ADAMTS13 recovery in acute thrombotic thrombocytopenic purpura after caplacizumab therapy.

ABSTRACT: Caplacizumab prevents the interaction between von Willebrand factor and platelets and is used to treat immune thrombotic thrombocytopenic purpura (iTTP). Its administration has been associated with a delay in ADAMTS13 activity restoration after plasma exchange (PEX) suspension. We analyzed the outcomes of 113 iTTP episodes, 75 of which were treated with caplacizumab, in 108 patients from the Spanish Registry of Thrombotic Thrombocytopenic Purpura. Caplacizumab shortened the time to platelet count normalization and reduced PEX requirement, exacerbations, and relapses. There was no difference in the time to achieve ADAMTS13 activity ≥20% after PEX end between caplacizumab-treated and nontreated episodes (median [interquartile range], 14.5 [7.7-27.2] vs 13.0 [8.0-29.0] days, P = .653). However, considering the 36 episodes in which caplacizumab was started ≤3 days after iTTP diagnosis, the time for ADAMTS13 restoration from PEX end was higher than in those episodes in which caplacizumab was started >3 days after iTTP diagnosis (20.0 [12.0-43.0] vs 11.0 [3.5-20.0] days, P = .003) or than in non-caplacizumab-treated episodes (P = .033). This finding could be related to a significantly shorter duration of PEX in early caplacizumab-treated episodes than in late caplacizumab-treated episodes (5.5 [4.0-9.0] vs 15.0 [11.0-21.5] days, P < .001) or non-caplacizumab-treated episodes (11.0 [6.0-26.0] days, P < .001). There were no differences in time to ADAMTS-13 restoration from PEX start (28.0 [17.2-47.5], 27.0 [19.0-37.5] and 29.5 [15.2-45.0] days in early caplacizumab-treated, late caplacizumab-treated and non-caplacizumab-treated episodes). Early administered caplacizumab does not prevent the requirement for immunosuppression but has beneficial effects by shortening PEX requirement without major safety concerns.

Dystrophin missense mutations alter focal adhesion tension and mechanotransduction.

Dystrophin is an essential muscle protein that contributes to cell membrane stability by mechanically linking the actin cytoskeleton to the extracellular matrix via an adhesion complex called the dystrophin-glycoprotein complex. The absence or impaired function of dystrophin causes muscular dystrophy. Focal adhesions (FAs) are also mechanosensitive adhesion complexes that connect the cytoskeleton to the extracellular matrix. However, the interplay between dystrophin and FA force transmission has not been investigated. Using a vinculin-based bioluminescent tension sensor, we measured FA tension in transgenic C2C12 myoblasts expressing wild-type (WT) dystrophin, a nonpathogenic single nucleotide polymorphism (SNP) (I232M), or two missense mutations associated with Duchenne (L54R), or Becker muscular dystrophy (L172H). Our data revealed cross talk between dystrophin and FAs, as the expression of WT or I232M dystrophin increased FA tension compared to dystrophin-less nontransgenic myoblasts. In contrast, the expression of L54R or L172H did not increase FA tension, indicating that these disease-causing mutations compromise the mechanical function of dystrophin as an FA allosteric regulator. Decreased FA tension caused by these mutations manifests as defective migration, as well as decreased Yes-associated protein 1 (YAP) activation, possibly by the disruption of the ability of FAs to transmit forces between the extracellular matrix and cytoskeleton. Our results indicate that dystrophin influences FA tension and suggest that dystrophin disease-causing missense mutations may disrupt a cellular tension-sensing pathway in dystrophic skeletal muscle.

Phosphorylation alters the mechanical stiffness of a model fragment of the dystrophin homologue utrophin.

