteristics (90 Wh kg-1 at 29 kW kg-1) in combination with robust cycling stability over 10,000 cycles, with a capacity fade of only 0.0018% per cycle.

Eco-Friendly Synthesis of 3D Disordered Carbon Materials for High-Performance Dual Carbon Na-Ion Capacitors.

An eco-friendly and sustainable salt-templating approach was proposed for the production of anode materials with a 3D sponge-like structure for sodium-ion capacitors using gluconic acid as carbon precursor and sodium carbonate as water-removable template. The optimized carbon material combined porous thin walls that provided short diffusional paths, a highly disordered microstructure with dilated interlayer spacing, and a large oxygen content, all of which facilitated Na ion transport and provided plenty of active sites for Na adsorption. This material provided a capacity of 314 mAh g-1 at 0.1 A g-1 and 130 mAh g-1 at 10 A g-1 . When combined with a 3D highly porous carbon cathode (SBET ≈2300 m2 g-1 ) synthesized from the same precursor, the Na-ion capacitor showed high specific energy/power, that is 110 Wh kg-1 at low power and still 71 Wh kg-1 at approximately 26 kW kg-1 , and a good capacity retention of 70 % over 10000 cycles.

More Sustainable Chemical Activation Strategies for the Production of Porous Carbons.

The preparation of porous carbons attracts a great deal of attention given the importance of these materials in many emerging applications, such as hydrogen storage, CO2 capture, and energy storage in supercapacitors and batteries. In particular, porous carbons produced by applying chemical activation methods are preferred because of the high pore development achieved. However, given the environmental risks associated with conventional activating agents such as KOH, the development of greener chemical activation methodologies is an important objective. This Review summarizes recent progress in the production of porous carbons by using more sustainable strategies based on chemical activation. The use of less-corrosive chemical agents as an alternative to KOH is thoroughly reviewed. In addition, progress achieved to date by using emerging self-activation methodologies applied to organic salts and biomass products is also discussed.

Boosting High-Performance in Lithium-Sulfur Batteries via Dilute Electrolyte.

Polysulfide shuttle effects, active material losses, formation of resistive surface layers, and continuous electrolyte consumption create a major barrier for the lightweight and low-cost lithium-sulfur (Li-S) battery adoption. Tuning electrolyte composition by using additives and most importantly by substantially increasing electrolyte molarity was previously shown to be one of the most effective strategies. Contrarily, little attention has been paid to dilute and super-diluted LiTFSI/DME/DOL/LiNO3 based-electrolytes, which have been thought to aggravate the polysulfide dissolution and shuttle effects. Here we challenge this conventional wisdom and demonstrate outstanding capabilities of a dilute (0.1 mol L-1 of LiTFSI in DME/DOL with 1 wt. % LiNO3) electrolyte to enable better electrode wetting, greatly improved high-rate capability, and stable cycle performance for high sulfur loading cathodes and low electrolyte/sulfur ratio in Li-S cells. Overall, the presented study shines light on the extraordinary ability of such electrolyte systems to suppress short-chain polysulfide dissolution and polysulfide shuttle effects.

Straightforward synthesis of Sulfur/N,S-codoped carbon cathodes for Lithium-Sulfur batteries.

An upgrade of the scalable fabrication of high-performance sulfur-carbon cathodes is essential for the widespread commercialization of this technology. Herein we present a simple, cost-effective and scalable approach for the fabrication of cathodes comprising sulfur and high-surface area, N,S-codoped carbons. The method involves the use of a sulfur salt, i.e. sodium thiosulfate, as activating agent, sulfur precursor and S-dopant, and polypyrrole as carbon precursor and N-dopant. In this way, the production of the porous host and the incorporation of sulfur are combined in the same procedure. The porous hosts thus produced have BET surface areas in excess of 2000 m2 g-1, a micro-mesoporous structure, as well as sulfur and nitrogen contents of 5-6 wt% and ~2 wt%, respectively. The elemental sulfur content in the composites can be precisely modulated in the range of 24 to ca. 90 wt% by controlling the amount of sodium thiosulfate used. Remarkably, these porous carbons are able to accommodate up to 80 wt% sulfur exclusively within their porosity. When analyzed in lithium-sulfur batteries, these sulfur-carbon composites show high specific capacities of 1100 mAh g-1 at a low C-rate of 0.1 C and above 500 mAh g-1 at a high rate of 2 C for sulfur contents in the range of 50-80 wt%. Remarkably, the composites with 51-65 wt% S can still provide above 400 mAh g-1 at an ultra-fast rate of 4 C (where a charge and discharge cycle takes only ten minutes). The good rate capability and sulfur utilization was additionally assessed for cathodes with a high sulfur content (65-74%) and a high sulfur loading (>5 mg cm-2). In addition, cathodes of 4 mg cm-2 successfully cycled for 260 cycles at 0.2 C showed only a low loss of 0.12%/cycle.

