Tau reduction with artificial microRNAs modulates neuronal physiology and improves tauopathy phenotypes in mice.

Abnormal tau accumulation is the hallmark of several neurodegenerative diseases, named tauopathies. Strategies aimed at reducing tau in the brain are promising therapeutic interventions, yet more precise therapies would require targeting specific nuclei and neuronal subpopulations affected by disease while avoiding global reduction of physiological tau. Here, we developed artificial microRNAs directed against the human MAPT mRNA to dwindle tau protein by engaging the endogenous RNA interference pathway. In human differentiated neurons in culture, microRNA-mediated tau reduction diminished neuronal firing without affecting neuronal morphology or impairing axonal transport. In the htau mouse model of tauopathy, we locally expressed artificial microRNAs in the prefrontal cortex (PFC), an area particularly vulnerable to initiating tau pathology in this model. Tau knockdown prevented the accumulation of insoluble and hyperphosphorylated tau, modulated firing activity of putative pyramidal neurons, and improved glucose uptake in the PFC. Moreover, such tau reduction prevented cognitive decline in aged htau mice. Our results suggest target engagement of designed tau-microRNAs to effectively reduce tau pathology, providing a proof of concept for a potential therapeutic approach based on local tau knockdown to rescue tauopathy-related phenotypes.

Factors Predicting Prolonged Mechanical Ventilation in Guillain-Barré Syndrome.

BACKGROUND: Up to 30% of patients with Guillain-Barré syndrome require mechanical ventilation and 5% die due to acute complications of mechanical ventilation. There is a considerable group of patients that will need prolonged mechanical ventilation (considered as >14 days) and should be considered for early tracheostomy. The objective of this study is to identify risk factors for prolonged mechanical ventilation. METHODS: We prospectively analyzed patients with Guillain-Barré diagnosis with versus without prolonged mechanical ventilation. We considered clinical and electrophysiological characteristics and analyzed factors associated with prolonged mechanical ventilation. RESULTS: Three hundred and three patients were included; 29% required mechanical ventilation. When comparing the groups, patients with prolonged invasive mechanical ventilation (IMV) have a lower score on the Medical Research Council score (19.5 ± 16.2 vs 27.4 ± 17.5, p = 0.03) and a higher frequency of dysautonomia (42.3% vs 19.4%, p = 0.037), as well as lower amplitudes of the distal compound muscle action potential (CMAP) of the median nerve [0.37 (RIQ 0.07-2.25) vs. 3.9 (RIQ1.2-6.4), p = <0.001] and ulnar nerve [0.37 (RIQ0.0-3.72) vs 1.5 (RIQ0.3-6.6), p = <0.001], and higher frequency of severe axonal damage in these nerves (distal CMAP ≤ 1.0 mV). Through binary logistic regression, severe axonal degeneration of the median nerve is an independent risk factor for prolonged IMV OR 4.9 (95%CI 1.1-21.5) p = 0.03, AUC of 0.774, (95%CI 0.66-0.88), p = < 0.001. CONCLUSIONS: Severe median nerve damage is an independent risk factor for prolonged mechanical ventilation.

The uncharacterized Pseudomonas aeruginosa PA4189 is a novel and efficient aminoacetaldehyde dehydrogenase.

