Imaging spatiotemporal translation regulation in vivo.

Translation is regulated spatiotemporally to direct protein synthesis when and where it is needed. RNA localization and local translation have been observed in various subcellular compartments, allowing cells to rapidly and finely adjust their proteome post-transcriptionally. Local translation on membrane-bound organelles is important to efficiently synthesize proteins targeted to the organelles. Protein-RNA phase condensates restrict RNA spatially in membraneless organelles and play essential roles in translation regulation and RNA metabolism. In addition, the temporal translation kinetics not only determine the amount of protein produced, but also serve as an important checkpoint for the quality of ribosomes, mRNAs, and nascent proteins. Translation imaging provides a unique capability to study these fundamental processes in the native environment. Recent breakthroughs in imaging enabled real-time visualization of translation of single mRNAs, making it possible to determine the spatial distribution and key biochemical parameters of in vivo translation dynamics. Here we reviewed the recent advances in translation imaging methods and their applications to study spatiotemporal translation regulation in vivo.

Distribution and molecular evolution of the anti-CRISPR family AcrIF7.

Anti-clustered regularly interspaced short palindromic repeats (CRISPRs) are proteins capable of blocking CRISPR-Cas systems and typically their genes are located on mobile genetic elements. Since their discovery, numerous anti-CRISPR families have been identified. However, little is known about the distribution and sequence diversity of members within a family, nor how these traits influence the anti-CRISPR's function and evolution. Here, we use AcrIF7 to explore the dissemination and molecular evolution of an anti-CRISPR family. We uncovered 5 subclusters and prevalent anti-CRISPR variants within the group. Remarkably, AcrIF7 homologs display high similarity despite their broad geographical, ecological, and temporal distribution. Although mainly associated with Pseudomonas aeruginosa, AcrIF7 was identified in distinct genetic backgrounds indicating horizontal dissemination, primarily by phages. Using mutagenesis, we recreated variation observed in databases but also extended the sequence diversity of the group. Characterisation of the variants identified residues key for the anti-CRISPR function and other contributing to its mutational tolerance. Moreover, molecular docking revealed that variants with affected function lose key interactions with its CRISPR-Cas target. Analysis of publicly available data and the generated variants suggests that the dominant AcrIF7 variant corresponds to the minimal and optimal anti-CRISPR selected in the family. Our study provides a blueprint to investigate the molecular evolution of anti-CRISPR families.

Virome analysis of Desmodus rotundus tissue samples from the Amazon region.

BACKGROUND: Bats are renowned for harboring a high viral diversity, their characteristics contribute to emerging infectious diseases. However, environmental and anthropic factors also play a significant role in the emergence of zoonotic viruses. Metagenomic is an important tool for investigating the virome of bats and discovering new viruses. RESULTS: Twenty-four families of virus were detected in lung samples by sequencing and bioinfomatic analysis, the largest amount of reads was focused on the Retroviridae and contigs assembled to Desmodus rotundus endogenous retrovirus, which was feasible to acquire complete sequences. The reads were also abundant for phages. CONCLUSION: This lung virome of D. rotundus contributes valuable information regarding the viral diversity found in bats, which is useful for understanding the drivers of viral cycles and their ecology in this species. The identification and taxonomic categorization of viruses hosted by bats carry epidemiological significance due to the potential for viral adaptation to other animals and humans, which can have severe repercussions for public health. Furthermore, the characterization of endogenized viruses helps to understanding the host genome and the evolution of the species.

Paralog editing tunes rice stomatal density to maintain photosynthesis and improve drought tolerance.