Duchenne muscular dystrophy is a lethal muscle wasting disease caused by the absence of the protein dystrophin. Utrophin is a dystrophin homologue currently under investigation as a protein replacement therapy for Duchenne muscular dystrophy. Dystrophin is hypothesized to function as a molecular shock absorber that mechanically stabilizes the sarcolemma. While utrophin is homologous with dystrophin from a molecular and biochemical perspective, we have recently shown that full-length utrophin expressed in eukaryotic cells is stiffer than what has been reported for dystrophin fragments expressed in bacteria. In this study, we show that differences in expression system impact the mechanical stiffness of a model utrophin fragment encoding the N terminus through spectrin repeat 3 (UtrN-R3). We also demonstrate that UtrN-R3 expressed in eukaryotic cells was phosphorylated while bacterial UtrN-R3 was not detectably phosphorylated. Using atomic force microscopy, we show that phosphorylated UtrN-R3 exhibited significantly higher unfolding forces compared to unphosphorylated UtrN-R3 without altering its actin-binding activity. Consistent with the effect of phosphorylation on mechanical stiffness, mutating the phosphorylated serine residues on insect eukaryotic protein to alanine decreased its stiffness to levels not different from unphosphorylated bacterial protein. Taken together, our data suggest that the mechanical properties of utrophin may be tuned by phosphorylation, with the potential to improve its efficacy as a protein replacement therapy for dystrophinopathies.

Follow-Up Study of 17-ß Estradiol, Prolactin and Progesterone with the Kinetics and Prevalence of T. gondii Infection in Pregnant Women.

Toxoplasmosis is an infection caused by the parasite Toxoplasma gondii. One-third of the world's population has come into contact with this parasite. In Mexico, the prevalence is between 15% and 50% in the general population and 34.9% in women with high-risk pregnancies. In pregnancy, the highest incidence of infection occurs in the third trimester and fetal damage is inversely proportional to gestational age. Maternal hormones play a fundamental role in the immune response. There are very few studies, with controversial results, on the levels of increased hormones and their relationship to the kinetics of T. gondii infections during pregnancy. The aim was to determine the serum levels of 17-ß estradiol, prolactin, and progesterone, and their association with anti-T. gondii antibodies' kinetics in pregnancy. Fifty-two pregnant patients were studied. A questionnaire with sociodemographic and clinical aspects was used. Afterward, 10 mL of venous blood was collected by venipuncture every trimester. The concentrations of 17-ß estradiol, progesterone, and prolactin were measured, using the ELISA method. In addition, anti-Toxoplasma IgG and IgM antibodies were also determined in the first, second, and third trimester. The prevalence of anti-Toxoplasma IgG antibodies was 26.92% in the first and second trimester and 32.7% in the third trimester. In seropositive women, 17-ß estradiol increased in the second and third trimesters of pregnancy. Progesterone increased significantly p < 0.039 in the third trimester in these women, while prolactin increased in the second trimester with a statistical significance of p < 0.021. In addition, 17-ß estradiol, progesterone, and prolactin are associated with T. gondii infection during pregnancy. New studies are necessary to clarify the specific mechanisms of immune response related to these hormones during pregnancy.

Genomic Gigantism is not Associated with Reduced Selection Efficiency in Neotropical Salamanders.

Genome size variation in eukaryotes has myriad effects on organismal biology from the genomic to whole-organism level. Large genome size may be associated with lower selection efficiency because lower effective population sizes allow fixation of deleterious mutations via genetic drift, increasing genome size and decreasing selection efficiency. Because of a hypothesized negative relationship between genome size and recombination rate per base pair, increased genome size could also increase the effect of linked selection in the genome, decreasing the efficiency with which natural selection can fix or remove mutations. We used a transcriptomic dataset of 15 and a subset of six Neotropical salamander species ranging in genome size from 12 to 87 pg to study the relationship between genome size and efficiency of selection. We estimated dN/dS of salamanders with small and large genomes and tested for relaxation of selection in the larger genomes. Contrary to our expectations, we did not find a significant relationship between genome size and selection efficiency or strong evidence for higher dN/dS values in species with larger genomes for either species set. We also found little evidence for relaxation of selection in species with larger genomes. A positive correlation between genome size and range size (a proxy of population size) in this group disagrees with predictions of stronger drift in species with larger genomes. Our results highlight the complex interactions between the many forces shaping genomic variation in organisms with genomic gigantism.

The prognostic impact of non-driver gene mutations and variant allele frequency in primary myelofibrosis.

Prognostic impact of non-MPN driver gene mutations in primary myelofibrosis. MIPSS70: Mutation-Enhanced International Prognostic Score System.

Correlation Between Tacrolimus Levels in Blood Samples Obtained from Central Catheter and Peripheral Venipuncture in Lung Transplant Patients (Ven-Cat Study).