Neither the Pseudomonas aeruginosa aldehyde dehydrogenase encoded by the PA4189 gene nor its ortholog proteins have been biochemically or structurally characterized and their physiological function is unknown. We cloned the PA4189 gene, obtained the PA4189 recombinant protein, and studied its structure-function relationships. PA4189 is an NAD+-dependent aminoaldehyde dehydrogenase highly efficient with protonated aminoacetaldehyde and 3-aminopropionaldehyde, which are much more preferred to the non-protonated species as indicated by pH studies. Based on the higher activity with aminoacetaldehyde than with 3-aminopropionaldehyde, we propose that aminoacetaldehyde might be the PA4189 physiological substrate. Even though at the physiological pH of P. aeruginosa cells the non-protonated aminoacetaldehyde species will be predominant, and despite the competition of these species with the protonated ones, PA4189 would very efficiently oxidize ACTAL in vivo, producing glycine. To our knowledge, PA4189 is the first reported enzyme that might metabolize ACTAL, which is considered a dead-end metabolite because its consuming reactions are unknown. The PA4189 crystal structure reported here suggested that the charge and size of the active-site residue Glu457, which narrows the aldehyde-entrance tunnel, greatly define the specificity for small positively charged aldehydes, as confirmed by the kinetics of the E457G and E457Q variants. Glu457 and the residues that determine Glu457 conformation inside the active site are conserved in the PA4189 orthologs, which we only found in proteobacteria species. Also is conserved the PA4189 genomic neighborhood, which suggests that PA4189 participates in an uncharacterized metabolic pathway. Our results open the door to future efforts to characterize this pathway.

Prognostic Implications of Early Albuminocytological Dissociation in Guillain-Barré Syndrome.

BACKGROUND: Half of Guillain-Barré syndrome (GBS) present elevated cerebrospinal fluid (CSF) protein levels within 1 week since symptom onset and 80% within 2 weeks. Our objective was to determine the clinical and prognostic implication of albuminocytological dissociation in early GBS. METHODS: An ambispective cohort study was conducted. Good outcome was considered if the patient was able to walk unaided (Guillain-Barré disability score [GDS] ≤ 2 points) at 3-month follow-up. Patients were classified into two groups: with and without albuminocytological dissociation; we compared clinical and paraclinic characteristics between the groups. We analyzed clinical and electrophysiological factors related to presenting early dissociation through a multivariate model. RESULTS: We included 240 patients who fulfilled Asbury criteria for GBS. On further selection, only 94 patients fulfilled inclusion. Mean age was 45.94 ± 17.1 years and 67% were male. Median time from symptom onset to admission was 5 days (IQR 3-6). Regarding albuminocytological dissociation and electrophysiological variants, we found a significant difference: acute inflammatory demyelinating polyneuropathy (AIDP) [60.6% vs 26.2%, p = 0.002], acute motor axonal neuropathy (AMAN) [21.2% vs 49.1%, p = 0.009] and acute motor sensory axonal neuropathy (AMSAN) [12.1% vs 1.6%, p = 0.05]. We did not observe significant differences in recovery of independent walking in short term between both groups. The presence of conduction block in any variant (OR 3.21, 95% CI 1.12-9.16, p = 0.02) and absence of sural registration (OR 5.69, 95% CI 1.48-21.83, p = 0.011) were independent factors related to early dissociation. CONCLUSIONS: Early dissociation (<7 days) is not associated with any particular clinical feature or unfavorable outcome. It is more common to see in AIDP rather than axonal variants.

Incidence of Guillain-Barré syndrome following SARS-CoV-2 immunization: Analysis of a nationwide registry of recipients of 81 million doses of seven vaccines.