Rice (Oryza sativa) is of paramount importance for global nutrition, supplying at least 20% of global calories. However, water scarcity and increased drought severity are anticipated to reduce rice yields globally. We explored stomatal developmental genetics as a mechanism for improving drought resilience in rice while maintaining yield under climate stress. CRISPR/Cas9-mediated knockouts of the positive regulator of stomatal development STOMAGEN and its paralog EPIDERMAL PATTERNING FACTOR-LIKE10 (EPFL10) yielded lines with ∼25% and 80% of wild-type stomatal density, respectively. epfl10 lines with moderate reductions in stomatal density were able to conserve water to similar extents as stomagen lines but did not suffer from the concomitant reductions in stomatal conductance, carbon assimilation, or thermoregulation observed in stomagen knockouts. Moderate reductions in stomatal density achieved by editing EPFL10 present a climate-adaptive approach for safeguarding yield in rice. Editing the paralog of STOMAGEN in other species may provide a means for tuning stomatal density in agriculturally important crops beyond rice.

Toward Understanding How Staphylococcal Protein A Inhibits IgG-Mediated Phagocytosis.

IgG molecules are crucial for the human immune response against bacterial infections. IgGs can trigger phagocytosis by innate immune cells, like neutrophils. To do so, IgGs should bind to the bacterial surface via their variable Fab regions and interact with Fcγ receptors and complement C1 via the constant Fc domain. C1 binding to IgG-labeled bacteria activates the complement cascade, which results in bacterial decoration with C3-derived molecules that are recognized by complement receptors on neutrophils. Next to FcγRs and complement receptors on the membrane, neutrophils also express the intracellular neonatal Fc receptor (FcRn). We previously reported that staphylococcal protein A (SpA), a key immune-evasion protein of Staphylococcus aureus, potently blocks IgG-mediated complement activation and killing of S. aureus by interfering with IgG hexamer formation. SpA is also known to block IgG-mediated phagocytosis in absence of complement, but the mechanism behind it remains unclear. In this study, we demonstrate that SpA blocks IgG-mediated phagocytosis and killing of S. aureus and that it inhibits the interaction of IgGs with FcγRs (FcγRIIa and FcγRIIIb, but not FcγRI) and FcRn. Furthermore, our data show that multiple SpA domains are needed to effectively block IgG1-mediated phagocytosis. This provides a rationale for the fact that SpA from S. aureus contains four to five repeats. Taken together, our study elucidates the molecular mechanism by which SpA blocks IgG-mediated phagocytosis and supports the idea that in addition to FcγRs, the intracellular FcRn is also prevented from binding IgG by SpA.

Citizens from 13 countries share similar preferences for COVID-19 vaccine allocation priorities.

How does the public want a COVID-19 vaccine to be allocated? We conducted a conjoint experiment asking 15,536 adults in 13 countries to evaluate 248,576 profiles of potential vaccine recipients who varied randomly on five attributes. Our sample includes diverse countries from all continents. The results suggest that in addition to giving priority to health workers and to those at high risk, the public favors giving priority to a broad range of key workers and to those with lower income. These preferences are similar across respondents of different education levels, incomes, and political ideologies, as well as across most surveyed countries. The public favored COVID-19 vaccines being allocated solely via government programs but were highly polarized in some developed countries on whether taking a vaccine should be mandatory. There is a consensus among the public on many aspects of COVID-19 vaccination, which needs to be taken into account when developing and communicating rollout strategies.

Staphylococcal protein A inhibits complement activation by interfering with IgG hexamer formation.

Immunoglobulin (Ig) G molecules are essential players in the human immune response against bacterial infections. An important effector of IgG-dependent immunity is the induction of complement activation, a reaction that triggers a variety of responses that help kill bacteria. Antibody-dependent complement activation is promoted by the organization of target-bound IgGs into hexamers that are held together via noncovalent Fc-Fc interactions. Here we show that staphylococcal protein A (SpA), an important virulence factor and vaccine candidate of Staphylococcus aureus, effectively blocks IgG hexamerization and subsequent complement activation. Using native mass spectrometry and high-speed atomic force microscopy, we demonstrate that SpA blocks IgG hexamerization through competitive binding to the Fc-Fc interaction interface on IgG monomers. In concordance, we show that SpA interferes with the formation of (IgG)6:C1q complexes and prevents downstream complement activation on the surface of S. aureus. Finally, we demonstrate that IgG3 antibodies against S. aureus can potently induce complement activation and opsonophagocytic killing even in the presence of SpA. Together, our findings identify SpA as an immune evasion protein that specifically blocks IgG hexamerization.

