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1.
Nat Chem ; 2024 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-39322782

RESUMEN

The exposure of molecules to attosecond extreme-ultraviolet (XUV) pulses offers a unique opportunity to study the early stages of coupled electron-nuclear dynamics in which the role played by the different degrees of freedom is beyond standard chemical intuition. We investigate, both experimentally and theoretically, the first steps of charge-transfer processes initiated by prompt ionization in prototype donor-π-acceptor molecules, namely nitroanilines. Time-resolved measurement of this process is performed by combining attosecond XUV-pump/few-femtosecond infrared-probe spectroscopy with advanced many-body quantum chemistry calculations. We show that a concerted nuclear and electronic motion drives electron transfer from the donor group on a sub-10-fs timescale. This is followed by a sub-30-fs relaxation process due to the probing of the continuously spreading nuclear wave packet in the excited electronic states of the molecular cation. These findings shed light on the role played by electron-nuclear coupling in donor-π-acceptor systems in response to photoionization.

2.
Mult Scler ; 30(11-12): 1503-1513, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39263885

RESUMEN

BACKGROUND: Evidence on the impact of dimethyl fumarate (DMF) during pregnancy in women with multiple sclerosis (MS) is limited. OBJECTIVES: To investigate disease activity and pregnancy outcomes in a retrospective cohort of women exposed to DMF in early pregnancy. METHODS: Women discontinuing DMF after pregnancy confirmation were identified from 29 Italian MS Centers. Disease activity 12 months before conception, during pregnancy, and 12 months postpartum were recorded, exploring reactivation predictors. Pregnancy and fetal outcomes were assessed. RESULTS: The study analyzed 137 pregnancies (12 pregnancy losses, 125 live births) from 137 women (mean age 32.9 ± 4.7 years), discontinuing DMF within a median (interquartile range (IQR)) interval of 4.9 (3.7-5.7) weeks from conception. In live birth pregnancies, annualized relapse rate (ARR) significantly decreased during pregnancy (ARR = 0.07, 95% confidence interval (CI): 0.03-0.14, p = 0.021) compared to pre-conception (ARR = 0.21 (95% CI: 0.14-0.30)) and increased postpartum ((ARR = 0.22 (95% CI: 0.15-0.32), p = 0.006). Median time to first relapse (TTFR) was 3.16 (IQR: 1:87-5.42) months. Higher pre-conception relapse number (hazard ratio (HR) = 2.33, 95% CI: 1.08-5.02) and Expanded Disability Status Scale (EDSS; HR = 1.81, 95% CI: 1.17-2.74) were associated with shorter TTFR, while treatment resumption with longer TTFR (HR = 0.29, 95% CI: 0.11-0.74). Fetal outcomes were unaffected by DMF exposure. CONCLUSION: DMF discontinuation does not increase relapse risk during pregnancy. Early therapy restart prevents postpartum relapses. Early DMF exposure shows no adverse fetal outcomes.


Asunto(s)
Dimetilfumarato , Inmunosupresores , Esclerosis Múltiple , Complicaciones del Embarazo , Resultado del Embarazo , Humanos , Femenino , Embarazo , Dimetilfumarato/efectos adversos , Adulto , Italia , Complicaciones del Embarazo/tratamiento farmacológico , Estudios Retrospectivos , Esclerosis Múltiple/tratamiento farmacológico , Inmunosupresores/efectos adversos , Recurrencia
3.
Neurology ; 103(4): e209697, 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39102614