BACKGROUND AND PURPOSE: Information on Guillain-Barré syndrome (GBS) as an adverse event following immunization (AEFI) against SARS-CoV-2 remains scarce. We aimed to report GBS incidence as an AEFI among adult (≥18 years) recipients of 81,842,426 doses of seven anti-SARS-CoV-2 vaccines between December 24, 2020, and October 29, 2021, in Mexico. METHODS: Cases were retrospectively collected through passive epidemiological surveillance. The overall observed incidence was calculated according to the total number of administered doses. Vaccines were analyzed individually and by vector as mRNA-based (mRNA-1273 and BNT162b2), adenovirus-vectored (ChAdOx1 nCov-19, rAd26-rAd5, Ad5-nCoV, and Ad26.COV2-S), and inactivated whole-virion-vectored (CoronaVac) vaccines. RESULTS: We identified 97 patients (52 males [53.6%]; median [interquartile range] age 44 [33-60] years), for an overall observed incidence of 1.19/1,000,000 doses (95% confidence interval [CI] 0.97-1.45), with incidence higher among Ad26.COV2-S (3.86/1,000,000 doses, 95% CI 1.50-9.93) and BNT162b2 recipients (1.92/1,00,000 doses, 95% CI 1.36-2.71). The interval (interquartile range) from vaccination to GBS symptom onset was 10 (3-17) days. Preceding diarrhea was reported in 21 patients (21.6%) and mild COVID-19 in four more (4.1%). Only 18 patients were tested for Campylobacter jejuni (positive in 16 [88.9%]). Electrophysiological examinations were performed in 76 patients (78.4%; axonal in 46 [60.5%] and demyelinating in 25 [32.8%]); variants were similar across the platforms. On admission, 91.8% had a GBS disability score ≥3. Seventy-five patients (77.3%) received intravenous immunoglobulin, received seven plasma exchange (7.2%), and 15 (15.5%) were treated conservatively. Ten patients (10.3%) died, and 79.1% of survivors were unable to walk independently. CONCLUSIONS: Guillain-Barré syndrome was an extremely infrequent AEFI against SARS-CoV-2. The protection provided by these vaccines outweighs the risk of developing GBS.

Phosphorylation of S11 in PHR1 negatively controls its transcriptional activity.

Plant responses to phosphate starvation (-Pi) are very well characterized at the biochemical and molecular levels. The expression of thousands of genes is modified under this stress condition, depending on the action of Phosphate starvation response 1 (PHR1). Existing data indicate that neither the PHR1 transcript nor the quantity or localization of its protein increase during nutrient stress, raising the question of how its activity is regulated. Here, we present data showing that SnRK1 kinase is able to phosphorylate some phosphate starvation response proteins (PSRs), including PHR1. Based on a model of the three-dimensional structure of the catalytic subunit SnRK1α1, docking simulations predicted the binding modes of peptides from PHT1;8, PHO1 and PHR1 with SnRK1. PHR1 recombinant protein interacted in vitro with the catalytic subunits SnRK1α1 and SnRK1α2. A BiFC assay corroborated the in vivo interaction between PHR1 and SnRK1α1 in the cytoplasm and nucleus. Analysis of phosphorylated residues suggested the presence of one phosphorylated site containing the SnRK1 motif at S11, and mutation in this residue disrupted the incorporation of 32 P, suggesting that it is a major phosphorylation site. Electrophoretic mobility shift assay results indicated that the binding of PHR1 to P1BS motifs was not influenced by phosphorylation. Importantly, transient expression assays in Arabidopsis protoplasts showed a decrease in PHR1 activity in contrast with the S11A mutant, suggesting a role for Ser11 as a negative regulatory phosphorylation site. Taken together, these findings suggest that phosphorylation of PHR1 at Ser11 is a mechanism to control the PHR1-mediated adaptive response to -Pi.

Tau mis-splicing correlates with motor impairments and striatal dysfunction in a model of tauopathy.

Tauopathies are neurodegenerative diseases caused by the abnormal metabolism of the microtubule associated protein tau (MAPT), which is highly expressed in neurons and critically involved in microtubule dynamics. In the adult human brain, the alternative splicing of exon 10 in MAPT pre-mRNA produces equal amounts of protein isoforms with either three (3R) or four (4R) microtubule binding domains. Imbalance in the 3R:4R tau ratio is associated with primary tauopathies that develop atypical parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration. Yet, the development of effective therapies for those pathologies is an unmet goal. Here we report motor coordination impairments in the htau mouse model of tauopathy which harbour abnormal 3R:4R tau isoforms content, and in contrast to TauKO mice, are unresponsive to l-DOPA. Preclinical-PET imaging, array tomography and electrophysiological analyses indicated the dorsal striatum as the candidate structure mediating such phenotypes. Indeed, local modulation of tau isoforms by RNA trans-splicing in the striata of adult htau mice, prevented motor coordination deficits and restored basal neuronal firing. Together, these results suggest that abnormal striatal tau isoform content might lead to parkinsonian-like phenotypes and demonstrate a proof of concept that modulation of tau mis-splicing is a plausible disease-modifying therapy for some primary tauopathies.