BACKGROUND: Following lung transplantation (LT), receiving immunosuppressive therapy is crucial. Tacrolimus is considered a drug with a narrow therapeutic range and its use requires constant monitoring. This study aimed to evaluate the correlation between tacrolimus levels obtained from central venous catheter and direct venipuncture in adult patients undergoing LT. METHODS: This prospective study included LT patients hospitalized in conventional ward carrying a central catheter through which no intravenous tacrolimus was administered. Trough samples were obtained through direct puncture and from the central catheter. Pearson correlation coefficient was calculated to quantify the mean difference between the 2 measures. RESULTS: A total of 54 sample pairs from 16 LT patients were obtained, mostly male (81.3%) and bilateral transplant recipients (93.8%); the transplant procedure was the primary reason for admission (81.3%). The difference in tacrolimus levels between both samples was 0.3 (0.1-0.6) mcg/L, with the measurement for the samples obtained through venipuncture being mostly higher than that for those obtained from the catheter. A strong correlation was observed between the tacrolimus levels in the samples obtained from the catheter and through venipuncture (Pearson correlation coefficient, 0.991; P < 0.001; R2 = 0.982). CONCLUSIONS: There is an excellent correlation between tacrolimus levels obtained from venipuncture and those obtained from central venous catheter in LT patients undergoing oral tacrolimus therapy.

Experimental Determination of the Standard Enthalpy of Formation of Trimellitic Acid and Its Prediction by Supervised Learning.

The standard molar enthalpy of formation for trimellitic acid (TMAc) in the crystalline phase at 298.15 K, ΔfHm°(cr), was calculated experimentally from the enthalpy of combustion through combustion calorimetry experiments. Likewise, the standard molar enthalpy of sublimation was determined from the standard molar enthalpy of fusion and from the standard molar enthalpy of vaporization from differential scanning calorimetry and thermogravimetry, respectively. Subsequently, the standard molar enthalpies of formation in the gas-phase at 298.15 K, ΔfHm°(g), were calculated. The enthalpies of formation for TMAc, hemimellitic, and trimesic acids were predicted using multiple linear regression (MLR) with a nonreplacement evaluation technique. MLR was applied to the data set that allowed estimating these thermochemical properties with an R2 greater than 0.99. This model was used to compare the predicted and experimental results for benzene carboxylic acids.

High-risk pregnancy and its relationship with the neurodevelopment and behavior of 2-year-old children.

High-risk pregnancies elevate maternal stress, impacting offspring neurodevelopment and behavior. This study, involving 112 participants, aimed to compare perceived stress, neurodevelopment, and behavior in high-risk and low-risk pregnancies. Two groups, high-risk and low-risk, were assessed during pregnancy for stress using hair cortisol and psychological analysis. At 24 months post-birth, their children's neurodevelopment and behavior were evaluated. Results revealed higher perceived stress and pregnancy-related concerns in high-risk pregnancies, contrasting with low-risk pregnancies. Offspring from high-risk pregnancies displayed elevated internalizing behavior scores, while low-risk pregnancies showed higher externalizing behavior scores. Additionally, women in low-risk pregnancies exhibited increased cortisol concentrations 24 months post-delivery. These findings underscore the necessity for early stress detection and prevention programs during pregnancy, particularly in high-risk cases, to enhance maternal and infant health.

The effects of low ambient temperature on steroidogenesis and mitochondrial functions in the testes of wild ground squirrels (Spermophilus dauricus).

Seasonal reproduction is a widely used breeding strategy in wildlife, especially vertebrates inhabiting temperate regions. Generally, ambient temperature is considered a significant factor influencing the reproductive status of animals. In the present study, wild ground squirrels (Spermophilus dauricus), typical seasonal breeders, were used as an animal model to investigate the mechanism behind the impact of low ambient temperature on testicular function. To simulate the winter environment of wild ground squirrels, we lowered the temperature gradient in the rearing environment to 4 °C. At sampling, the body surface temperature of the squirrels reared under normal ambient temperature (22 °C, NAT group) and the low ambient temperature (4 °C, LAT group) were 31.5 °C and 22.8 °C, respectively. Subsequently, we conducted immunohistochemical assays, qPCR, and enzyme-linked immunosorbent assays (ELISA) to examine the variations in testicular functions, as well as the dynamics and functions of mitochondria, in the squirrels of NAT and LAT groups. As a result, the levels of positive immunostaining for PCNA, P21, and P27 were significantly lower in the testes of LAT group, while the levels of immunostaining for Cleaved Caspase-3 and TUNEL were significantly higher. In addition, the low-temperature treatment reduced the expression level of steroidogenesis-related genes, including LHR, FSHR, GATA-4, P450scc, and P450arom, and decreased the testosterone concentration. Moreover, markers of mitochondrial fission and fusion, DRP1 and MFN2, respectively, were increased in the testes of LAT group. Additionally, the mRNA level of SOD1 was notably higher in the testes of LAT group. In conclusion, the low ambient temperature inhibited spermatogenesis, steroidogenesis, as well as mitochondrial dynamics and functions in the testes of wild ground squirrels.