RESUMEN

BACKGROUND AND OBJECTIVES: The diagnostic process for myofibrillar myopathies (MFM) and distal myopathies (DM) is particularly complex because of the large number of causative genes, the existence of still molecularly undefined disease entities, and the overlapping features between the 2 categories. This study aimed to characterize a large cohort of patients affected by MFM and DM and identify the most important diagnostic and prognostic aspects of these diseases. METHODS: Patients with either a myopathological diagnosis of MFM or a clinical diagnosis of DM were included in this retrospective multicentric national study. Demographic, genetic, clinical, and histopathologic data of anonymized patients were collected from the neuromuscular centers of the Italian Association of Myology network. RESULTS: Data regarding 132 patients with MFM (mean age 57.0 ± 15.8 years, 49% female) and 298 patients with DM (mean age 50.7 ± 15.9 years, 40% female) were gathered from 20 neuromuscular centers. 69 patients fulfilled the criteria for both groups (distal myopathies with myofibrillar pathology, DM-MP). Molecular confirmation was achieved in 63% of the patients. Fifty-two percent of the patients with MFM carried pathogenic variants in either DES (n = 30), MYOT (n = 20), or DNAJB6 (n = 18), which were also the most frequent disease-causing genes in DM-MP, while GNE (n = 44) and MYH7 (n = 23) were the genes most commonly carrying pathogenic variants in DM. The mean age at onset varied from <25 years in patients with causative variants in MYH7 and DYSF to 59 years in patients with myotilinopathies. Cardiac involvement was reported in 29% of patients with MFM and 16% of patients with DM, with DES and MYH7 variants significantly associated with the development of cardiomyopathy. Respiratory impairment was more prevalent in patients with TTN and DES variants and rare in other disorders such as GNE myopathy and dysferlinopathies, which were instead associated, together with DNAJB6-related and PLIN4-related myopathies, with the risk of losing ambulation during the disease course. DISCUSSION: The Italian cohort of patients with MFM and DM recapitulates the phenotypic heterogeneity and the partial overlap between the 2 groups. However, in relative contrast to the encountered phenotypic variability, only 5 genes accounted for most of the molecular diagnoses. Specific genetic entities are associated with significantly increased risk of developing cardiorespiratory complications or loss of ambulation, which has relevant prognostic implications.


Asunto(s)
Miopatías Distales , Miopatías Estructurales Congénitas , Humanos , Femenino , Masculino , Persona de Mediana Edad , Italia , Adulto , Miopatías Distales/genética , Miopatías Distales/patología , Miopatías Distales/epidemiología , Estudios Retrospectivos , Anciano , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología
4.
Light Sci Appl ; 13(1): 197, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39164239

RESUMEN

Isolated attosecond pulse (IAP) generation usually involves the use of short-medium gas cells operated at high pressures. In contrast, long-medium schemes at low pressures are commonly perceived as inherently unsuitable for IAP generation due to the nonlinear phenomena that challenge favourable phase-matching conditions. Here we provide clear experimental evidence on the generation of isolated extreme-ultraviolet attosecond pulses in a semi-infinite gas cell, demonstrating the use of extended-medium geometries for effective production of IAPs. To gain a deeper understanding we develop a simulation method for high-order harmonic generation (HHG), which combines nonlinear propagation with macroscopic HHG solving the 3D time-dependent Schrödinger equation at the single-atom level. Our simulations reveal that the nonlinear spatio-temporal reshaping of the driving field, observed in the experiment as a bright plasma channel, acts as a self-regulating mechanism boosting the phase-matching conditions for the generation of IAPs.

5.
Struct Dyn ; 11(4): 044303, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39175799

RESUMEN

Understanding photoinjection in semiconductors-a fundamental physical process-represents the first step toward devising new opto-electronic devices, capable of operating on unprecedented time scales. Fostered by the development of few-femtosecond, intense infrared pulses, and attosecond spectroscopy techniques, ultrafast charge injection in solids has been the subject of intense theoretical and experimental investigation. Recent results have shown that while under certain conditions photoinjection can be ascribed to a single, well-defined phenomenon, in a realistic multi-band semiconductor like Ge, several competing mechanisms determine the sub-cycle interaction of an intense light field with the atomic and electronic structure of matter. In this latter case, it is yet unclear how the complex balance between the different physical mechanisms is altered by the chosen interaction geometry, dictated by the relative orientation between the crystal lattice and the laser electric field direction. In this work, we investigate ultrafast photoinjection in a Ge monocrystalline sample with attosecond temporal resolution under two distinct orientations. Our combined theoretical and experimental effort suggests that the physical mechanisms determining carrier excitation in Ge are largely robust against crystal rotation. Nevertheless, the different alignment between the laser field and the crystal unit cell causes non-negligible changes in the momentum distribution of the excited carriers and their injection yield. Further experiments are needed to clarify whether the crystal orientation can be used to tune the photoinjection of carriers in a semiconductor at these extreme time scales.