Experience of a telehealth and education program with maternal and perinatal outcomes in a low-resource region in Colombia.

INTRODUCTION: Maternal morbidity and mortality rates associated with perinatal care remain a significant public health concern. Rural populations from low and middle-income countries have multiple barriers to access that contribute to a lack of adherence to prenatal care, and high rates of maternal mortality and morbidity. An intervention model based on telehealth and education was implemented between a tertiary high complex care hospital and a second-level hospital from a limited source region. OBJECTIVES: We sought to identify an association in maternal and perinatal care quality indicators after implementing a model based on telehealth and education for patients with obstetric emergencies between two hospitals in a southwestern region of Colombia. METHODS: We conducted an ecological study between 2017 and 2019 to compare before and after obstetric emergency care through telemedicine from a secondary care center (Hospital Francisco de Paula Santander-HFPS) to the referral center (Fundación Valle del Lili-FVL). The intervention included verification visits to determine the installed capacity of care, a concerted improvement plan, and on-site educational training modules in obstetric and perinatal care. RESULTS: There were 102 and 148 patients treated before and after telemedicine implementation respectively. Clinical indicators after model implementation showed a reduction in perinatal mortality of 29%. In addition, a reduction in the need for transfusion of blood products due to postpartum hemorrhage was observed as well as the rate of eclampsia. CONCLUSIONS: Implementing a model based on telehealth and education between secondary and tertiary care centers allowed the strengthening of the security of care in obstetric emergencies and had a positive effect on perinatal mortality.

Very low peroneal nerve compound muscle action potential amplitude predicts poor outcome in patients with Guillain-Barré syndrome: a prospective cohort.

INTRODUCTION: Twenty percent of patients with Guillain-Barré syndrome (GBS) have poor outcomes despite proper management. The aim of the study was to characterize electrophysiological factors related to poor outcome in patients with GBS. METHODS: We conducted an observational study from a prospective cohort of 91 patients with GBS in a tertiary healthcare center in Mexico, from 2017 to 2019. Demographics and nerve conduction studies were performed on admission, and a 3-month follow-up for GBS disability score was ensued, allocating patients in good (GBS disability score ≤ 2) and poor outcome (GBS disability score ≥ 3) groups. A logistic regression analysis for independent walk at 3 months was performed. Kaplan-Meier estimator curves for independent walk in very low (< 20% LLN) and low-normal ( ≥20% LLN) peroneal nerve CMAPs are presented. RESULTS: From the 91 GBS patients included, 37 (40.6%) did not regain independent walk at 3 months. Axonal variants were more common in the poor outcome group (31.4% vs 59.4%, p = 0.01) as well as AIDP variants with motor conduction block (6.6% vs 42.4%, p = 0.018). Univariable analysis was statistically significant for very low median, ulnar, tibial, and peroneal CMAP amplitudes in poor outcome patients; however, multivariable analysis was only significant for very low peroneal nerve CMAP amplitude (OR 3.6 [1.1-11.5, p = 0.024]). Conversely, a greater proportion of GBS patients with low-normal CMAPs recovered independent walk at 90 days (75% vs 30%, p < 0.001). CONCLUSION: Severe axonal injury of the peroneal nerve, axonal, and AIDP with motor conduction block variants predicts worse functional outcome regarding independent walk at 3 months.

Desorption of Coffee Pulp Used as an Adsorbent Material for Cr(III and VI) Ions in Synthetic Wastewater: A Preliminary Study.

