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The genus Lonomia Walker, 1855 (Lepidoptera: Saturniidae) is of particular interest to the medical community, since the scoli of these caterpillars harbor a venom that induces hemorrhaging in humans. In Colombia, deadly encounters with Lonomia achelous (Cramer, 1777), have been reported since 2000. There is little information on the main biological and ecological aspects of this genus to help better understand and develop prevention strategies. This study aimed to describe morphological and biological aspects (especially of immature stages) of four recently reported species of Lonomia in Colombia that pose a risk to humans. We collected caterpillars and adults from five localities and reared them under laboratory conditions. Specimens were identified using DNA barcoding and dissection of adult male genitalia. We provided the first description, to our knowledge, of part of the life cycles of Lonomia casanarensis Brechlin, 2017 and Lonomia orientoandensis Brechlin & Meister, 2011 and the complete life cycles of Lonomia columbiana Lemaire, 1972 and Lonomia orientocordillera Brechlin, Käch & Meister, 2013. We also present the first records of the parasitoids of L. orientocordillera, and L. casanarensis and new host plants. This information will guide not only their morphological recognition and the identification of their parasitoids and hosts, but also will guide rearing methods of these and other Lonomia species in new studies to prevent incidents with humans and create specific antivenoms., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Toro-Vargas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Coronavirus disease 2019 (COVID-19) is an acute viral disease with millions of cases worldwide. Although the number of daily new cases and deaths has been dropping, there is still a need for therapeutic alternatives to deal with severe cases. A promising strategy to prospect new therapeutic candidates is to investigate the regulatory mechanisms involved in COVID-19 progression using integrated transcriptomics approaches. In this work, we aimed to identify COVID-19 Master Regulators (MRs) using a series of publicly available gene expression datasets of lung tissue from patients which developed the severe form of the disease. We were able to identify a set of six potential COVID-19 MRs related to its severe form, namely TAL1, TEAD4, EPAS1, ATOH8, ERG, and ARNTL2. In addition, using the Connectivity Map drug repositioning approach, we identified 52 different drugs which could be used to revert the disease signature, thus being candidates for the design of novel clinical treatments. Furthermore, we compared the identified signature and drugs with the ones obtained from the analysis of nasopharyngeal swab samples from infected patients and preclinical cell models. This comparison showed significant similarities between them, although also revealing some limitations on the overlap between clinical and preclinical data in COVID-19, highlighting the need for careful selection of the best model for each disease stage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Caterpillars of the Neotropical genus Lonomia (Lepidoptera: Saturniidae) are responsible for some fatal envenomation of humans in South America inducing hemostatic disturbances in patients upon skin contact with the caterpillars' spines. Currently, only two species have been reported to cause hemorrhagic syndromes in humans: Lonomia achelous and Lonomia obliqua. However, species identifications have remained largely unchallenged despite improved knowledge of venom diversity and growing evidence that the taxonomy used over past decades misrepresents and underestimates species diversity. Here, we revisit the taxonomic diversity and distribution of Lonomia species using the most extensive dataset assembled to date, combining DNA barcodes, morphological comparisons, and geographical information. Considering new evidence for seven undescribed species as well as three newly proposed nomenclatural changes, our integrative approach leads to the recognition of 60 species, of which seven are known or strongly suspected to cause severe envenomation in humans. From a newly compiled synthesis of epidemiological data, we also examine the consequences of our results for understanding Lonomia envenomation risks and call for further investigations of other species' venom activities. This is required and necessary to improve alertness in areas at risk, and to define adequate treatment strategies for envenomed patients, including performing species identification and assessing the efficacy of anti-Lonomia serums against a broader diversity of species., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 González et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Toxoplasmosis is a neglected parasitic disease necessitating public health control. Host cell invasion by Toxoplasma occurs at different stages of the parasite's life cycle and is crucial for survival and establishment of infection. In tachyzoites, which are responsible for acute toxoplasmosis, invasion involves the formation of a molecular bridge between the parasite and host cell membranes, referred to as the moving junction (MJ). The MJ is shaped by the assembly of AMA1 and RON2, as part of a complex involving additional RONs. While this essential process is well characterized in tachyzoites, the invasion process remains unexplored in bradyzoites, which form cysts and are responsible for chronic toxoplasmosis and contribute to the dissemination of the parasite between hosts. Here, we show that bradyzoites invade host cells in an MJ-dependent fashion but differ in protein composition from the tachyzoite MJ, relying instead on the paralogs AMA2 and AMA4. Functional characterization of AMA4 reveals its key role for cysts burden during the onset of chronic infection, while being dispensable for the acute phase. Immunizations with AMA1 and AMA4, alone or in complex with their rhoptry neck respective partners RON2 and RON2 L1 , showed that the AMA1-RON2 pair induces strong protection against acute and chronic infection, while the AMA4-RON2 L1 complex targets more selectively the chronic form. Our study provides important insights into the molecular players of bradyzoite invasion and indicates that invasion of cyst-forming bradyzoites contributes to cyst burden. Furthermore, we validate AMA-RON complexes as potential vaccine candidates to protect against toxoplasmosis.

