Direct Decarboxylation of Trifluoroacetates Enabled by Iron Photocatalysis.

Trifluoroacetates are the most abundant and accessible sources of trifluoromethyl groups, which are key components in pharmaceuticals and agrochemicals. The generation of trifluoromethyl reactive radicals from trifluoroacetates requires their decarboxylation, which is hampered by their high oxidation potential. This constitutes a major challenge for redox-based methods, because of the need to pair the redox potentials with trifluoroacetate. Here we report a strategy based on iron photocatalysis to promote the direct photodecarboxylation of trifluoroacetates that displays reactivity features that escape from redox limitations. Our synthetic design has enabled the use of trifluoroacetates for the trifluoromethylation of more easily oxidizable organic substrates, offering new opportunities for late-stage derivatization campaigns using chemical feedstocks, Earth-abundant catalysts, and visible-light.

The impact of the SARS-CoV-2 pandemic on the demographic, clinical and social profiles of patients admitted to the Pneumology Department for a COPD exacerbation.

INTRODUCTION: Although a reduction in admissions for pathologies other than SARS-CoV-2 has been reported during the pandemic, there are hardly any specific studies in relation to COPD. The objective of this study was to analyse differences in the profile of those admitted for AEPOC and their prognosis during this period. METHODS: Prospective study (SocioEPOC validation cohort) conducted in two hospitals. Demographic, clinical and social characteristics were compared among patients admitted for an AECOPD before and after the declaration of the COVID-19 healthcare emergency. Mortality and the need for hospital care in the following 3 months were analysed. RESULTS: 340 patients (76.6% male, 72 years, FEV1 43.5%) were included, 174 in the post-pandemic phase. During pandemic, especially before population-level vaccination, admissions for AECOPD were in patients with more severe disease and with a higher level of eosinophils. No differences were found in social profile, except they had more informal caregivers. The mortality rate at 90 days was the same (9%), although those admitted during the pandemic came for more hospital visits in the following 3 months (53.8% vs. 42%; p = 0.003), with the pandemic phase being an independent predictor of this possibility (OR = 1.6.; 95% IC = 1.1-2.6). CONCLUSIONS: In the first few months of the pandemic, the clinical profile of patients hospitalised for an AECOPD differed from that both prior to this period and during the latter months of the pandemic, with minimal changes at the social level. Although the mortality rate were similar, unscheduled hospital visits increased during the COVID-19 pandemic.

Soluble mutant huntingtin drives early human pathogenesis in Huntington's disease.

Huntington's disease (HD) is an incurable inherited brain disorder characterised by massive degeneration of striatal neurons, which correlates with abnormal accumulation of misfolded mutant huntingtin (mHTT) protein. Research on HD has been hampered by the inability to study early dysfunction and progressive degeneration of human striatal neurons in vivo. To investigate human pathogenesis in a physiologically relevant context, we transplanted human pluripotent stem cell-derived neural progenitor cells (hNPCs) from control and HD patients into the striatum of new-born mice. Most hNPCs differentiated into striatal neurons that projected to their target areas and established synaptic connexions within the host basal ganglia circuitry. Remarkably, HD human striatal neurons first developed soluble forms of mHTT, which primarily targeted endoplasmic reticulum, mitochondria and nuclear membrane to cause structural alterations. Furthermore, HD human cells secreted extracellular vesicles containing mHTT monomers and oligomers, which were internalised by non-mutated mouse striatal neurons triggering cell death. We conclude that interaction of mHTT soluble forms with key cellular organelles initially drives disease progression in HD patients and their transmission through exosomes contributes to spread the disease in a non-cell autonomous manner.

RTP801 regulates motor cortex synaptic transmission and learning.