Evaluation of Multiple RNA Extraction Protocols for Chikungunya Virus Screening in Aedes aegypti Mosquitoes.

Chikungunya virus (Togaviridae, Alphavirus; CHIKV) is a mosquito-borne global health threat. The main urban vector of CHIKV is the Aedes aegypti mosquito, which is found throughout Brazil. Therefore, it is important to carry out laboratory tests to assist in the virus's diagnosis and surveillance. Most molecular biology methodologies use nucleic acid extraction as the first step and require quality RNA for their execution. In this context, four RNA extraction protocols were evaluated in Ae. aegypti experimentally infected with CHIKV. Six pools were tested in triplicates (n = 18), each containing 1, 5, 10, 20, 30, or 40 mosquitoes per pool (72 tests). Four commercial kits were compared: QIAamp®, Maxwell®, PureLink®, and PureLink® with TRIzol®. The QIAamp® and PureLink® with TRIzol® kits had greater sensitivity. Two negative correlations were observed: as the number of mosquitoes per pool increases, the Ct value decreases, with a higher viral load. Significant differences were found when comparing the purity and concentration of RNA. The QIAamp® protocol performed better when it came to lower Ct values and higher RNA purity and concentration. These results may provide help in CHIKV entomovirological surveillance planning.

Five years after the collapse of the Fundão Dam: lessons from temporal monitoring of chemistry and acute toxicity.

In November 2015, the Fundão Dam break released millions of tons of metal-rich tailings into the Doce River Basin (DRB), causing catastrophic damage and potential ecological effects that reached the Atlantic Ocean. This study aimed to evaluate the geochemistry and toxicity of water and sediments collected in the DRB from 2015 to 2019 and to determine the spatial and temporal trends. Water and sediment samples were analyzed for metals and As by inductively coupled plasma optical emission spectrometry (ICP-OES), and acute toxicity for Daphnia similis or D. magna. Results were explored using geochemical indices and correlation analyzes. Overall, higher concentrations of metals and As in water and sediments were observed immediately after dam breakage, but the levels exhibited a decreasing trend over time, although the levels of some elements such as As and Mn remained high in the upper DRB. The geochemical indices indicated mostly low to moderate contamination, and the enrichment factor (EF) demonstrated a higher enrichment of Mn in the upper DRB. Acute toxicity to water fleas (D. similis and D. magna) was occasionally observed in waters and sediments, but the reference samples were toxic, and the short-term effects were not correlated with metals and As. Overall, the results showed limited bioavailability of metals and As and a decreasing trend in their concentrations, indicating an ongoing recovery process in DRB. These results are important to decision-making regarding the disaster and actions for environmental restoration.

Intake and digestibility of four rations with different fiber levels in alpacas (Vicugna pacos).

The aim of this study was to evaluated the impact of different fibre levels in alpaca diet on voluntary feed intake and apparent digestibility, and to estimate the digestibility of organic matter (OMD) from the content of crude protein (CP) in feces. The study was carried out with twelve alpacas (36.7 ± 6.4 kg body weight- BW), which were offered 4 treatments with different neutral detergent fiber content (NDF. T1: 40.3%; T2: 62%; T3: 68%; T4: 72%) under a switch back design. Absolute daily dry matter intake (DMI) was higher for T1 (678 g/d) than T4 (312 g/d) (p ≥ 005). NDF intake was similar between treatments when related to BW or MW (on average 1% BW and 22 g/kg MW. p ≥ 0.05). Water intake (L/kg DMI) was higher in T1 compared to the other treatments, with values ranging from 2.9 L/kg DMI(T1) to 2.8 L/kg DMI(T4), respectively (p ≤ 0.05). Digestibility of dry matter, organic matter and CP was higher in T1 than in the other treatments, with average values ranging from 72% for T1 to 32% for T4 (p ≤ 0.05). NDF digestibility was similar among treatments (p ≥ 0.05). The regression equation generated to predict OMD (y) was as follows: y = 0.360 + 0.08294*fecal CP (g/kg OM). Further studies will indicate whether faecal nitrogen can be used to estimate digestibility and hence diet quality in South American camelids.