Apicomplexan parasites possess secretory organelles called rhoptries that undergo regulated exocytosis upon contact with the host. This process is essential for the parasitic lifestyle of these pathogens and relies on an exocytic machinery sharing structural features and molecular components with free-living ciliates. However, how the parasites coordinate exocytosis with host interaction is unknown. Here, we performed a Tetrahymena-based transcriptomic screen to uncover novel exocytic factors in Ciliata and conserved in Apicomplexa. We identified membrane-bound proteins, named CRMPs, forming part of a large complex essential for rhoptry secretion and invasion in Toxoplasma. Using cutting-edge imaging tools, including expansion microscopy and cryo-electron tomography, we show that, unlike previously described rhoptry exocytic factors, TgCRMPs are not required for the assembly of the rhoptry secretion machinery and only transiently associate with the exocytic site-prior to the invasion. CRMPs and their partners contain putative host cell-binding domains, and CRMPa shares similarities with GPCR proteins. Collectively our data imply that the CRMP complex acts as a host-molecular sensor to ensure that rhoptry exocytosis occurs when the parasite contacts the host cell., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Objective: To study the occurrence of alexithymia in obese adolescents., Methods: Cross-sectional study with 102 obese adolescents. Sociodemographic, clinical, and psychometric data (alexithymia and binge eating) were analyzed The Brazilian version of the Toronto Alexithymia Scale and Binge Eating Scale were used for psychometric data collection. Statistical analysis was performed using the Kolmogorov-Smirnov test, Student's t-test, ANOVA, chi-square, linear regression, and logistic regression. The study was approved by Research Ethics Committee., Results: A 22% occurrence of alexithymia was observed. Considering the category "possible alexithymia", half of the participants presented some alexithymic behavior. Adolescents with alexithymia had higher binge eating scores (alexithymia 16,2 versus possible alexithymia 11,7 versus no alexithymia 8,5; ANOVA p < 0,0005) and three times more binge eating behavior than adolescents with no alexithymia or possible alexithymia (alexithymia 36.4% versus 17.2% possible alexithymia versus 11.8% no alexithymia; chi-square = 6,2, p = 0.04). In simple linear regression, alexithymia scores were positively associated with binge eating scores (r 2  = 0,4; p = 0,002). Binary logistic regression showed a three times higher probability of an adolescent with severe obesity to meet the criteria for alexithymia., Conclusions: There was a 22% occurrence of alexithymia in obese adolescents. It was positively associated with obesity severity and higher binge eating scores, suggesting a relationship between severe obesity, alexithymia, and binge eating behavior., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2021 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Background: Alzheimer's disease (AD) is a multifactorial and complex neuropathology that involves impairment of many intricate molecular mechanisms. Despite recent advances, AD pathophysiological characterization remains incomplete, which hampers the development of effective treatments. In fact, currently, there are no effective pharmacological treatments for AD. Integrative strategies such as transcription regulatory network and master regulator analyses exemplify promising new approaches to study complex diseases and may help in the identification of potential pharmacological targets., Methods: In this study, we used transcription regulatory network and master regulator analyses on transcriptomic data of human hippocampus to identify transcription factors (TFs) that can potentially act as master regulators in AD. All expression profiles were obtained from the Gene Expression Omnibus database using the GEOquery package. A normal hippocampus transcription factor-centered regulatory network was reconstructed using the ARACNe algorithm. Master regulator analysis and two-tail gene set enrichment analysis were employed to evaluate the inferred regulatory units in AD case-control studies. Finally, we used a connectivity map adaptation to prospect new potential therapeutic interventions by drug repurposing., Results: We identified TFs with already reported involvement in AD, such as ATF2 and PARK2, as well as possible new targets for future investigations, such as CNOT7, CSRNP2, SLC30A9, and TSC22D1. Furthermore, Connectivity Map Analysis adaptation suggested the repositioning of six FDA-approved drugs that can potentially modulate master regulator candidate regulatory units (Cefuroxime, Cyproterone, Dydrogesterone, Metrizamide, Trimethadione, and Vorinostat)., Conclusions: Using a transcription factor-centered regulatory network reconstruction we were able to identify several potential molecular targets and six drug candidates for repositioning in AD. Our study provides further support for the use of bioinformatics tools as exploratory strategies in neurodegenerative diseases research, and also provides new perspectives on molecular targets and drug therapies for future investigation and validation in AD.