Some of the diverse agro-industrial waste generated in primary or secondary stages have proved to be promising biomaterials for treating aqueous effluents contaminated, in this case, with heavy metals. Therefore, it is necessary to know their optimal operating conditions and the regeneration or reusability of the solid by-product, an aspect related to desorption. Considering the above, this article presents the findings of a preliminary study related to the desorption process of coffee pulp without physicochemical modification (Castilla variety), an agricultural waste used as a sorbent of Cr(III and VI) ions in synthetic wastewater. The desorption efficiency of four eluting agents at defined concentrations (0.10M)-HC1, HNO3, H2SO4, and EDTA-was evaluated in a time interval of 1 to 9 days. Likewise, the proposals for the sorption and/or desorption mechanisms proposed and reported in the literature with respect to the use of biosorbents derived from the coffee crop are presented. With respect to the results, the coffee pulp used in previous studies of the adsorption of chromium species mentioned (optimal conditions in synthetic water of particle size 180 µm, dose 20 g·L-1, agitation 100 RPM, room temperature, time of 90 to 105 min) showed efficiencies in the removal of Cr(III) and Cr(VI) of 93.26% and 74.80%, respectively. Regarding the extracting substances used, H2SO4 0.10 M was the one that presented the highest desorption percentage in both chromic species, with a desorption of 45.75% Cr(VI) and 66.84% Cr(III) in periods of 5 and 9 days, respectively, with agitation of 100 RPM and room temperature. Finally, the dissemination of preliminary results on the desorption of coffee pulp contaminated with chromic species without physicochemical modification is novel in this study, as similar work with this specific material has not yet been reported in the literature. On the other hand, the limitations of the study and future research are related to the evaluation at different concentrations and of other extractor solutions that allow improving the efficiency of desorption of these chemical species in a shorter time from the coffee pulp (with and without modification) as well as the reuse cycles. As a result, the desorption of coffee pulp used as an adsorbent material in real water could help researchers identify the possible interfering factors that affect the process (foreign anions and cations, organic matter, environmental conditions, among others).

Guillain-Barré syndrome is infrequent among recipients of the BNT162b2 mRNA COVID-19 vaccine.

Vaccines are the most effective strategy to mitigate the global impact of COVID-19. However, vaccine hesitancy is common, particularly among minorities. Guillain-Barré syndrome (GBS) is the most common autoimmune illness of the peripheral nervous system, occurring at an incidence of 1.1/100,000 worldwide. A causal link between mRNA vaccines and GBS has not been previously evaluated. We analyzed a cohort of 3,890,250 Hispanic/Latinx recipients of the BNT162b2 mRNA vaccine (613,780 of whom had already received both doses) for incident GBS occurring within 30 days from vaccine administration. Seven cases of GBS were detected among first-dose recipients, for an observed incidence of 0.18/100,000 administered doses during the prespecified timeframe of 30 days. No cases were reported after second-dose administration. Our data suggest that, among recipients of the BNT162b2 mRNA vaccine, GBS may occur at the expected community-based rate; however, this should be taken with caution as the current incidence of GBS among the unvaccinated population against COVID-19 is still undetermined. We hope that this preliminary data will increase the public perception of safety toward mRNA-based vaccines and reduce vaccine hesitancy.

Neurologic adverse events among 704,003 first-dose recipients of the BNT162b2 mRNA COVID-19 vaccine in Mexico: A nationwide descriptive study.

mRNA vaccines against SARS-CoV-2 are remarkably effective. Limited information exists about the incidence of adverse events following immunization (AEFI) with their use. We conducted a prospective observational study including data from 704,003 first-doses recipients; 6536 AEFI were reported, of whom 65.1% had at least one neurologic AEFI (non-serious 99.6%). Thirty-three serious events were reported; 17 (51.5%) were neurologic (observed frequency, 2.4/100,000 doses). At the time of writing this report, 16/17 cases had been discharged without deaths. Our data suggest that the BNT162b2 mRNA COVID-19 vaccine is safe; its individual and societal benefits outweigh the low percentage of serious neurologic AEFI. This information should help to dissipate hesitancy towards this new vaccine platform.