6.
Rheumatol Int ; 44(11): 2403-2409, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38976028

RESUMEN

Currently, standardized magnetic resonance imaging (MRI) scoring systems and protocols for assessment of idiopathic inflammatory myopathies (IIMs) in children and adults are lacking. Therefore, we will perform a scoping review of the literature to collate and evaluate the existing semi-quantitative and quantitative MRI scoring systems and protocols for the assessment and monitoring of skeletal muscle involvement in patients with IIMs. The aim is to compile evidence-based information that will facilitate the future development of a universal standardized MRI scoring system for both research and clinical applications in IIM. A systematic search of electronic databases (PubMed, EMBASE, and Cochrane) will be undertaken to identify relevant articles published between January 2000 and October 2023. Data will be synthesized narratively. This scoping review seeks to comprehensively summarize and evaluate the evidence on the scanning protocols and scoring systems used in the assessment of diagnosis, disease activity, and damage using skeletal muscle MRI in IIMs. The results will allow the development of consensus recommendations for clinical practice and enable the standardization of research methods for the MRI assessment of skeletal muscle changes in patients with IIMs.


Asunto(s)
Imagen por Resonancia Magnética , Músculo Esquelético , Miositis , Humanos , Imagen por Resonancia Magnética/métodos , Miositis/diagnóstico por imagen , Músculo Esquelético/diagnóstico por imagen , Niño , Adulto , Imagen de Cuerpo Entero/métodos , Proyectos de Investigación
7.
Mult Scler Relat Disord ; 87: 105594, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38718748

RESUMEN

BACKGROUND: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years. METHODS: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement. RESULTS: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Factores Inmunológicos , Esclerosis Múltiple Recurrente-Remitente , Natalizumab , Humanos , Natalizumab/uso terapéutico , Natalizumab/administración & dosificación , Femenino , Masculino , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Adulto , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/farmacología , Estudios Retrospectivos , Adulto Joven , Progresión de la Enfermedad
8.
ACS Photonics ; 11(4): 1673-1683, 2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38645995

RESUMEN

High-order harmonic generation (HHG) arising from the nonperturbative interaction of intense light fields with matter constitutes a well-established tabletop source of coherent extreme-ultraviolet and soft X-ray radiation, which is typically emitted as attosecond pulse trains. However, ultrafast applications increasingly demand isolated attosecond pulses (IAPs), which offer great promise for advancing precision control of electron dynamics. Yet, the direct generation of IAPs typically requires the synthesis of near-single-cycle intense driving fields, which is technologically challenging. In this work, we theoretically demonstrate a novel scheme for the straightforward and compact generation of IAPs from multicycle infrared drivers using hollow capillary fibers (HCFs). Starting from a standard, intense multicycle infrared pulse, a light transient is generated by extreme soliton self-compression in a HCF with decreasing pressure and is subsequently used to drive HHG in a gas target. Owing to the subcycle confinement of the HHG process, high-contrast IAPs are continuously emitted almost independently of the carrier-envelope phase (CEP) of the optimally self-compressed drivers. This results in a CEP-robust scheme which is also stable under macroscopic propagation of the high harmonics in a gas target. Our results open the way to a new generation of integrated all-fiber IAP sources, overcoming the efficiency limitations of usual gating techniques for multicycle drivers.