Essential Role of Astrocytes in Learning and Memory.

One of the most biologically relevant functions of astrocytes within the CNS is the regulation of synaptic transmission, i.e., the physiological basis for information transmission between neurons. Changes in the strength of synaptic connections are indeed thought to be the cellular basis of learning and memory. Importantly, astrocytes have been demonstrated to tightly regulate these processes via the release of several gliotransmitters linked to astrocytic calcium activity as well as astrocyte-neuron metabolic coupling. Therefore, astrocytes seem to be integrators of and actors upon learning- and memory-relevant information. In this review, we focus on the role of astrocytes in learning and memory processes. We delineate the recognized inputs and outputs of astrocytes and explore the influence of manipulating astrocytes on behaviour across diverse learning paradigms. We conclude that astrocytes influence learning and memory in various manners. Appropriate astrocytic Ca2+ dynamics are being increasingly identified as central contributors to memory formation and retrieval. In addition, astrocytes regulate brain rhythms essential for cognition, and astrocyte-neuron metabolic cooperation is required for memory consolidation.

Novel Pitolisant-Derived Sulfonyl Compounds for Alzheimer Disease.

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disorder characterized by cognitive decline, memory loss, behavioral changes, and other neurological symptoms. Considering the urgent need for new AD therapeutics, in the present study we designed, synthesized, and evaluated multitarget compounds structurally inspired by sulfonylureas and pitolisant with the aim of obtaining multitarget ligands for AD treatment. Due to the diversity of chemical scaffolds, a novel strategy has been adopted by merging into one structure moieties displaying H3R antagonism and acetylcholinesterase inhibition. Eight compounds, selected by their binding activity on H3R, showed a moderate ability to inhibit acetylcholinesterase activity in vitro, and two of the compounds (derivatives 2 and 7) were also capable of increasing acetylcholine release in vitro. Among the tested compounds, derivative 2 was identified and selected for further in vivo studies. Compound 2 was able to reverse scopolamine-induced cognitive deficits with results comparable to those of galantamine, a drug used in clinics for treating AD. In addition to its efficacy, this compound showed moderate BBB permeation in vitro. Altogether, these results point out that the fragment-like character of compound 2 leads to an optimal starting point for a plausible medicinal chemistry approach for this novel strategy.

Preliminary Screening on Antibacterial Crude Secondary Metabolites Extracted from Bacterial Symbionts and Identification of Functional Bioactive Compounds by FTIR, HPLC and Gas Chromatography-Mass Spectrometry.

Secondary metabolites, bioactive compounds produced by living organisms, can unveil symbiotic relationships in nature. In this study, soilborne entomopathogenic nematodes associated with symbiotic bacteria (Xenorhabdus stockiae and Photorhabdus luminescens) were extracted from solvent supernatant containing secondary metabolites, demonstrating significant inhibitory effects against E. coli, S. aureus, B. subtilus, P. mirabilis, E. faecalis, and P. stutzeri. The characterization of these secondary metabolites by Fourier transforms infrared spectroscopy revealed amine groups of proteins, hydroxyl and carboxyl groups of polyphenols, hydroxyl groups of polysaccharides, and carboxyl groups of organic acids. Furthermore, the obtained crude extracts were analyzed by high-performance liquid chromatography for the basic identification of potential bioactive peptides. Gas chromatography-mass spectrometry analysis of ethyl acetate extracts from Xenorhabdus stockiae identified major compounds including nonanoic acid derivatives, proline, paromycin, octodecanal derivatives, trioxa-5-aza-1-silabicyclo, 4-octadecenal, methyl ester, oleic acid, and 1,2-benzenedicarboxylicacid. Additional extraction from Photorhabdus luminescens yielded functional compounds such as indole-3-acetic acid, phthalic acid, 1-tetradecanol, nemorosonol, 1-eicosanol, and unsaturated fatty acids. These findings support the potential development of novel natural antimicrobial agents for future pathogen suppression.