Lifestyle factors, diet and attention-deficit/hyperactivity disorder in Spanish children - an observational study.

Background: The aetiology of Attention Deficit Hyperactivity Disorder (ADHD) continues to be debated, although several contributing factors have been acknowledged.Objective: Assess the association between weight, birth attributes, exercise and sleep habits, dietary intake and adherence to a Mediterranean diet, and impulsive behaviour on Spanish ADHD children. Establish whether specific food groups (not just adherence to the Mediterranean diet) associate with impulsive behaviour.Methods: This observational cross-sectional study included 57 ADHD children from Madrid (Spain). Demographic, clinical data, sleep, exercise and technology-use habits were obtained. Anthropometric measurements included height and weight. Adherence to the Mediterranean diet was assessed using the KIDMED test. Barratt Impulsivity Scale version-11c was used to assess impulsivity. Subjects were divided into three groups for analysis, according to their age (6-10 years, children; 11-13 years, pre-adolescents; 14-16 years, adolescents).Results: There were clear associations between those who had higher BIS scores and who slept less at weekends (49.4 ± 10.16 vs. 43.8 ± 12.51), who adhered poorly to the Mediterranean diet (49.9 ± 11.72 vs. 41.6 ± 16.52), who used internet and technological devices for >3 h/day (45.5 ± 13.6 vs. 44.7 ± 12.11), who were born with >2.5 kg (46.1 ± 11.61 vs. 42.9 ± 15.29), who were delivered by caesarean (45.1 ± 12.78 vs. 44.7 ± 12.5) and who were not breastfed (45.0 ± 13.38 vs. 44.8 ± 12.39). Subjects exercising more than 3 days a week also scored slightly higher (45.4±14.02 vs. 44.6±11.85) in the BIS.Conclusion: There is a need to follow up the link between ADHD and sleep onset difficulties, dietary patterns, technological habits, perinatal factors, breastfeeding and birth delivery mode.

Effect of Helicobacter pylori and Helminth Coinfection on the Immune Response to Mycobacterium tuberculosis.

Tuberculosis remains one of the main causes of morbidity and mortality worldwide despite decades of efforts to eradicate the disease. Although the immune response controls the infection in most infected individuals (90%), the ability of the bacterium to persist throughout the host's life leads to a risk of reactivation. Underlying conditions including human immunodeficiency virus (HIV) infection, organ transplantation, and immunosuppressive therapies are considered risk factors for progression to active disease. However, many individuals infected with Mycobacterium tuberculosis may develop clinical disease in the absence of underlying immunosuppression. It is also possible that unknown conditions may drive the progression to disease. The human microbiota can be an important modulator of the immune system; it can not only trigger inflammatory disorders, but also drive the response to other infectious diseases. In developing countries, chronic mucosal infections with Helicobacter pylori and helminths may be particularly important, as these infections frequently coexist throughout the host's life. However, little is known about the interactions of these pathogens with the immune system and their effects on M. tuberculosis clinical disease, if any. In this review, we discuss the potential effects of H. pylori and helminth co-infections on the immune response to M. tuberculosis. This may contribute to our understanding of host-pathogen interactions and in designing new strategies for the prevention and control of tuberculosis.

Structural and biochemical evidence of the glucose 6-phosphate-allosteric site of maize C4-phosphoenolpyruvate carboxylase: its importance in the overall enzyme kinetics.