The PD-1:PD-L1 immune signaling axis mediates suppression of T-cell-dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c(+)CD11b(+)CD8(-)CD209a(+)) and human (CD1c(+)CD19(-)) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-κB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-κB activation. Further mechanistic investigations showed that PD-1 blocked NF-κB-dependent cytokine release in a SHP-2-dependent manner. Conversely, inhibition of NF-κB-mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer., (©2015 American Association for Cancer Research.)

Plasmodium falciparum and Toxoplasma gondii are widely studied parasites in phylum Apicomplexa and the etiological agents of severe human malaria and toxoplasmosis, respectively. These intracellular pathogens have evolved a sophisticated invasion strategy that relies on delivery of proteins into the host cell, where parasite-derived rhoptry neck protein 2 (RON2) family members localize to the host outer membrane and serve as ligands for apical membrane antigen (AMA) family surface proteins displayed on the parasite. Recently, we showed that T. gondii harbors a novel AMA designated as TgAMA4 that shows extreme sequence divergence from all characterized AMA family members. Here we show that sporozoite-expressed TgAMA4 clusters in a distinct phylogenetic clade with Plasmodium merozoite apical erythrocyte-binding ligand (MAEBL) proteins and forms a high-affinity, functional complex with its coevolved partner, TgRON2L1. High-resolution crystal structures of TgAMA4 in the apo and TgRON2L1-bound forms complemented with alanine scanning mutagenesis data reveal an unexpected architecture and assembly mechanism relative to previously characterized AMA-RON2 complexes. Principally, TgAMA4 lacks both a deep surface groove and a key surface loop that have been established to govern RON2 ligand binding selectivity in other AMAs. Our study reveals a previously underappreciated level of molecular diversity at the parasite-host-cell interface and offers intriguing insight into the adaptation strategies underlying sporozoite invasion. Moreover, our data offer the potential for improved design of neutralizing therapeutics targeting a broad range of AMA-RON2 pairs and apicomplexan invasive stages.

Plasmodium falciparum is responsible for severe malaria which is one of the most prevalent and deadly infectious diseases in the world. The antimalarial therapeutic arsenal is hampered by the onset of resistance to all known pharmacological classes of compounds, so new drugs with novel mechanisms of action are critically needed. Albitiazolium is a clinical antimalarial candidate from a series of choline analogs designed to inhibit plasmodial phospholipid metabolism. Here we developed an original chemical proteomic approach to identify parasite proteins targeted by albitiazolium during their native interaction in living parasites. We designed a bifunctional albitiazolium-derived compound (photoactivable and clickable) to covalently crosslink drug-interacting parasite proteins in situ followed by their isolation via click chemistry reactions. Mass spectrometry analysis of drug-interacting proteins and subsequent clustering on gene ontology terms revealed parasite proteins involved in lipid metabolic activities and, interestingly, also in lipid binding, transport, and vesicular transport functions. In accordance with this, the albitiazolium-derivative was localized in the endoplasmic reticulum and trans-Golgi network of P. falciparum. Importantly, during competitive assays with albitiazolium, the binding of choline/ethanolamine phosphotransferase (the enzyme involved in the last step of phosphatidylcholine synthesis) was substantially displaced, thus confirming the efficiency of this strategy for searching albitiazolium targets.