BACKGROUND: RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death in in vitro and in vivo models of Parkinson's and Huntington's diseases and is up regulated in compromised neurons in human postmortem brains of both neurodegenerative disorders. Indeed, in both Parkinson's and Huntington's disease mouse models, RTP801 knockdown alleviates motor-learning deficits. RESULTS: We investigated the physiological role of RTP801 in neuronal plasticity and we found RTP801 in rat, mouse and human synapses. The absence of RTP801 enhanced excitatory synaptic transmission in both neuronal cultures and brain slices from RTP801 knock-out (KO) mice. Indeed, RTP801 KO mice showed improved motor learning, which correlated with lower spine density but increased basal filopodia and mushroom spines in the motor cortex layer V. This paralleled with higher levels of synaptosomal GluA1 and TrkB receptors in homogenates derived from KO mice motor cortex, proteins that are associated with synaptic strengthening. CONCLUSIONS: Altogether, these results indicate that RTP801 has an important role modulating neuronal plasticity and motor learning. They will help to understand its role in neurodegenerative disorders where RTP801 levels are detrimentally upregulated.

Sociodemographic and Clinical Variables Related to the Overburden of the Informal Caregivers of Patients Hospitalized for Chronic Obstructive Pulmonary Disease Exacerbations.

Objective: To increase our knowledge of the patient variables related to the overburden of the caregivers of patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPDs). Methodology: This was a cross-sectional study of patients with severe COPD who have informal caregivers. We performed a multivariate analysis of sociodemographic (economic situation, care, dependence, social risk, and use of social services) and clinical (degree of dyspnea, previous hospitalizations, disease impact, pulmonary function, and comorbidity) factors and related these to the burden of informal caregivers, as evaluated using the Zarit scale. Results: The study included 91 patients, age 72.6±8.7 years and 80 were male (89.7%); the mean modified Medical Research Council dyspnea scale (mMRC) score was 2.5±0.8; mean FEV1 was 39.5 ± 13.2%; and 70 patients (76.9%) were dependent for basic activities. Of the informal caregivers, 90 (90.9%) were women, 49 (49.4%) were partners or spouses, and 29 (29.6%) were daughters. The mean Zarit questionnaire score was 51.4±14.2, with 63 of carers (69.2%) perceiving some overburden, and 34 (37.4%) describing the overburden as mild-moderate. The variables related to informal caregiver overburden in the multivariate study were the previous use of social resources [OR = 8.1 (95% CI = 1.03-69.9); p = 0.04], degree of mMRC dyspnea 3-4 [OR =4.7 (95% CI = 1.7-13.2); p = 0.003], and two or more admissions for AEPOC in the previous year [OR = 4.5 (95% CI = 1.7-13.2); p = 0.003]. Of the informal caregivers of patients who had presented two or more of these variables, 92.3% perceived an overburden. Conclusion: The variables associated with overburden are easily accessible in patient medical records, or can be obtained by interviewing patients or their relatives. This information would allow to detect and assess the overburden of informal caregivers to provide an early warning of this problem.

M2 cortex-dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington's disease.

Huntington's disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of the basal ganglia. The cerebral cortex is the main striatal afferent, and progressive cortico-striatal disconnection characterizes HD. We mapped striatal network dysfunction in HD mice to ultimately modulate the activity of a specific cortico-striatal circuit to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo indicates cortico-striatal and thalamo-striatal functional network deficits and reduced glutamate/glutamine ratio in the striatum of HD mice. Moreover, optogenetically-induced glutamate release from M2 cortex terminals in the dorsolateral striatum (DLS) was undetectable in HD mice and striatal neurons show blunted electrophysiological responses. Remarkably, repeated M2-DLS optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that selective stimulation of the M2-DLS pathway can become an effective therapeutic strategy in HD.

Decreased Myocyte Enhancer Factor 2 Levels in the Hippocampus of Huntington's Disease Mice Are Related to Cognitive Dysfunction.