Functional respiratory impairment and related factors in patients with interstitial pneumonia with autoimmune features (IPAF): Multicenter study from NEREA registry.

BACKGROUND: The objective of the present study is to describe the characteristics of interstitial pneumonia with autoimmune features (IPAF) patients, to assess the incidence rate of functional respiratory impairment over time and to evaluate the influence of therapeutic alternatives on the prognosis of these patients. METHODS: A longitudinal observational multicenter study was performed (NEREA registry). It was carried out by a multidisciplinary team in seven Hospitals of Madrid. Patients were included from IPAF diagnosis. MAIN OUTCOME: poor prognosis as functional respiratory impairment (relative decline in FVC % defined as ≥ 5% every 6 months). Covariates: therapy, sociodemographic, clinical, radiological patterns, laboratory and functional tests. STATISTICS: Survival techniques were used to estimate IR per 100 patients-semester with their 95% confidence interval [CI]. The influence of covariates in prognosis were analyzed through cox multivariate regression models (hazard ratio (HR) and [CI]). RESULTS: 79 IPAF were included, with a mean and a maximum follow-up of 3.17 and 12 years respectively. Along the study, 77.2% received treatment (52 glucocorticoids, 25 mycophenolate, 21 azathioprine, 15 rituximab and 11 antifibrotics). IR was 23.9 [19.9-28.8], and 50% of IPAF developed functional respiratory impairment after 16 months from its diagnosis. Multivariate analysis: usual interstitial pneumonia (UIP) had poorer prognosis compared to non-specific interstitial pneumonia (NSIP) (p = 0.001). In NSIP, positive ANA, increased the risk of poor prognosis. In UIP, glucocorticoids (HR: 0.53 [0.34-0.83]), age (HR: 1.04 [1.01-1.07]), and Ro-antibodies (HR: 0.36 [0.19-0.65]) influenced the prognosis. CONCLUSIONS: IPAF have functional impairment during the first years of disease. Factors predicting deterioration differ between radiographic patterns. Our real-life study suggests the potential benefit of particular therapies in IPAF.

Factors Influencing Bacterial and Fungal Skin Communities of Montane Salamanders of Central Mexico.

Host microbial communities are increasingly seen as an important component of host health. In amphibians, the first land vertebrates that are threatened by a fungal skin disease globally, our understanding of the factors influencing the microbiome of amphibian skin remains incomplete because recent studies have focused almost exclusively on bacteria, and little information exists on fungal communities associated with wild amphibian species. In this study, we describe the effects of host phylogeny, climate, geographic distance, and infection with a fungal pathogen on the composition and structure of bacterial and fungal communities in seven tropical salamander species that occur in the Trans-Mexican Volcanic Belt of Central Mexico. We find that host phylogenetic relatedness is correlated with bacterial community composition while a composite climatic variable of temperature seasonality and precipitation is significantly associated with fungal community composition. We also estimated co-occurrence networks for bacterial and fungal taxa and found differences in the degree of connectivity and the distribution of negative associations between the two networks. Our results suggest that different factors may be responsible for structuring the bacterial and fungal communities of amphibian skin and that the inclusion of fungi in future studies could shed light on important functional interactions within the microbiome.

The use of medium cutoff dialyzers in patients with multiple myeloma and acute kidney injury requiring hemodialysis: A systematic review.