Desarrollo de una fórmula magistral de clofazimina para el tratamiento de tuberculosis extremadamente resistente en paciente lactante / Clofazimine suspension formulation for treating extremely resistant tuberculosis in a nursing patient

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Pore Characteristics for Efficient CO2 Storage in Hydrated Carbons.

Development of new approaches for carbon dioxide (CO2) capture is important in both scientific and technological aspects. One of the emerging methods in CO2 capture research is based on the use of gas-hydrate crystallization in confined porous media. Pore dimensions and surface functionality of the pores play important roles in the efficiency of CO2 capture. In this report, we summarize work on several porous carbons (PCs) that differ in pore dimensions that range from supermicropores to mesopores, as well as surfaces ranging from hydrophilic to hydrophobic. Water was imbibed into the PCs, and the CO2 uptake performance, in dry and hydrated forms, was determined at pressures of up to 54 bar to reveal the influence of pore characteristics on the efficiency of CO2 capture and storage. The final hydrated carbon materials had H2O-to-carbon weight ratios of 1.5:1. Upon CO2 capture, the H2O/CO2 molar ratio was found to be as low as 1.8, which indicates a far greater CO2 capture capacity in hydrated PCs than ordinarily seen in CO2-hydrate formations, wherein the H2O/CO2 ratio is 5.72. Our mechanistic proposal for attainment of such a low H2O/CO2 ratio within the PCs is based on the finding that most of the CO2 is captured in gaseous form within micropores of diameter <2 nm, wherein it is blocked by external CO2-hydrate formations generated in the larger mesopores. Therefore, to have efficient high-pressure CO2 capture by this mechanism, it is necessary to have PCs with a wide pore size distribution consisting of both micropores and mesopores. Furthermore, we found that hydrated microporous or supermicroporous PCs do not show any hysteretic CO2 uptake behavior, which indicates that CO2 hydrates cannot be formed within micropores of diameter 1-2 nm. Alternatively, mesoporous and macroporous carbons can accommodate higher yields of CO2 hydrates, which potentially limits the CO2 uptake capacity in those larger pores to a H2O/CO2 ratio of 5.72. We found that high nitrogen content prevents the formation of CO2 hydrates presumably due to their destabilization and associated increase in system entropy via stronger noncovalent interactions between the nitrogen functional groups and H2O or CO2.

Boosting the Oxygen Reduction Electrocatalytic Performance of Nonprecious Metal Nanocarbons via Triple Boundary Engineering Using Protic Ionic Liquids.

The oxygen reduction reaction (ORR) in aqueous media plays a critical role in sustainable and clean energy technologies such as polymer electrolyte membrane and alkaline fuel cells. In this work, we present a new concept to improve the ORR performance by engineering the interface reaction at the electrocatalyst/electrolyte/oxygen triple-phase boundary using a protic and hydrophobic ionic liquid and demonstrate the wide and general applicability of this concept to several Pt-free catalysts. Two catalysts, Fe-N codoped and metal-free N-doped carbon electrocatalysts, are used as a proof of concept. The ionic liquid layer grafted at the nanocarbon surface creates a water-equilibrated secondary reaction medium with a higher O2 affinity toward oxygen adsorption, promoting the diffusion toward the catalytic active site, while its protic character provides sufficient H+/H3O+ conductivity, and the hydrophobic nature prevents the resulting reaction product water from accumulating and blocking the interface. Our strategy brings obvious improvements in the ORR performance in both acid and alkaline electrolytes, while the catalytic activity of FeNC-nanocarbon outperforms commercial Pt-C in alkaline electrolytes. We believe that this research will pave new routes toward the development of high-performance ORR catalysts free of noble metals via careful interface engineering at the triple point.