Decreased Hepatic and Serum Levels of IL-10 Concur with Increased Lobular Inflammation in Morbidly Obese Patients.

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. Accumulating evidence in animal models suggests that loss of interleukin-10 (IL-10) anti-inflammatory actions might contribute to lobular inflammation, considered one of the first steps toward NASH development. However, the role of IL-10 in lobular inflammation remains poorly explored in humans. We examined mRNA and protein levels of IL-10 in liver biopsies and serum samples from morbidly obese patients, investigating the relationship between IL-10 and lobular inflammation degree. Materials and Methods: We prospectively enrolled morbidly obese patients of both sexes, assessing the lobular inflammation grade by the Brunt scoring system to categorize participants into mild (n = 7), moderate (n = 19), or severe (n = 13) lobular inflammation groups. We quantified the hepatic mRNA expression of IL-10 by quantitative polymerase chain reaction and protein IL-10 levels in liver and serum samples by Luminex Assay. We estimated statistical differences by one-way analysis of variance (ANOVA) and Tukey's multiple comparison test. Results: The hepatic expression of IL-10 significantly diminished in patients with severe lobular inflammation compared with the moderate lobular inflammation group (p = 0.01). The hepatic IL-10 protein levels decreased in patients with moderate or severe lobular inflammation compared with the mild lobular inflammation group (p = 0.008 and p = 0.0008, respectively). In circulation, IL-10 also significantly decreased in subjects with moderate or severe lobular inflammation compared with the mild lobular inflammation group (p = 0.005 and p < 0.0001, respectively). Conclusions: In liver biopsies and serum samples of morbidly obese patients, the protein levels of IL-10 progressively decrease as lobular inflammation increases, supporting the hypothesis that lobular inflammation develops because of the loss of the IL-10-mediated anti-inflammatory counterbalance.

Intravenous Vitamin C as an Add-on Therapy for the Treatment of Sepsis in an Intensive Care Unit: A Prospective Cohort Study.

Background and Objectives: According to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), sepsis is defined as "life-threatening organ dysfunction caused by a dysregulated host response to infection". The increased presence of free radicals causes an increase in oxidative stress. Vitamin C is an essential water-soluble vitamin with antioxidant activity and immunoregulatory effects that plays a potential role in the treatment of bacterial infections. Our aim was to evaluate the effectiveness of adding vitamin C to the conventional treatment of sepsis to decrease its mortality rate. Materials and Methods: In a prospective cohort study, we included patients with a diagnosis of sepsis and a SOFA score ≥ 9 who were evaluated in an Intensive Care Unit at a secondary-care hospital. According to the intensive care specialist, they were treated using two different strategies: Group 1-patients with sepsis treated with conventional treatment without vitamin C; Group 2-patients with sepsis with the addition of vitamin C to conventional treatment. Results: We included 34 patients with sepsis. The incidence of mortality was 38%, and 47% of patients used vitamin C as an adjuvant to the basic treatment of sepsis. In the basal analyses, patients treated with use of vitamin C compared to patients treated without vitamin C required less use of glucocorticoids (75% vs. 100%, p = 0.039). At follow-up, patients treated without vitamin C had higher mortality than patients treated with vitamin C as an adjuvant for the treatment of sepsis (55.6% vs. 18.8%, p = 0.03). We observed that the use of vitamin C was a protective factor for mortality in patients with sepsis (RR: 0.54, 95% CI: 0.31-0.96, p = 0.03). Conclusions: The use of vitamin C as an adjuvant to treatment decreases the risk of mortality by 46% in patients with sepsis and SOFA ≥ 9 compared to patients treated without vitamin C as an adjuvant to sepsis.