Objective: To compare bone mineral density (BMD) and body composition (BC) of college students with different lifestyles., Methods: Transversal study with 85 students of Medicine (MED) and Physical Education (PE) at the Universidade Regional de Blumenau, SC, Brazil. The anthropometric, socio-demographic, clinical, and lifestyle variables were obtained through densitometric anamnesis and densitometric variables by dual-energy X-ray (DXA). The statistical tests used were: Student's t-test, Chi-square test, and logistic regression., Results: PE male students showed a higher amount of lean body mass (79.5 ± 5.9 vs. 75.1 ± 5.3; p = 0.03) and a lower amount of body fat (16.7 ± 6.1 vs. 21.6 ± 5.6; p = 0.02) and PE female students showed a higher amount of lean body mass (68.2 ± 5.5 vs. 65.3 ± 5.5; p = 0.05). The BMD of the neck of femur (NOF), total femur (TF), and total body (TB) was higher in PE students of both genders. PE students practiced more physical activities than MED students. Low bone mass (LBM) was more frequent in MED students (34.9% vs. 4.7%; p = 0.001), provided that the risk of a MED student to show LBM was nine times higher for lumbar spine (LS), five times for NOF, eight times for TF, and seven times for TB., Conclusion: BC and BMD were different among the students; MED students have shown a higher risk of having LBM, and PE students practiced more physical activities.

Background: Antigen B (AgB) is the major protein secreted by the Echinococcus granulosus metacestode and is involved in key host-parasite interactions during infection. The full comprehension of AgB functions depends on the elucidation of several structural aspects that remain unknown, such as its subunit composition and oligomeric states., Methodology/principal Findings: The subunit composition of E. granulosus AgB oligomers from individual bovine and human cysts was assessed by mass spectrometry associated with electrophoretic analysis. AgB8/1, AgB8/2, AgB8/3 and AgB8/4 subunits were identified in all samples analyzed, and an AgB8/2 variant (AgB8/2v8) was found in one bovine sample. The exponentially modified protein abundance index (emPAI) was used to estimate the relative abundance of the AgB subunits, revealing that AgB8/1 subunit was relatively overrepresented in all samples. The abundance of AgB8/3 subunit varied between bovine and human cysts. The oligomeric states formed by E. granulosus AgB and recombinant subunits available, rAgB8/1, rAgB8/2 and rAgB8/3, were characterized by native PAGE, light scattering and microscopy. Recombinant subunits showed markedly distinct oligomerization behaviors, forming oligomers with a maximum size relation of rAgB8/3>rAgB8/2>rAgB8/1. Moreover, the oligomeric states formed by rAgB8/3 subunit were more similar to those observed for AgB purified from hydatid fluid. Pressure-induced dissociation experiments demonstrated that the molecular assemblies formed by the more aggregative subunits, rAgB8/2 and rAgB8/3, also display higher structural stability., Conclusions/significance: For the first time, AgB subunit composition was analyzed in samples from single hydatid cysts, revealing qualitative and quantitative differences between samples. We showed that AgB oligomers are formed by different subunits, which have distinct abundances and oligomerization properties. Overall, our findings have significantly contributed to increase the current knowledge on AgB expression and structure, highlighting issues that may help to understand the parasite adaptive response during chronic infection.

Neospora caninum and Toxoplasma gondii are closely related, obligate intracellular parasites infecting a wide range of vertebrate hosts and causing abortion and neonatal morbidity and mortality. Several lines of evidence suggest that cross immunity between these two pathogens could be exploited in the design of strategies for heterologous vaccination. We assessed the ability of an attenuated strain of T. gondii ("mic1-3KO strain") conferring strong protection against chronic and congenital toxoplasmosis to protect mice against lethal N. caninum infection. Mice immunized with mic1-3KO tachyzoites by the oral and intraperitoneal routes developed a strong cellular Th1 response and displayed significant protection against lethal heterologous N. caninum infection, with survival rates of 70% and 80%, respectively, whereas only 30% of the nonimmunized mice survived. We report here the acquisition of heterologous protective immunity against N. caninum following immunization with a live attenuated mic1-3KO strain of T. gondii.