9.
Int J Mol Sci ; 25(8)2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38674141

RESUMEN

A few cases of multiple sclerosis (MS) onset after COVID-19 vaccination have been reported, although the evidence is insufficient to establish causality. The aim of this study is to compare cases of newly diagnosed relapsing-remitting MS before and after the outbreak of the COVID-19 pandemic and the impact of COVID-19 vaccination. Potential environmental and genetic predisposing factors were also investigated, as well as clinical patterns. This is a single-centre retrospective cohort study including all patients who presented with relapsing-remitting MS onset between January 2018 and July 2022. Data on COVID-19 vaccination administration, dose, and type were collected. HLA-DRB1 genotyping was performed in three subgroups. A total of 266 patients received a new diagnosis of relapsing-remitting MS in our centre, 143 before the COVID-19 pandemic (until and including March 2020), and 123 during the COVID-19 era (from April 2020). The mean number of new MS onset cases per year was not different before and during the COVID-19 era and neither were baseline patients' characteristics, type of onset, clinical recovery, or radiological patterns. Fourteen (11.4%) patients who subsequently received a new diagnosis of MS had a history of COVID-19 vaccination within one month before symptoms onset. Patients' characteristics, type of onset, clinical recovery, and radiological patterns did not differ from those of patients with non-vaccine-related new diagnoses of MS. The allele frequencies of HLA-DRB1*15 were 17.6% and 22.2% in patients with non-vaccine-related disease onset before and during the COVID-19 era, respectively, while no case of HLA-DRB1*15 was identified among patients with a new diagnosis of MS post-COVID-19 vaccine. In contrast, HLA-DRB1*08+ or HLA-DRB1*10+ MS patients were present only in this subgroup. Although a causal link between COVID-19 vaccination and relapsing-remitting MS cannot be detected, it is interesting to note and speculate about the peculiarities and heterogeneities underlying disease mechanisms of MS, where the interactions of genetics and the environment could be crucial also for the follow-up and the evaluation of therapeutic options.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Cadenas HLA-DRB1 , Haplotipos , SARS-CoV-2 , Humanos , Femenino , Masculino , Cadenas HLA-DRB1/genética , Adulto , COVID-19/genética , COVID-19/prevención & control , COVID-19/inmunología , COVID-19/epidemiología , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , Estudios Retrospectivos , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Persona de Mediana Edad , Vacunación , Esclerosis Múltiple Recurrente-Remitente/genética , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple/genética , Predisposición Genética a la Enfermedad
10.
J Neurol Neurosurg Psychiatry ; 95(2): 142-150, 2024 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-37775266

RESUMEN

BACKGROUND: The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI in Multiple Sclerosis) network to evaluate treatment response to injectable drugs can be adopted also to oral DMTs. METHODS: A multicentre dataset of 1200 patients who started three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) was collected within the MAGNIMS network. Disease activity after the first year was classified by the 'MAGNIMS' score based on the combination of relapses (0-≥2) and/or new T2 lesions (<3 or ≥3) on brain MRI. We explored the association of this score with the following 3-year outcomes: (1) confirmed disability worsening (CDW); (2) treatment failure (TFL); (3) relapse count between years 1 and 3. The additional value of contrast-enhancing lesions (CELs) and lesion location was explored. RESULTS: At 3 years, 160 patients experienced CDW: 12% of them scored '0' (reference), 18% scored '1' (HR=1.82, 95% CI 1.20 to 2.76, p=0.005) and 37% scored '2' (HR=2.74, 95% CI 1.41 to 5.36, p=0.003) at 1 year. The analysis of other outcomes provided similar findings. Considering the location of new T2 lesions (supratentorial vs infratentorial/spinal cord) and the presence of CELs improved the prediction of CDW and TFL, respectively, in patients with minimal MRI activity alone (one or two new T2 lesions). CONCLUSIONS: Early relapses and substantial MRI activity in the first year of treatment are associated with worse short-term outcomes in patients treated with some of the oral DMTs.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Inmunosupresores/efectos adversos , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Clorhidrato de Fingolimod/uso terapéutico , Recurrencia
11.
Int J Mol Sci ; 24(13)2023 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-37446317