Intrathecal administration of autologous mesenchymal stromal cells for spinal cord injury: Safety and efficacy of the 100/3 guideline.

BACKGROUND AIMS: Cell therapy with autologous mesenchymal stromal cells (MSCs) in patients with spinal cord injury (SCI) is beginning, and the search for its better clinical application is an urgent need. METHODS: We present a phase 2 clinical trial in patients with chronic SCI who received three intrathecal administrations of 100 x 106 MSCs and were followed for 10 months from the first administration. Efficacy analysis was performed on nine patients, and safety analysis was performed on 11 patients. Clinical scales, urodynamic, neurophysiological and neuroimaging studies were performed previous to treatment and at the end of the follow-up. RESULTS: The treatment was well-tolerated, without any adverse event related to MSC administration. Patients showed variable clinical improvement in sensitivity, motor power, spasms, spasticity, neuropathic pain, sexual function or sphincter dysfunction, regardless of the level or degree of injury, age or time elapsed from the SCI. In the course of follow-up three patients, initially classified as ASIA A, B and C, changed to ASIA B, C and D, respectively. In urodynamic studies, at the end of follow-up, 66.6% of the patients showed decrease in postmicturition residue and improvement in bladder compliance. At this time, neurophysiological studies showed that 55.5% of patients improved in somatosensory or motor-evoked potentials, and that 44.4% of patients improved in voluntary muscle contraction together with infralesional active muscle reinnervation. CONCLUSIONS: The present guideline for cell therapy is safe and shows efficacy in patients with SCI, mainly in recovery of sphincter dysfunction, neuropathic pain and sensitivity.

Cell therapy with autologous mesenchymal stromal cells in post-traumatic syringomyelia.

BACKGROUND AIMS: Recently, clinical studies show that cell therapy with mesenchymal stromal cells (MSCs) improves the sequelae chronically established in paraplegic patients, being necessary to know which of them can obtain better benefit. METHODS: We present here a phase 2 clinical trial that includes six paraplegic patients with post-traumatic syringomyelia who received 300 million MSCs inside the syrinx and who were followed up for 6 months. Clinical scales, urodynamic, neurophysiological, magnetic resonance (MR) and studies of ano-rectal manometry were performed to assess possible improvements. RESULTS: In all the cases, MR at the end of the study showed a clear reduction of the syrinx, and, at this time, signs of improvement in the urodynamic studies were found. Moreover, four patients improved in ano-rectal manometry. Four patients improved in neurophysiological studies, with signs of improvement in evoked potentials in three patients. In the American Spinal Injury Association (ASIA) assessment, only two patients improved in sensitivity, but clinical improvement in neurogenic bowel dysfunction was observed in four patients and three patients described improvement in bladder dysfunction. Spasms reduced in two of the five patients who had them previous to cell therapy, and spasticity was improved in the other two patients. Three patients had neuropathic pain before treatment, and it was reduced or disappeared completely during the study. Only two adverse events ocurred, without relation to the cell therapy. CONCLUSIONS: Cell therapy can be considered as a new alternative to the treatment of post-traumatic syringomyelia, achieving reduction of syrinx and clinical improvements in individual patients.

Optimization of the Pore Structure of Biomass-Based Carbons in Relation to Their Use for CO2 Capture under Low- and High-Pressure Regimes.