Objective: To evaluate the occurrence of osteopenia and the prognostic factors of bone mass in a pediatric group with type 1 diabetes., Methods: The following parameters were analyzed in a group of 23 patients with type 1 diabetes aged 10.9 -/+ 2.9 years: bone mineral density, serum C peptide, glycosylated hemoglobin, serum calcium, serum alkaline phosphatase, serum phosphorus and calciuria. Clinical variables included age, weight, height, body mass index, pubertal stage, insulin doses, duration of diabetes and calcium intake. Bone mineral density was evaluated in the lumbar spine and the results were expressed in deviation standard score by age and sex. Calcium intake was calculated based on feeding report, body mass index was calculated using the Quetelet formula and pubertal stage was defined according to the Tanner-Whitehouse criteria. Simple linear regression was used to analyze correlations between variables and the Mann-Whitney U test was used to compare groups., Results: Average bone mineral density was normal (-0.75 -/+ 1.01 SD). However we verified that 39.1% of the patients had osteopenia. When comparing data of osteopenic patients (n = 9) to non-osteopenic patients (n =1 4), we observed that C peptide of osteopenic group was higher than that of non-osteopenic group (0.56 -/+ 0.18 vs 0.29 -/+ 0.20; p < 0.05). Body mass index and C peptide correlated with bone mineral density. Duration of diabetes was inversely correlated with C peptide (p < 0.01) and directly correlated with insulin doses (p < 0.01)., Conclusion: Osteopenia occurred in 39.1% of the patients with type 1 diabetes. The presence of osteopenia was related to higher levels of C peptide.

Among pathologies prevalent in western societies, anorexia nervosa has increased over the last decade. Its effects on bone mass need to be defined, and prognostic factors, either clinical or biochemical, could aid clinicians in individual patient management. To determine which clinical and/or biochemical parameters could be related to bone mass status in adolescent female anorexia nervosa patients, 73 female patients were classified according to different stages of their illness and studied in terms of clinical and biochemical parameters and bone densitometric mineral content at lumbar spine. Patients (age 17.2 +/- 1.7 y, mean +/- SD) with Tanner pubertal stage 5, regular menstruation for more than 3 mo before the onset of secondary amenorrhea, and diagnosed with anorexia nervosa were consecutively studied and classified in three clinical situations: I) active phase (34 patients): undernourished and amenorrheic; II) weight recovered but still amenorrheic (20 patients); III) fully recovered (19 patients). Clinical data were recorded at the time of bone density measurement, concomitant with blood sample extraction for study of IGF-I, IGF-binding protein 3 (IGFBP-3), IGFBP-1, estradiol, sex hormone-binding globulin, dehydroepiandrosterone sulfate, prealbumin, amino-terminal propeptide of procollagen III, osteocalcin, bone alkaline phosphatase, carboxy-terminal propeptide of procollagen I, amino-terminal propeptide of procollagen I, carboxy-terminal telopeptide of collagen I, 25-OH-vitamin D, 1,25(OH)(2)-vitamin D, and parathormone. In addition, a 24-h urine collection was made for cortisol, GH, deoxypyridinoline, amino-terminal telopeptide of collagen I, and calcium and creatinine content analysis. IGF-I, estradiol, and biochemical bone formation markers were higher and IGFBP-1, sex hormone-binding globulin, and biochemical bone resorption markers were lower in the weight-recovered stages (stages II and III) compared with the active phase (stage I). Bone formation markers correlated positively with body mass index SD score and IGF-I, whereas bone resorption markers correlated negatively with body mass index SD score and estradiol. Although no statistically significant differences regarding lumbar spine bone mineral density SD score values were recorded among the three stages of the illness, the proportion of osteopenic patients was clearly lower among stage III patients. The actual bone mineral density was inversely related to the duration of amenorrhea and directly related to duration of postmenarcheal menses before amenorrhea. In addition, a subset of osteopenic patients (five of 19) in the fully clinically recovered group with accelerated bone turnover was identified. Normal circulating estrogen level exposure time predicts actual bone mineral density at lumbar spine in young adolescent anorexia nervosa patients. In addition to psychiatric and nutritional interventions, estrogen-deprivation periods must be shortened to less than 20 mo. Patients remaining osteopenic at full clinical recovery require additional follow-up studies.