BACKGROUND: Patients with multiple myeloma and high serum levels of circulating free light chains (FLC) have increased risk of acute kidney injury (AKI) secondary to cast nephropathy and is associated with poor survival. Despite removal of FLC by medium cutoff (MCO) dialyzer, the role of MCO hemodialysis (HD) in the treatment of cast nephropathy and its clinical benefits remain unknown. METHODS: A systematic review was conducted to establish the effectiveness of MCO dialyzer and clinical outcomes, compared to other forms of dialyzers in the removal of FLC, in myeloma patients with AKI. The primary outcome was effectiveness of MCO-HD in reducing serum FLC. The secondary outcomes were HD independence, estimated glomerular filtrate rate, mortality rates, length of hospitalization, rebound of serum FLC before the next dialysis, removal of other molecules during dialysis, and adverse events. RESULTS: We identified three case series, with a total of 17 patients. There were no randomized controlled trials (RCTs) or cohort studies. These case series showed that MCO dialyzer was effective in the removal of FLC and led to a reduction in FLC concentration post-dialysis. The majority of the case series did not have comparator arm and renal and/or other clinical outcomes. CONCLUSION: MCO dialyzer appeared to be effective in the removal of FLC based on the existing limited data. However, more data, particularly large-scale RCTs, are needed to assess the use of MCO dialyzer in reducing serum FLC and its effect on clinical outcomes in patients with multiple myeloma and AKI.

Comprehensive rehabilitation and job reintegration of people with severe mental illness in a Latin American country: REINTEGRA study protocol.

BACKGROUND: Despite the increasing use of comprehensive rehabilitation models for people with severe mental illness (SMI), there are still limitations to their implementation and replicability in a consensual way, particularly in Latin American countries. The REINTEGRA program aims to be a standardized model of comprehensive rehabilitation focused on psychosocial and cognitive improvement through a set of interventions on different areas of people's functionality, with the goal of reintegrating people with SMI into the labour market. In this paper we summarize the protocol for its subsequent implementation in a mental health institution in Mexico. METHOD: The protocol is based on a quasi-experimental, prospective longitudinal study, with a pragmatic or naturalistic control group. It will be carried out in three phases. Phase 1 consists of a series of interventions focused on psychosocial improvement; Phase 2 focuses on cognitive and behavioral improvement treatments; and Phase 3 targets psychosocial recovery through rehabilitation and reintegration into the labour market. The overall procedure will be monitored with standarized evaluations at different stages of the program. DISCUSSION: This study presents a model of integral rehabilitation of people with SMI. At the moment, one of the obstacles to overcome is the organization and procedural control of the different actors needed for its implementation (nurses, psychologists, doctors, companies, institutions, etc.). REINTEGRA will be the first comprehensive rehabilitation model that includes systematized procedures for job reinsertion for people with SMI in Mexico, which aims to be a standardized tool of easy adaptation and the replicability for other mental health centers and institutions.

Malnutrition in COVID-19 survivors: prevalence and risk factors.

BACKGROUND: Nutritional status is a critical factor throughout COVID-19 disease course. Malnutrition is associated with poor outcomes in hospitalized COVID-19 patients. AIM: To assess the prevalence of malnutrition and identify its associated factors in COVID-19 survivors. METHODS: Study cohort included 1230 COVID-19 survivors aged 18-86 attending a post-COVID-19 outpatient service. Data on clinical parameters, anthropometry, acute COVID-19 symptoms, lifestyle habits were collected through a comprehensive medical assessment. Malnutrition was assessed according to Global Leadership Initiative on Malnutrition (GLIM) criteria. RESULTS: Prevalence of malnutrition was 22% at 4-5 months after acute disease. Participants who were not hospitalized during acute COVID-19 showed a higher frequency of malnutrition compared to those who needed hospitalization (26% versus 19%, p < 0.01). Malnutrition was found in 25% COVID-19 survivors over 65 years of age compared to 21% younger participants (p < 0.01). After multivariable adjustment, the likelihood of being malnourished increased progressively and independently with advancing age (Odds ratio [OR] 1.02; 95% CI 1.01-1.03) and in male participants (OR 5.56; 95% CI 3.53-8.74). Malnutrition was associated with loss of appetite (OR 2.50; 95% CI 1.73-3.62), and dysgeusia (OR 4.05; 95% CI 2.30-7.21) during acute COVID-19. DISCUSSION: In the present investigation we showed that malnutrition was highly prevalent in a large cohort of COVID-19 survivors at 4-5 months from acute illness. CONCLUSIONS: Our findings highlight the need to implement comprehensive nutritional assessment and therapy as an integral part of care for COVID-19 patients.

Lipophorin receptors regulate mushroom body development and complex behaviors in Drosophila.