People suffering from Huntington's disease (HD) present cognitive deficits. Hippocampal dysfunction has been involved in the HD learning and memory impairment, but proteins leading this dysregulation are not fully characterized. Here, we studied the contribution of the family of transcription factors myocyte enhancer factor 2 (MEF2) to the HD cognitive deficits. To this aim, we first analyzed MEF2 protein levels and found that they are reduced in the hippocampus of exon-1 (R6/1) and full-length (HdhQ7/Q111) mutant huntingtin (mHTT) mice at the onset of cognitive dysfunction. By the analysis of MEF2 mRNA levels and mHTT-MEF2 interaction, we discarded that reduced MEF2 levels are due to changes in the transcription or sequestration in mHTT aggregates. Interestingly, we showed in R6/1 primary hippocampal cultures that reduction of MEF2 is strongly related to a basal and non-apoptotic caspase activity. To decipher the involvement of hippocampal decreased MEF2 in memory impairment, we used the BML-210 molecule that activates MEF2 transcriptional activity by the disruption MEF2-histone deacetylase class IIa interaction. BML-210 treatment increased the number and length of neurites in R6/1 primary hippocampal cultures. Importantly, this effect was prevented by transduction of lentiviral particles containing shRNA against MEF2. Then, we demonstrated that intraperitoneal administration of BML-210 (150 mg/Kg/day) for 4 days in R6/1 mice improved cognitive performance. Finally, we observed that BML-210 treatment also promoted the activation of MEF2-dependent memory-related genes and the increase of synaptic markers in the hippocampus of R6/1 mice. Our findings point out that reduced hippocampal MEF2 is an important mediator of cognitive dysfunction in HD and suggest that MEF2 slight basal activation could be a good therapeutic option.

Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy.

Astrocytes have emerged as crucial regulators of neuronal network activity, synapse formation, and underlying behavioral and cognitive processes. Despite some pathways have been identified, the communication between astrocytes and neurons remains to be completely elucidated. Unraveling this communication is crucial to design potential treatments for neurological disorders like temporal lobe epilepsy (TLE). The BDNF and TrkB molecules have emerged as very promising therapeutic targets. However, their modulation can be accompanied by several off-target effects such as excitotoxicity in case of uncontrolled upregulation or dementia, amnesia, and other memory disorders in case of downregulation. Here, we show that BDNF and TrkB from astrocytes modulate neuronal dysfunction in TLE models. First, conditional overexpression of BDNF from astrocytes worsened the phenotype in the lithium-pilocarpine mouse model. Our evidences pointed out to the astrocytic pro-BDNF isoform as a major player of this altered phenotype. Conversely, specific genetic deletion of BDNF in astrocytes prevented the increase in the number of firing neurons and the global firing rate in an in vitro model of TLE. Regarding to the TrkB, we generated mice with a genetic deletion of TrkB specifically in hippocampal neurons or astrocytes. Interestingly, both lines displayed neuroprotection in the lithium-pilocarpine model but only the mice with genetic deletion of TrkB in astrocytes showed significantly preserved spatial learning skills. These data identify the astrocytic BDNF and TrkB molecules as promising therapeutic targets for the treatment of TLE.

Social and clinical predictors of short- and long-term readmission after a severe exacerbation of copd.

INTRODUCTION AND OBJECTIVES: The aim of this study was to evaluate the predictive ability of multiple social, and clinical factors for readmission after a severe acute exacerbation of COPD (AECOPD) during various time periods. METHODS: We performed a prospective cohort study in which recruited patients with AECOPD. We systematically collected numerous clinical (symptoms, pulmonary function, comorbidities, and treatment) and social (financial situation, housing situation, family support, caregiver overload, ability to perform activities, and risk of social exclusion) variables using several questionnaires and indices. The patients were followed closely for one year and readmissions at 30, 60, and 365 days were analysed. RESULTS: 253 patients were included, aged 68.9±9.8years, FEV1 = 42.1%±14.2%, and a Charlson's index = 1.8±0.9. Of these patients, 20.2%, 39.6%, and 63.7% were readmitted within the first 30, 90, and 365 days after discharge, respectively. In the multivariate model applied, the variables that were independently associated with readmission over all three periods of the analysis were dependence to perform basic activities of daily living (BADLs) (odds ratio [OR] = 2.10-4.10) and a history of two or more admissions within the previous year (OR = 2.78-3.78). At 90 days, a history of bacterial isolates in a previous sputum culture (OR = 2.39) and at 365 days, a high grade of dyspnoea (OR = 2.51) and obesity (OR = 2.38) were also identified as predictors of hospital readmission. CONCLUSIONS: The patients' limitation to perform BADLs and their history of admissions for AECOPD were the best predictive variables for the likelihood of readmission when adjusted for many other social and clinical variables, regardless of the time period considered for such prediction.