RESUMEN

BACKGROUND: Sporadic inclusion body myositis (s-IBM) represents a unique disease within idiopathic inflammatory myopathies with a dual myodegenerative-autoimmune physiopathology and a lack of an efficacious treatment. Circulating miRNA expression could expand our knowledge of s-IBM patho-mechanisms and provide new potential disease biomarkers. To evaluate the expression of selected pre-amplified miRNAs in the serum of s-IBM patients compared to those of a sex- and age-matched healthy control group, we enrolled 14 consecutive s-IBM patients and 8 sex- and age-matched healthy controls. By using two different normalization approaches, we found one downregulated and three upregulated miRNAs. hsa-miR-192-5p was significantly downregulated, while hsa-miR-372-3p was found to be upregulated more in the s-IBM patients compared to the level of the controls. The other two miRNAs had a very low expression levels (raw Ct data > 29). hsa-miR-192-5p and hsa-miR-372-3p were found to be significantly dysregulated in the serum of s-IBM patients. These miRNAs are involved in differentiation and regeneration processes, thus possibly reflecting pathological mechanisms in s-IBM muscles and potentially representing disease biomarkers.


Asunto(s)
MicroARN Circulante , MicroARNs , Miositis por Cuerpos de Inclusión , Miositis , Humanos , MicroARN Circulante/genética , Miositis por Cuerpos de Inclusión/genética , MicroARNs/metabolismo , Biomarcadores
12.
Bioengineering (Basel) ; 10(7)2023 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-37508875

RESUMEN

INTRODUCTION: Cognitive impairment represents one of the most hidden and disabling clinical aspects of multiple sclerosis (MS). In this regard, the major challenges are represented by the need for a comprehensive and standardised cognitive evaluation of each patient, both at disease onset and during follow-up, and by the lack of clear-cut data on the effects of treatments. In the present review, we summarize the current evidence on the effects of the available oral disease-modifying treatments (DMTs) on cognitive outcome measures. MATERIALS AND METHODS: In this systematised review, we extract all the studies that reported longitudinally acquired cognitive outcome data on oral DMTs in MS patients. RESULTS: We found 29 studies that evaluated at least one oral DMT, including observational studies, randomised controlled trials, and their extension studies. Most of the studies (n = 20) evaluated sphingosine-1-phosphate (S1P) modulators, while we found seven studies on dimethyl fumarate, six on teriflunomide, and one on cladribine. The most frequently used cognitive outcome measures were SDMT and PASAT. Most of the studies reported substantial stability or mild improvement in cognitive outcomes in a short-time follow-up (duration of most studies ≤2 years). A few studies also reported MRI measures of brain atrophy. CONCLUSION: Cognitive outcomes were evaluated only in a minority of prospective studies on oral DMTs in MS patients with variable findings. More solid and numerous data are present for the S1P modulators. A standardised cognitive evaluation remains a yet unmet need to better clarify the possible positive effect of oral DMTs on cognition.

14.
Clin Exp Rheumatol ; 41(2): 370-378, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36762744

RESUMEN

OBJECTIVES: Sporadic inclusion body myositis (IBM) is a debilitating idiopathic inflammatory myopathy (IIM) which affects hand function, ambulation, and swallowing. There is no approved pharmacological therapy for IBM, and there is a lack of suitable outcome measure to assess the effect of an intervention. The IBM scientific interest group under IMACS reviewed the previously used outcome measures in IBM clinical studies to lay the path for developing a core set of outcome measures in IBM. METHODS: In this systematised review, we have extracted all outcome measures reported in IBM clinical studies to determine what measures were being used and to assess the need for optimising outcome measures in IBM. RESULTS: We found 13 observational studies, 17 open-label clinical trials, and 15 randomised control trials (RCTs) in IBM. Six-minute walk distance, IBM-functional rating scale (IBM-FRS), quantitative muscle testing, manual muscle testing, maximal voluntary isometric contraction testing, and thigh muscle volume measured by MRI were used as primary outcome measures. Twelve different outcome measures of motor function were used in IBM clinical trials. IBM-FRS was the most used measure of functionality. Swallowing function was reported as a secondary outcome measure in only 3 RCTs. CONCLUSIONS: There are inconsistencies in using outcome measures in clinical studies in IBM. The core set measures developed by the IMACS group for other IIMs are not directly applicable to IBM. As a result, there is an unmet need for an IBM-specific core set of measures to facilitate the evaluation of new potential therapeutics for IBM.