Risk Factors for Nontuberculous Mycobacteria Infections in Solid Organ Transplant Recipients: A Multinational Case-Control Study.

BACKGROUND: Risk factors for nontuberculous mycobacteria (NTM) infections after solid organ transplant (SOT) are not well characterized. Here we aimed to describe these factors. METHODS: Retrospective, multinational, 1:2 matched case-control study that included SOT recipients ≥12 years old diagnosed with NTM infection from 1 January 2008 to 31 December 2018. Controls were matched on transplanted organ, NTM treatment center, and post-transplant survival greater than or equal to the time to NTM diagnosis. Logistic regression on matched pairs was used to assess associations between risk factors and NTM infections. RESULTS: Analyses included 85 cases and 169 controls (59% male, 88% White, median age at time of SOT of 54 years [interquartile range {IQR} 40-62]). NTM infection occurred in kidney (42%), lung (35%), heart and liver (11% each), and pancreas transplant recipients (1%). Median time from transplant to infection was 21.6 months (IQR 5.3-55.2). Most underlying comorbidities were evenly distributed between groups; however, cases were older at the time of NTM diagnosis, more frequently on systemic corticosteroids and had a lower lymphocyte count (all P < .05). In the multivariable model, older age at transplant (adjusted odds ratio [aOR] 1.04; 95 confidence interval [CI], 1.01-1.07), hospital admission within 90 days (aOR, 3.14; 95% CI, 1.41-6.98), receipt of antifungals (aOR, 5.35; 95% CI, 1.7-16.91), and lymphocyte-specific antibodies (aOR, 7.73; 95% CI, 1.07-56.14), were associated with NTM infection. CONCLUSIONS: Risk of NTM infection in SOT recipients was associated with older age at SOT, prior hospital admission, receipt of antifungals or lymphocyte-specific antibodies. NTM infection should be considered in SOT patients with these risk factors.

Reemergence of Dengue Virus Serotype 3, Brazil, 2023.

We characterized 3 autochthonous dengue virus serotype 3 cases and 1 imported case from 2 states in the North and South Regions of Brazil, 15 years after Brazil's last outbreak involving this serotype. We also identified a new Asian lineage recently introduced into the Americas, raising concerns about future outbreaks.

Performance of the beta-glucan test for the diagnosis of invasive fusariosis and scedosporiosis: a meta-analysis.

The (1→3)-ß-D-glucan (BDG) is a component of the fungal cell wall that can be detected in serum and used as an adjunctive tool for the diagnosis of invasive mold infections (IMI) in patients with hematologic cancer or other immunosuppressive conditions. However, its use is limited by modest sensitivity/specificity, inability to differentiate between fungal pathogens, and lack of detection of mucormycosis. Data about BDG performance for other relevant IMI, such as invasive fusariosis (IF) and invasive scedosporiosis/lomentosporiosis (IS) are scarce. The objective of this study was to assess the sensitivity of BDG for the diagnosis of IF and IS through systematic literature review and meta-analysis. Immunosuppressed patients diagnosed with proven or probable IF and IS, with interpretable BDG data were eligible. A total of 73 IF and 27 IS cases were included. The sensitivity of BDG for IF and IS diagnosis was 76.7% and 81.5%, respectively. In comparison, the sensitivity of serum galactomannan for IF was 27%. Importantly, BDG positivity preceded the diagnosis by conventional methods (culture or histopathology) in 73% and 94% of IF and IS cases, respectively. Specificity was not assessed because of lacking data. In conclusion, BDG testing may be useful in patients with suspected IF or IS. Combining BDG and galactomannan testing may also help differentiating between the different types of IMI.