Social Profile of Patients Admitted for COPD Exacerbations. A Gender Analysis. / Perfil social de los pacientes que ingresan por una agudización de EPOC. Un análisis desde una perspectiva de género.

OBJECTIVE: To describe and compare from a gender perspective the social profile of patients admitted to a respiratory unit for COPD exacerbations (COPDE). METHODOLOGY: A cross-sectional study in patients with serious COPDE in which demographic, clinical, and social data (economic situation, care, dependency for basic and instrumental activities, social risk, caregiver overload, use of social services) were collected using questionnaires and indices such as Barthel, Lawton-Brody, Zarit, Barber, and Gijón. A descriptive analysis was made of patients' social and healthcare situation, compared on the basis of gender. RESULTS: We included 253 patients, aged 68.9±9.8years, 58 (23%) women, FEV1 42.1±14.2%, and Charlson index 1.8±0.9; 37.9% were active smokers. In total, 55.2% had an income of less than €800/month, 46.2% had some dependency for basic activities, and 89.3% for instrumental activities, 89% presented social fragility, while 64% were in a situation of social problem/risk; 49% had a caregiver, 83% in a non-formal arrangement, 90.9% of whom were women, with some overload reported by 69.2%. A total of 21.4% lived alone, and 22.9% had contacted social services. Women with COPDE are younger, smoke more actively, and have fewer comorbidities. They have more scant economic resources and assistance and are in a poorer socio-familiar situation, but they are less dependent for some activities. CONCLUSIONS: The social profile of patients with serious COPDE admitted to respiratory units is very unfavorable, especially among women. These inequalities appear to go beyond differences in the expression of COPD, and are associated with gender.

Dependence IN Performing Activities as a Predictor of Mortality Following Hospitalization for Chronic Obstructive Pulmonary Disease Exacerbation. / La dependencia para actividades como factor predictor de mortalidad tras una hospitalización por una agudización de enfermedad pulmonar obstructiva crónica.

INTRODUCTION: Scant evidence is available on whether dependency for basic (BADL) or instrumental (IADL) activities of daily living can be predictors of mortality after severe COPD exacerbation (COPDE). In addition, it is as yet unclear whether the inclusion of this parameter in a multidimensional score can improve the prediction of mortality. METHODOLOGY: Prospective cohort study, with follow-up of patients discharged after COPDE and multivariate analysis of clinical-demographic and dependency variables (Barthel and Lawton and Brody indices) as predictors of mortality. Three scores were generated (including or not including dependency for BADL and IADL) that were compared with each other and with other commonly used multidimensional indices (BODEx, ADO, DOSE, CODEx). RESULTS: In total, 247 patients were included, 112 (45%, 3); and 195 (72.4%) had some dependency for BADL and IADL. Survival was 631.7 (258.8) days, 95% confidence interval (95% CI), 60-912 days. Fifty-four (21.9%, 95% CI 17-27) patients died. Age> 60 years, FEV1 <50% and Charlson score ≥ 3 were independent predictors in the 3 models generated. Dependency for BADL and IADL were predictors in each of the models in which they were included. The score that included the dependency for BADL presented the best predictive capacity (area under the curve 0.818, 95% CI 0.757-0.879). Stratification into tertiles differentiated groups with a higher risk of death from the beginning of the follow-up (P<.01). CONCLUSIONS: Dependence for activities of daily living, especially the most elementary ones, is an independent predictor of mortality after a severe COPDE that is comparable to clinical variables. Its inclusion in multidimensional scores clearly improves predictive capacity.

Influence of the type of emphysema in the relationship between COPD and lung cancer.