A versatile chemical activation approach for the fabrication of sustainable porous carbons with a pore network tunable from micro- to hierarchical micro-/mesoporous is hereby presented. It is based on the use of a less corrosive and less toxic chemical, i.e., potassium oxalate, rather than the widely used KOH. The fabrication procedure is exemplified for glucose as precursor, although it can be extended to other biomass derivatives (saccharides) with similar results. When potassium oxalate alone is used as activating agent, highly microporous carbons are obtained (SBET ≈ 1300-1700 m2 g-1). When a melamine-mediated activation process is used, hierarchical micro-/mesoporous carbons with surface areas as large as 3500 m2 g-1 are obtained. The microporous carbons are excellent adsorbents for CO2 capture at low pressure and room temperature, able to adsorb 4.2-4.5 mmol CO2 g-1 at 1 bar and 1.1-1.4 mmol CO2 g-1 at 0.15 bar. However, the micro-/mesoporous carbons provide record-high room temperature CO2 uptakes at 30 bar of 32-33 mmol g-1 CO2 and 44-49 mmol g-1 CO2 at 50 bar. The findings demonstrate the key relevance of pore size in CO2 capture, with narrow micropores having the leading role at pressures <1 bar and supermicropores/small mesopores at high pressures. In this regard, the fabrication strategy presented here allows fine-tuning of the pore network to maximize both the overall CO2 uptake and the working capacity at any target pressure.

Repeated subarachnoid administrations of autologous mesenchymal stromal cells supported in autologous plasma improve quality of life in patients suffering incomplete spinal cord injury.

BACKGROUND AIMS: Cell therapy with mesenchymal stromal cells (MSCs) offers new hope for patients suffering from spinal cord injury (SCI). METHODS: Ten patients with established incomplete SCI received four subarachnoid administrations of 30 × 106 autologous bone marrow MSCs, supported in autologous plasma, at months 1, 4, 7 and 10 of the study, and were followed until the month 12. Urodynamic, neurophysiological and neuroimaging studies were performed at months 6 and 12, and compared with basal studies. RESULTS: Variable improvement was found in the patients of the series. All of them showed some degree of improvement in sensitivity and motor function. Sexual function improved in two of the eight male patients. Neuropathic pain was present in four patients before treatment; it disappeared in two of them and decreased in another. Clear improvement in bladder and bowel control were found in all patients suffering previous dysfunction. Before treatment, seven patients suffered spasms, and two improved. Before cell therapy, nine patients suffered variable degree of spasticity, and 3 of them showed clear decrease at the end of follow-up. At this time, nine patients showed infra-lesional electromyographic recordings suggesting active muscle reinnervation, and eight patients showed improvement in bladder compliance. After three administrations of MSCs, mean values of brain-derived neurotrophic factor, glial-derived neurotrophic factor, ciliary neurotrophic factor, and neurotrophin 3 and 4 showed slight increases compared with basal levels, but without statistically significant difference. CONCLUSIONS: Administration of repeated doses of MSCs by subarachnoid route is a well-tolerated procedure that is able to achieve progressive and significant improvement in the quality of life of patients suffering incomplete SCI.

Aqueous Dispersions of Graphene from Electrochemically Exfoliated Graphite.

A facile and environmentally friendly synthetic strategy for the production of stable and easily processable dispersions of graphene in water is presented. This strategy represents an alternative to classical chemical exfoliation methods (for example the Hummers method) that are more complex, harmful, and dangerous. The process is based on the electrochemical exfoliation of graphite and includes three simple steps: 1) the anodic exfoliation of graphite in (NH4 )2 SO4 , 2) sonication to separate the oxidized graphene sheets, and 3) reduction of oxidized graphene to graphene. The procedure makes it possible to convert around 30 wt % of the initial graphite into graphene with short processing times and high yields. The graphene sheets are well dispersed in water, have a carbon/oxygen atomic ratio of 11.7, a lateral size of about 0.5-1 µm, and contain only a few graphene layers, most of which are bilayer sheets. The processability of this type of aqueous dispersion has been demonstrated in the fabrication of macroscopic graphene structures, such as graphene aerogels and graphene films, which have been successfully employed as absorbents or as electrodes in supercapacitors, respectively.

A Green Approach to High-Performance Supercapacitor Electrodes: The Chemical Activation of Hydrochar with Potassium Bicarbonate.