Activation of phosphoenolpyruvate carboxylase (PEPC) enzymes by glucose 6-phosphate (G6P) and other phospho-sugars is of major physiological relevance. Previous kinetic, site-directed mutagenesis and crystallographic results are consistent with allosteric activation, but the existence of a G6P-allosteric site was questioned and competitive activation-in which G6P would bind to the active site eliciting the same positive homotropic effect as the substrate phosphoenolpyruvate (PEP)-was proposed. Here, we report the crystal structure of the PEPC-C4 isozyme from Zea mays with G6P well bound into the previously proposed allosteric site, unambiguously confirming its existence. To test its functionality, Asp239-which participates in a web of interactions of the protein with G6P-was changed to alanine. The D239A variant was not activated by G6P but, on the contrary, inhibited. Inhibition was also observed in the wild-type enzyme at concentrations of G6P higher than those producing activation, and probably arises from G6P binding to the active site in competition with PEP. The lower activity and cooperativity for the substrate PEP, lower activation by glycine and diminished response to malate of the D239A variant suggest that the heterotropic allosteric activation effects of free-PEP are also abolished in this variant. Together, our findings are consistent with both the existence of the G6P-allosteric site and its essentiality for the activation of PEPC enzymes by phosphorylated compounds. Furthermore, our findings suggest a central role of the G6P-allosteric site in the overall kinetics of these enzymes even in the absence of G6P or other phospho-sugars, because of its involvement in activation by free-PEP.

A Review of Caffeine Adsorption Studies onto Various Types of Adsorbents.

A systematic literature review of publications from 2000 to 2020 was carried out to identify research trends on adsorbent materials for the removal of caffeine from aqueous solutions. Publications were retrieved from three databases (Scopus, Web of Science, and Google Scholar). Words "adsorption AND caffeine" were examined into titles, abstracts, and keywords. A brief bibliometric analysis was performed with emphasis on the type of publication and of most cited articles. Materials for the removal of caffeine were classified according to the type of material into three main groups: organic, inorganic, and composites, each of them subdivided into different subgroups consistent with their origin or production. Tables resume for each subgroup of adsorbents the key information: specific surface area, dose, pH, maximum adsorption capacity, and isotherm models for the removal of caffeine. The highest adsorption capacities were achieved by organic adsorbents, specifically those with granular activated carbon (1961.3 mg/g) and grape stalk activated carbon (916.7 mg/g). Phenyl-phosphate-based porous organic polymer (301 mg/g), natural sandy loam sediment (221.2 mg/g), composites of MCM-48 encapsulated graphene oxide (153.8 mg/g), and organically modified clay (143.7 mg/g) showed adsorption capacities lower than those of activated carbons. In some activated carbons, a relation between the specific surface area (SSA) and the maximum adsorption capacity (Q max) was found.

Diagnostic performance of two different maternal near-miss approaches in a High Obstetric Risk Unit.

Maternal near-miss (MNM) is a maternal quality care indicator. The World Health Organization (WHO) defines it as a state in which a woman nearly dies but survives due to a complication during pregnancy, birth, or puerperium. The Latin American Federation of Obstetrics and Gynecology (FLASOG) and the Colombian National Health Institute (INS) established recommendations for the event's epidemiological surveillance; nonetheless, the operational definitions of the cases are different. This retrospective study examined the approaches of FLASOG and INS versus the WHO approach (gold standard) for the assessment of MNM in a high obstetric risk unit. Patients admitted with at least one criterion of the WHO, FLASOG, or INS approach for the definition of MNM from March 2016 to March 2017 were included. Sensitivity, specificity, positive and negative predictive value (PPV, NPV) were evaluated, as well as the Receiver Operating Characteristics (ROC) curve of the FLASOG and INS. MNM classification compared to WHO system as reference. The results highlight that the WHO classification establishes very high boundaries for some of the diagnostic criteria and the lack of standardization of the MNM criteria among the different proposals in Latin America hinders the applicability in Colombia and other countries with a similar situation.

Heat stress influence the microbiota and organic acids concentration in beef cattle rumen.