INTRODUCTION: There are no studies analyzing the relationship between emphysema and lung cancer (LC). With this aim and in order to make some comparisons between different clinical variables, we carried out the present study. METHODS: This is a case-control study, patients with COPD and LC being the cases and subjects with stable COPD being the controls. Clinical and functional parameters, as well as the existence of radiological emphysema, were evaluated in a qualitative and quantitative way, using a radiological density of -950 Hounsfield units as a cutoff point in the images. The existence of several different types of emphysema (centrilobular, paraseptal, panacinar, or bullae) was analyzed, allowing patients to have more than one simultaneously. The extent to which lobes were involved was evaluated and the extension of emphysema was graduated for each type and location, following a quantitative scale. Differences between cases and controls were compared by using bivariate and multivariate analyzes with results expressed as OR and 95% CI. RESULTS: We included 169 cases and 74 controls, 84% men with a FEV1 (%) of 61.7±18.5, with 90.1% non-exacerbators. Most of them (50%) were active smokers and 47.2% were ex-smokers. Emphysema was found in 80.2% of the subjects, the most frequent type being centrilobular (34.4%). The only significantly different factor was the presence of paraseptal emphysema (alone or combined; OR =2.2 [95% CI =1.1-4.3, P = 0.03]), with adenocarcinoma being significantly more frequent in paraseptal emphysema with respect to other types (67.2% vs 32.8%, P =0.03). CONCLUSION: Patients with COPD and paraseptal emphysema could be a risk group for the development of LC, especially adenocarcinoma subtype.

Reliability and usefulness of spirometry performed during admission for COPD exacerbation.

OBJECTIVES: Although not currently recommended, spirometry during hospitalization due to exacerbation of chronic obstructive pulmonary disease (COPD) is an opportunity to enhance the diagnosis of this disease. The aim of the present study was to assess the usefulness and reliability of spirometry before hospital discharge, comparing it to measurements obtained during clinical stability. METHODS: This prospective longitudinal observational study compares spirometry results before and 8 weeks after discharge in consecutive patients admitted for COPD exacerbation. Concordance between results was assessed by the Kappa index, intraclass correlation coefficient, and Bland-Altman graphs. RESULTS: From an initial population of 179 COPD patients, 100 completed the study (mean age 67.8 years, 83% men, 35% active smokers, FEV1 at clinical stability 40.3%). Forty-nine patients could not complete the study because they did not reach clinical stability. In three patients with obstructive spirometry during admission, the results were normal at follow-up. In the remaining patients, the COPD diagnosis was confirmed at stability with acceptable concordance. In 27 cases, spirometry improved more than 200 mL.No variables were found to be associated with this improvement or to explain it. CONCLUSIONS: This study provides information on the role of spirometry prior to hospital discharge in patients admitted for COPD exacerbation, demonstrating that it is a valid and reproducible method, representing an opportunity toimprove COPD diagnosis.

Chelerythrine promotes Ca2+-dependent calpain activation in neuronal cells in a PKC-independent manner.

BACKGROUND: Chelerythrine is widely used as a broad range protein kinase C (PKC) inhibitor, but there is controversy about its inhibitory effect. Moreover, it has been shown to exert PKC-independent effects on non-neuronal cells. METHODS: In this study we investigated possible off-target effects of chelerythrine on cultured cortical rodent neurons and a neuronal cell line. RESULTS: We found that 10µM chelerythrine, a commonly used concentration in neuronal cultures, reduces PKC and cAMP-dependent protein kinase substrates phosphorylation in mouse cultured cortical neurons, but not in rat primary cortical neurons or in a striatal cell line. Furthermore, we found that incubation with chelerythrine increases pERK1/2 levels in all models studied. Moreover, our results show that chelerythrine promotes calpain activation as assessed by the cleavage of spectrin, striatal-enriched protein tyrosine phosphatase and calcineurin A. Remarkably, chelerythrine induces a concentration-dependent increase in intracellular Ca2+ levels that mediates calpain activation. In addition, we found that chelerythrine induces ERK1/2- and calpain-independent caspase-3 activation that can be prevented by the Ca2+ chelator BAPTA-AM. CONCLUSIONS: This is the first report showing that chelerythrine promotes Ca2+-dependent calpain activation in neuronal cells, which has consequences for the interpretation of studies using this compound. GENERAL SIGNIFICANCE: Chelerythrine is still marketed as a specific PKC inhibitor and extensively used in signal transduction studies. We believe that the described off-target effects should preclude its use as a PKC inhibitor in future works.