BACKGROUND: Drosophila melanogaster lipophorin receptors (LpRs), LpR1 and LpR2, are members of the LDLR family known to mediate lipid uptake in a range of organisms from Drosophila to humans. The vertebrate orthologs of LpRs, ApoER2 and VLDL-R, function as receptors of a glycoprotein involved in development of the central nervous system, Reelin, which is not present in flies. ApoER2 and VLDL-R are associated with the development and function of the hippocampus and cerebral cortex, important association areas in the mammalian brain, as well as with neurodevelopmental and neurodegenerative disorders linked to those regions. It is currently unknown whether LpRs play similar roles in the Drosophila brain. RESULTS: We report that LpR-deficient flies exhibit impaired olfactory memory and sleep patterns, which seem to reflect anatomical defects found in a critical brain association area, the mushroom bodies (MB). Moreover, cultured MB neurons respond to mammalian Reelin by increasing the complexity of their neurite arborization. This effect depends on LpRs and Dab, the Drosophila ortholog of the Reelin signaling adaptor protein Dab1. In vitro, two of the long isoforms of LpRs allow the internalization of Reelin, suggesting that Drosophila LpRs interact with human Reelin to induce downstream cellular events. CONCLUSIONS: These findings demonstrate that LpRs contribute to MB development and function, supporting the existence of a LpR-dependent signaling in Drosophila, and advance our understanding of the molecular factors functioning in neural systems to generate complex behaviors in this model. Our results further emphasize the importance of Drosophila as a model to investigate the alterations in specific genes contributing to neural disorders.

[Historical evolution of World Health Organization guidelines on antimicrobial resistanceEvolução histórica da Organização Mundial da Saúde e a resistência aos antimicrobianos]. / Evolución histórica de la Organización Mundial de la Salud y la resistencia a los antimicrobianos.

Objective: Show the evolution of guidelines on public health policies focused on antimicrobial resistance (AMR) issued by the World Health Organization (WHO) between 1948 and 2022. Other related government actions are also mentioned. Methods: A detailed review was conducted of World Health Assembly and WHO Executive Board archives. A textual analysis was conducted of AMR-related resolutions that guide the design of government policies and actions for WHO Member States. A systematic search was carried out in SCOPUS, PubMed, and grey literature under the category of public health policies on AMR. Results: AMR has become the greatest threat to public health, putting at risk the achievement of the Sustainable Development Goals. WHO resolutions are presented as evidence of guidelines to combat AMR. The One Health approach and related strategies, initiatives, plans, and programs are mentioned. A gap was identified in the research and development of new antimicrobials, requiring further analysis. Conclusions: WHO has made efforts to combat AMR. This has generated comprehensive development of public health policies to be implemented by the governments of Member States as they see fit.

Objetivo: Apresentar a evolução das diretrizes sobre políticas públicas de saúde voltadas para a resistência microbiana a medicamentos ou resistência aos antimicrobianos (RAM) publicadas pela Organização Mundial da Saúde (OMS) de 1948 a 2022. Além disso, mencionam-se outras ações governamentais relacionadas. Métodos: Procedeu-se a uma revisão detalhada dos arquivos da Assembleia Mundial da Saúde e do Conselho Executivo da OMS. Realizou-se uma análise textual das resoluções sobre RAM, que orientam a formulação de políticas e ações governamentais para os Estados Membros da OMS. Fez-se também uma busca sistemática nas plataformas SCOPUS e Pubmed e na literatura cinzenta, com a categoria de análise "políticas públicas de saúde sobre RAM". Resultados: A RAM tornou-se a maior ameaça à saúde pública e prejudica o cumprimento dos Objetivos de Desenvolvimento Sustentável. Apresentamos as resoluções da OMS como evidência de diretrizes para combater a RAM. Nesses termos, mencionam-se a abordagem "Saúde Única" e estratégias, iniciativas, planos e programas relacionados. Identificou-se uma lacuna na pesquisa e no desenvolvimento de novos antimicrobianos, o que requer uma análise mais aprofundada. Conclusões: A OMS envidou esforços para combater a RAM, o que levou ao desenvolvimento integral de políticas públicas de saúde a serem aplicadas pelos Estados Membros, em conformidade com a soberania de seus governos.