Sustainable synthesis schemes for the production of porous carbons with appropriate textural properties for use as supercapacitor electrodes are in high demand. In this work a greener option to the widely used but corrosive KOH is proposed for the production of highly porous carbons. Hydrochar products are used as carbon precursors. It is demonstrated that a mild alkaline potassium salt such as potassium bicarbonate is very effective to generate porosity in hydrochar to lead to materials with large surface areas (> 2000 m(2) g(-1) ) and a tunable pore size distribution. Furthermore, the use of KHCO3 instead of KOH gives rise to a significant 10 % increase in the yield of activated carbon, and the spherical morphology of hydrochar is retained, which translates into better packing properties and reduced ion diffusion distances. These features lead to a supercapacitor performance that can compete with, and even surpass, that of KOH-activated hydrochar in a variety of electrolytes.

Fe-N-Doped Carbon Capsules with Outstanding Electrochemical Performance and Stability for the Oxygen Reduction Reaction in Both Acid and Alkaline Conditions.

High surface area N-doped mesoporous carbon capsules with iron traces exhibit outstanding electrocatalytic activity for the oxygen reduction reaction in both alkaline and acidic media. In alkaline conditions, they exhibit more positive onset (0.94 V vs RHE) and half-wave potentials (0.83 V vs RHE) than commercial Pt/C, while in acidic media the onset potential is comparable to that of commercial Pt/C with a peroxide yield lower than 10%. The Fe-N-doped carbon catalyst combines high catalytic activity with remarkable performance stability (3500 cycles between 0.6 and 1.0 V vs RHE), which stems from the fact that iron is coordinated to nitrogen. Additionally, the newly developed electrocatalyst is unaffected by the methanol crossover effect in both acid and basic media, contrary to commercial Pt/C. The excellent catalytic behavior of the Fe-N-doped carbon, even in the more relevant acid medium, is attributable to the combination of chemical functions (N-pyridinic, N-quaternary, and Fe-N coordination sites) and structural properties (large surface area, open mesoporous structure, and short diffusion paths), which guarantees a large number of highly active and fully accessible catalytic sites and rapid mass-transfer kinetics. Thus, this catalyst represents an important step forward toward replacing Pt catalysts with cheaper alternatives. In this regard, an alkaline anion exchange membrane fuel cell was assembled with Fe-N-doped mesoporous carbon capsules as the cathode catalyst to provide current and power densities matching those of a commercial Pt/C, which indicates the practical applicability of the Fe-N-carbon catalyst.

Versatile Cellulose-Based Carbon Aerogel for the Removal of Both Cationic and Anionic Metal Contaminants from Water.

Hydrothermal carbonization of cellulose in the presence of the globular protein ovalbumin leads to the formation of nitrogen-doped carbon aerogel with a fibrillar continuous carbon network. The protein plays here a double role: (i) a natural source of nitrogen functionalities (2.1 wt %) and (ii) structural directing agent (S(BET) = 38 m(2)/g). The applicability in wastewater treatment, namely, for heavy metal removal, was examined through adsorption of Cr(VI) and Pb(II) ion solely and in a mixed bicomponent aqueous solutions. This cellulose-based carbogel shows an enhanced ability to remove both Cr(VI) (∼68 mg/g) and Pb(II) (∼240 mg/g) from the targeted solutions in comparison to other carbon materials reported in the literature. The presence of competing ions showed little effect on the adsorption efficiency toward Cr(VI) and Pb(II).

Superior capacitive performance of hydrochar-based porous carbons in aqueous electrolytes.

Biomass-based highly porous carbons with excellent performances in aqueous electrolyte-based supercapacitors have been developed. The synthesis of these materials is based on the chemical activation of biomass-based hydrochar. The addition of melamine to the activation mixture leads to porous carbons with a porosity consisting of micropores/small mesopores. Furthermore, melamine promotes the introduction of nitrogen heteroatoms in the carbon framework, along with abundant oxygen functionalities, to improve the wettability. The materials produced in the presence or absence of melamine exhibit high specific capacitances in aqueous electrolytes (>270 F g(-1) in H2 SO4 and >190 F g(-1) in Li2SO4). Additionally, the mesopores present in the melamine-based micro-/mesoporous carbons notably improve the ion-transport kinetics, especially in Li2SO4. Furthermore, in Li2SO4, they remain stable up to a cell voltage of 1.6 V; thus exhibiting superior energy and power characteristics than those in H2 SO4.