IF and IS are severe fungal infections for which diagnosis is often delayed. This meta-analysis shows that beta-glucan testing in serum had a sensitivity of about 80% for IF/IS and could detect the disease earlier compared to conventional diagnostic tests.

Role of indigenous microorganisms and organics in the release of iron and trace elements from sediments impacted by iron mine tailings from failed Fundão dam.

After Fundão Dam failure in 2015, most of Gualaxo do Norte River in Doce River Basin in Brazil became silted by iron mining tailings consisting mainly of fine-grained quartz, hematite, and goethite. Previous work pointed to the possibility of reductive dissolution of iron and manganese from tailings, leading to mobilization of iron, manganese and trace elements. Several microorganisms were shown to reduce Fe(III) to Fe(II) and Mn(III, IV) to Mn(II) "in vitro", but their roles in mobilization of Fe and trace elements from freshwater sediments are poorly understood. In this work, bottom sediments and water collected in Gualaxo do Norte River were used to build anoxic microcosms amended with acetate, glucose or yeast extract, in order to access if heterotrophic microorganisms, either fermenters or dissimilatory Fe reducers, could reduce Fe(III) from minerals in the sediments to soluble Fe(II), releasing trace elements. The Fe(II) concentrations were measured over time, and trace elements concentrations were evaluated at the end of the experiment. In addition, minerals and biopolymers in bottom sediments were quantified. Results showed that organic substrates, notably glucose, fuelled microbial reduction of iron minerals and release of Fe(II), Mn, Ba, Al and/or Zn from sediments. In general, higher concentrations of organic substrates elicited mobilization of larger amounts of Fe(II) and trace elements from sediments. The results point to the possibility of mobilization of huge amounts of iron and trace elements from sediments to water if excess biodegradable organic matter is released in rivers affected by iron mine tailings.

Association of personal, behavioral and positive psychological variables with somatization and number of diseases in Mexican general population: the influence of gender.

The objective of the study is to determine the personal, behavioral and psychological variables associated with somatization and the number of diseases in each gender from a sample of Mexican general population. They answered a questionnaire of behavioral and psychological variables including somatization and the sum of 16 different diseases and any additional one, finally the body mass index (BMI) was measured. A total of 164 participants (women = 90, men = 74) were included. We observed that women had more somatization and number of diseases than men and that more variables (mainly psychological) were associated with somatization and with the number of diseases in women than in men. Among the variables most negatively correlated in women with both variables were sleep quality (r = -0.525 and r = -0.536, p < 0.001), self-acceptance (r = -0.460 and r = -0.501, p < 0.001), positive relations with others (r = -0.447 and r = -0.441 p < 0.001), environmental mastery (r = -0.414, p < 0.001, for both variables), purpose in life and optimism; while men only showed a low negative correlation between emotion regulation and the number of diseases (r = -0.289, p < 0.05). The positive associated variables in women were anxiety, negative emotions and depression; while men showed a lower correlation between these three variables only with somatization. The somatization and age were positively related to the number of diseases in both genders and the BMI was significantly associated with the number of diseases only in men. In conclusion, women had more somatization and number of diseases than men and also had more relation between psychological variables and the two dependent variables than men, which could in part explains the higher values of somatization and the number of diseases in women, considering that they usually present higher values of psychopathological variables.

Protein Phosphorylation Alterations in Myotonic Dystrophy Type 1: A Systematic Review.