Asunto(s)
Miositis por Cuerpos de Inclusión , Miositis , Humanos , Músculo Esquelético , Miositis/complicaciones , Evaluación de Resultado en la Atención de Salud , Caminata
15.
Eur J Ophthalmol ; 33(6): NP133-NP136, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36624618

RESUMEN

We present a case of a 61-year-old woman with an atypical non-arteritic anterior ischemic optic neuropathy (NA-AION) as a unique manifestation of COVID-19. Furthermore, the patient worsened after Pfizer-BioNTech COVID-19 vaccine administration. Our findings suggest that NA-AION could result from microangiopathic/thrombotic events that may occur during SARS-CoV-2 infection and/or vaccination against COVID-19. This report sheds light on possible ophthalmologic complications of COVID-19.

16.
Biomaterials ; 292: 121930, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36493716

RESUMEN

Current available treatments of Multiple Sclerosis (MS) reduce neuroinflammation acting on different targets on the immune system, but potentially lead to severe side effects and have a limited efficacy in slowing the progression of the disease. Here, we evaluated in vitro the immunomodulatory potential of a new class of nanoparticles - liposomes, constituted by a double-layer of phosphatidylserine (PSCho/PS), and double-faced, with an outer layer of phosphatidylserine and an inner layer of phosphatidic acid (PSCho/PA), either alone or in the presence of the myelin basic protein (MBP) peptide (residues 85-99) (PSCho/PS-MBP and PSCho/PA-MBP). Results showed that PSCho/PS are equally and efficiently internalized by pro- and anti-inflammatory macrophages (M1 and M2 respectively), while PSCho/PA were internalized better by M2 than M1. PSCho/PS liposomes were able to inhibit the secretion of innate pro-inflammatory cytokine IL-1ß. PSCho/PS liposomes expanded Tregs, reducing Th1 and Th17 cells, while PSCho/PA liposomes were unable to dampen pro-inflammatory T cells and to promote immune-regulatory phenotype (Treg). The ability of PSCho/PS liposomes to up-regulate Treg cells was more pronounced in MS patients with high basal expression of M2 markers. PSCho/PS liposomes were more effective in decreasing Th1 (but not Th17) cells in MS patients with a disease duration >3 months. On the other hand, down-modulation of Th17 cells was evident in MS patients with active, Gadolinium enhancing lesions at MRI and in MS patients with a high basal expression of M1-associated markers in the monocytes. The same findings were observed for the modulation of MBP-driven Th1/Th17/Treg responses. These observations suggest that early MS associate to a hard-wired pro-Th1 phenotype of M1 that is lost later during disease course. On the other hand, acute inflammatory events reflect a temporary decrease of M2 phenotype that however is amenable to restauration upon treatment with PSCho/PS liposomes. Thus, together these data indicate that monocytes/macrophages may play an important regulatory function during MS course and suggest a role for PSCho/PS and PSCho/PS-MBP as new therapeutic tools to dampen the pro-inflammatory immune responses and to promote its regulatory branch.