The objective of this study was to evaluate the effect of heat stress on meta-taxonomic and metabolic profiles of prokaryotes in beef cattle rumen. Six pure-breed Nellore heifers with ruminal cannulas were used in the study. Six treatments were tested in a 6 × 6 Latin Square with six periods of 21days. The treatments were evaluated in a 2 × 2 + 2 factorial arrangement, consisting of 4 combinations: two temperatures conditions (thermoneutral, TN: 24 °C; and heat stress, HS: 34 °C) and two dietary energy concentration [low-energy (37% non-fibrous carbohydrates - NFC, 12 Mcal of metabolizable energy per kg of dry matter) or high-energy concentration (50.5% NFC, 18.49 Mcal of metabolizable energy per kg of dry matter)] plus two additional treatments with animals maintained in TN conditions but with your intake restricted (TN-RI) to the same of the heifers in HS with the two dietary energy concentration. The meta-genome was sequenced by MiSeq Sequencing System platform, and the DNA sequences were analysed using Geneious 10.2.3 software. The metabolic profile was evaluated by liquid and gas chromatography. Animals under HS presented lower (P = 0.04) prokaryote richness than animals under TN conditions. The genera Flavonifractor (1.4%), Treponema (0.6%) and Ruminococcus (0.9%) showed the lowest (P < 0.04) and Carnobacterium (7.7%) the highest (P = 0.02) relative abundance when the animals were submitted to HS, in relation to animals in TN. A total of 49 different metabolites were identified in the ruminal samples. The concentration of isobutyric acid (4.32 mM) was highest in bovine rumen under HS conditions. Heat stress influenced the microbiota and concentration of some organic acids in beef cattle rumen. There was a reduction in the richness of rumen in cattle under heat stress, but the diversity of prokaryotes was not affected.

A Small Step, a Giant Leap: Somatic Hypermutation of a Single Amino Acid Leads to Anti-La Autoreactivity.

The anti-La mab 312B, which was established by hybridoma technology from human-La transgenic mice after adoptive transfer of anti-human La T cells, immunoprecipitates both native eukaryotic human and murine La protein. Therefore, it represents a true anti-La autoantibody. During maturation, the anti-La mab 312B acquired somatic hypermutations (SHMs) which resulted in the replacement of four aa in the complementarity determining regions (CDR) and seven aa in the framework regions. The recombinant derivative of the anti-La mab 312B in which all the SHMs were corrected to the germline sequence failed to recognize the La antigen. We therefore wanted to learn which SHM(s) is (are) responsible for anti-La autoreactivity. Humanization of the 312B ab by grafting its CDR regions to a human Ig backbone confirms that the CDR sequences are mainly responsible for anti-La autoreactivity. Finally, we identified that a single amino acid replacement (D > Y) in the germline sequence of the CDR3 region of the heavy chain of the anti-La mab 312B is sufficient for anti-La autoreactivity.

And Yet It Moves: Oxidation of the Nuclear Autoantigen La/SS-B Is the Driving Force for Nucleo-Cytoplasmic Shuttling.

Decades ago, we and many other groups showed a nucleo-cytoplasmic translocation of La protein in cultured cells. This shuttling of La protein was seen after UV irradiation, virus infections, hydrogen peroxide exposure and the Fenton reaction based on iron or copper ions. All of these conditions are somehow related to oxidative stress. Unfortunately, these harsh conditions could also cause an artificial release of La protein. Even until today, the shuttling and the cytoplasmic function of La/SS-B is controversially discussed. Moreover, the driving mechanism for the shuttling of La protein remains unclear. Recently, we showed that La protein undergoes redox-dependent conformational changes. Moreover, we developed anti-La monoclonal antibodies (anti-La mAbs), which are specific for either the reduced form of La protein or the oxidized form. Using these tools, here we show that redox-dependent conformational changes are the driving force for the shuttling of La protein. Moreover, we show that translocation of La protein to the cytoplasm can be triggered in a ligand/receptor-dependent manner under physiological conditions. We show that ligands of toll-like receptors lead to a redox-dependent shuttling of La protein. The shuttling of La protein depends on the redox status of the respective cell type. Endothelial cells are usually resistant to the shuttling of La protein, while dendritic cells are highly sensitive. However, the deprivation of intracellular reducing agents in endothelial cells makes endothelial cells sensitive to a redox-dependent shuttling of La protein.