Among the most common muscular dystrophies in adults is Myotonic Dystrophy type 1 (DM1), an autosomal dominant disorder characterized by myotonia, muscle wasting and weakness, and multisystemic dysfunctions. This disorder is caused by an abnormal expansion of the CTG triplet at the DMPK gene that, when transcribed to expanded mRNA, can lead to RNA toxic gain of function, alternative splicing impairments, and dysfunction of different signaling pathways, many regulated by protein phosphorylation. In order to deeply characterize the protein phosphorylation alterations in DM1, a systematic review was conducted through PubMed and Web of Science databases. From a total of 962 articles screened, 41 were included for qualitative analysis, where we retrieved information about total and phosphorylated levels of protein kinases, protein phosphatases, and phosphoproteins in DM1 human samples and animal and cell models. Twenty-nine kinases, 3 phosphatases, and 17 phosphoproteins were reported altered in DM1. Signaling pathways that regulate cell functions such as glucose metabolism, cell cycle, myogenesis, and apoptosis were impaired, as seen by significant alterations to pathways such as AKT/mTOR, MEK/ERK, PKC/CUGBP1, AMPK, and others in DM1 samples. This explains the complexity of DM1 and its different manifestations and symptoms, such as increased insulin resistance and cancer risk. Further studies can be done to complement and explore in detail specific pathways and how their regulation is altered in DM1, to find what key phosphorylation alterations are responsible for these manifestations, and ultimately to find therapeutic targets for future treatments.

Leukocyte Telomere Length Predicts Severe Disability in Relapsing-Remitting Multiple Sclerosis and Correlates with Mitochondrial DNA Copy Number.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease that affects the nervous system. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) are potential biomarkers of neurological disability and neural damage. Our objective was to assess the LTL and mtDNA-CN in relapsing-remitting MS (RRMS). We included 10 healthy controls, 75 patients with RRMS, 50 of whom had an Expanded Disability Status Scale (EDSS) from 0 to 3 (mild to moderate disability), and 25 had an EDSS of 3.5 to 7 (severe disability). We use the Real-Time Polymerase Chain Reaction (qPCR) technique to quantify absolute LTL and absolute mtDNA-CN. ANOVA test show differences between healthy control vs. severe disability RRMS and mild-moderate RRMS vs. severe disability RRMS (p = 0.0130). LTL and mtDNA-CN showed a linear correlation in mild-moderate disability RRMS (r = 0.378, p = 0.007). Furthermore, we analyzed LTL between RRMS groups with a ROC curve, and LTL can predict severe disability (AUC = 0.702, p = 0.0018, cut-off < 3.0875 Kb, sensitivity = 75%, specificity = 62%), whereas the prediction is improved with a logistic regression model including LTL plus age (AUC = 0.762, p = 0.0001, sensitivity = 79.17%, specificity = 80%). These results show that LTL is a biomarker of disability in RRMS and is correlated with mtDNA-CN in mild-moderate RRMS patients.

Genetic Variant HLA-DRB1*0403 and Therapeutic Response to Disease-Modifying Therapies in Multiple Sclerosis: A Case-Control Study.

Multiple sclerosis (MS) is a chronic and demyelinating disease with an autoimmune origin, which leads to neurodegeneration and progressive disability. Approximately 30 to 50% of patients do not respond optimally to disease-modifying therapies (DMTs), and therapeutic response may be influenced by genetic factors such as genetic variants. Therefore, our study aimed to investigate the association of the HLA-DRB1*0403 genetic variant and therapeutic response to DMTs in MS. We included 105 patients with MS diagnosis. No evidence of disease activity based on the absence of clinical relapse, disability progression or radiological activity (NEDA-3) was used to classify the therapeutic response. Patients were classified as follows: (a) controls: patients who achieved NEDA-3; (b) cases: patients who did not achieve NEDA-3. DNA was extracted from peripheral blood leukocytes. HLA-DRB1*0403 genetic variant was analyzed by quantitative polymerase chain reaction (qPCR) using TaqMan probes. NEDA-3 was achieved in 86.7% of MS patients treated with DMTs. Genotype frequencies were GG 50.5%, GA 34.3%, and AA 15.2%. No differences were observed in the genetic variant AA between patients who achieved NEDA-3 versus patients who did not achieve NEDA-3 (48.7% vs. 43.1%, p = 0.6). We concluded that in Mexican patients with MS, HLA-DRB1*0403 was not associated with the therapeutic response to DMTs.