Asunto(s)
Esclerosis Múltiple , Nanopartículas , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Liposomas/metabolismo , Fosfatidilserinas , Macrófagos/metabolismo , Fenotipo
17.
Mol Neurobiol ; 60(1): 36-50, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36215027

RESUMEN

Several biomarkers from multiple sclerosis (MS) patients' biological fluids have been considered to support diagnosis, predict disease course, and evaluate treatment response. In this study, we assessed the CSF concentration of selected molecules implicated in the MS pathological process. To investigate the diagnostic and prognostic significance of CSF concentration of target candidate biomarkers in both relapsing (RMS, n = 107) and progressive (PMS, n = 18) MS patients and in other inflammatory (OIND, n = 10) and non-inflammatory (ONIND, n = 15) neurological disorders. We measured the CSF concentration of APRIL, BAFF, CHI3L1, CCL-2, CXCL-8, CXCL-10, CXCL-12, CXCL-13 through a Luminex Assay. MS patients were prospectively evaluated, and clinical and radiological activity were recorded. CHI3L1 and CXCL13 CSF levels were significantly higher in both MS groups compared to control groups, while CCL2, BAFF, and APRIL concentrations were lower in RMS patients compared to PMS and OIND. Considering RMS patients with a single demyelinating event, higher concentrations of CHI3L1, CXCL10, CXCL12, and CXCL13 were recorded in patients who converted to clinically defined MS(CDMS). RMS patients in the CXCL13 and CHI3L1 high concentration group had a significantly higher risk of relapse (HR 12.61 and 4.57), MRI activity (HR 7.04 and 2.46), and of any evidence of disease activity (HR 12.13 and 2.90) during follow-up. CSF CXCL13 and CHI3L1 levels represent very good prognostic biomarkers in RMS patients, and therefore can be helpful in the treatment choice. Higher CSF concentrations of neuro-inflammatory biomarkers were associated with a higher risk of conversion to CDMS in patients with a first clinical demyelinating event. Differential CSF BAFF and APRIL levels between RMS and PMS suggest a different modulation of B-cells pathways in the different phases of the disease.


Asunto(s)
Quimiocina CXCL13 , Proteína 1 Similar a Quitinasa-3 , Esclerosis Múltiple , Humanos , Biomarcadores/líquido cefalorraquídeo , Quimiocina CXCL13/líquido cefalorraquídeo , Progresión de la Enfermedad , Esclerosis Múltiple/diagnóstico , Recurrencia , Proteína 1 Similar a Quitinasa-3/líquido cefalorraquídeo
19.
J Phys Chem Lett ; 13(48): 11169-11175, 2022 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-36445180

RESUMEN

Dissociation of the ethylene cation is a prototypical multistep pathway in which the exact mechanisms leading to internal energy conversions are not fully known. For example, it is still unclear how the energy is exactly redistributed among the internal modes and which step is rate-determining. Here we use few-femtosecond extreme-ultraviolet pulses of tunable energy to excite a different superposition of the four lowest states of C2H4+ and probe the subsequent fast relaxation with a short infrared pulse. Our results demonstrate that the infrared pulse photoexcites the cationic ground state (GS) to higher excited states, producing a hot GS upon relaxation, which enhances the fragmentation yield. As the photoexcitation probability of the GS strongly depends on the molecular geometry, the probing by the IR pulse provides information about the ultrafast excited-state dynamics and the type of conical intersection (planar or twisted) involved in the first 20 fs of the nonradiative relaxation.

20.
Nat Commun ; 13(1): 7103, 2022 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-36402766

RESUMEN

The advent of ultrafast laser science offers the unique opportunity to combine Floquet engineering with extreme time resolution, further pushing the optical control of matter into the petahertz domain. However, what is the shortest driving pulse for which Floquet states can be realised remains an unsolved matter, thus limiting the application of Floquet theory to pulses composed by many optical cycles. Here we ionized Ne atoms with few-femtosecond pulses of selected time duration and show that a Floquet state can be observed already with a driving field that lasts for only 10 cycles. For shorter pulses, down to 2 cycles, the finite lifetime of the driven state can still be explained using an analytical model based on Floquet theory. By demonstrating that the amplitude and number of Floquet-like sidebands in the photoelectron spectrum can be controlled not only with the driving laser pulse intensity and frequency, but also by its duration, our results add a new lever to the toolbox of Floquet engineering.

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