Initiation of translation by cricket paralysis virus IRES requires its translocation in the ribosome.

The cricket paralysis virus internal ribosome entry site (CrPV-IRES) is a folded structure in a viral mRNA that allows initiation of translation in the absence of any host initiation factors. By using recent advances in single-particle electron cryomicroscopy, we have solved the structure of CrPV-IRES bound to the ribosome of the yeast Kluyveromyces lactis in both the canonical and rotated states at overall resolutions of 3.7 and 3.8 Å, respectively. In both states, the pseudoknot PKI of the CrPV-IRES mimics a tRNA/mRNA interaction in the decoding center of the A site of the 40S ribosomal subunit. The structure and accompanying factor-binding data show that CrPV-IRES binding mimics a pretranslocation rather than initiation state of the ribosome. Translocation of the IRES by elongation factor 2 (eEF2) is required to bring the first codon of the mRNA into the A site and to allow the start of translation.

Structure of the mammalian ribosome-Sec61 complex to 3.4 Å resolution.

Cotranslational protein translocation is a universally conserved process for secretory and membrane protein biosynthesis. Nascent polypeptides emerging from a translating ribosome are either transported across or inserted into the membrane via the ribosome-bound Sec61 channel. Here, we report structures of a mammalian ribosome-Sec61 complex in both idle and translating states, determined to 3.4 and 3.9 Å resolution. The data sets permit building of a near-complete atomic model of the mammalian ribosome, visualization of A/P and P/E hybrid-state tRNAs, and analysis of a nascent polypeptide in the exit tunnel. Unprecedented chemical detail is observed for both the ribosome-Sec61 interaction and the conformational state of Sec61 upon ribosome binding. Comparison of the maps from idle and translating complexes suggests how conformational changes to the Sec61 channel could facilitate translocation of a secreted polypeptide. The high-resolution structure of the mammalian ribosome-Sec61 complex provides a valuable reference for future functional and structural studies.

Structural changes enable start codon recognition by the eukaryotic translation initiation complex.

During eukaryotic translation initiation, initiator tRNA does not insert fully into the P decoding site on the 40S ribosomal subunit. This conformation (POUT) is compatible with scanning mRNA for the AUG start codon. Base pairing with AUG is thought to promote isomerization to a more stable conformation (PIN) that arrests scanning and promotes dissociation of eIF1 from the 40S subunit. Here, we present a cryoEM reconstruction of a yeast preinitiation complex at 4.0 Å resolution with initiator tRNA in the PIN state, prior to eIF1 release. The structure reveals stabilization of the codon-anticodon duplex by the N-terminal tail of eIF1A, changes in the structure of eIF1 likely instrumental in its subsequent release, and changes in the conformation of eIF2. The mRNA traverses the entire mRNA cleft and makes connections to the regulatory domain of eIF2?, eIF1A, and ribosomal elements that allow recognition of context nucleotides surrounding the AUG codon.

Selective TnsC recruitment enhances the fidelity of RNA-guided transposition.

Bacterial transposons are pervasive mobile genetic elements that use distinct DNA-binding proteins for horizontal transmission. For example, Escherichia coli Tn7 homes to a specific attachment site using TnsD1, whereas CRISPR-associated transposons use type I or type V Cas effectors to insert downstream of target sites specified by guide RNAs2,3. Despite this targeting diversity, transposition invariably requires TnsB, a DDE-family transposase that catalyses DNA excision and insertion, and TnsC, a AAA+ ATPase that is thought to communicate between transposase and targeting proteins4. How TnsC mediates this communication and thereby regulates transposition fidelity has remained unclear. Here we use chromatin immunoprecipitation with sequencing to monitor in vivo formation of the type I-F RNA-guided transpososome, enabling us to resolve distinct protein recruitment events before integration. DNA targeting by the TniQ-Cascade complex is surprisingly promiscuous-hundreds of genomic off-target sites are sampled, but only a subset of those sites is licensed for TnsC and TnsB recruitment, revealing a crucial proofreading checkpoint. To advance the mechanistic understanding of interactions responsible for transpososome assembly, we determined structures of TnsC using cryogenic electron microscopy and found that ATP binding drives the formation of heptameric rings that thread DNA through the central pore, thereby positioning the substrate for downstream integration. Collectively, our results highlight the molecular specificity imparted by consecutive factor binding to genomic target sites during RNA-guided transposition, and provide a structural roadmap to guide future engineering efforts.

eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining.

Translation initiation defines the identity and quantity of a synthesized protein. The process is dysregulated in many human diseases1,2. A key commitment step is when the ribosomal subunits join at a translation start site on a messenger RNA to form a functional ribosome. Here, we combined single-molecule spectroscopy and structural methods using an in vitro reconstituted system to examine how the human ribosomal subunits join. Single-molecule fluorescence revealed when the universally conserved eukaryotic initiation factors eIF1A and eIF5B associate with and depart from initiation complexes. Guided by single-molecule dynamics, we visualized initiation complexes that contained both eIF1A and eIF5B using single-particle cryo-electron microscopy. The resulting structure revealed how eukaryote-specific contacts between the two proteins remodel the initiation complex to orient the initiator aminoacyl-tRNA in a conformation compatible with ribosomal subunit joining. Collectively, our findings provide a quantitative and architectural framework for the molecular choreography orchestrated by eIF1A and eIF5B during translation initiation in humans.

Publisher Correction: Structural basis of DNA targeting by a transposon-encoded CRISPR-Cas system.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Structural basis of DNA targeting by a transposon-encoded CRISPR-Cas system.

Bacteria use adaptive immune systems encoded by CRISPR and Cas genes to maintain genomic integrity when challenged by pathogens and mobile genetic elements1-3. Type I CRISPR-Cas systems typically target foreign DNA for degradation via joint action of the ribonucleoprotein complex Cascade and the helicase-nuclease Cas34,5, but nuclease-deficient type I systems lacking Cas3 have been repurposed for RNA-guided transposition by bacterial Tn7-like transposons6,7. How CRISPR- and transposon-associated machineries collaborate during DNA targeting and insertion remains unknown. Here we describe structures of a TniQ-Cascade complex encoded by the Vibrio cholerae Tn6677 transposon using cryo-electron microscopy, revealing the mechanistic basis of this functional coupling. The cryo-electron microscopy maps enabled de novo modelling and refinement of the transposition protein TniQ, which binds to the Cascade complex as a dimer in a head-to-tail configuration, at the interface formed by Cas6 and Cas7 near the 3' end of the CRISPR RNA (crRNA). The natural Cas8-Cas5 fusion protein binds the 5' crRNA handle and contacts the TniQ dimer via a flexible insertion domain. A target DNA-bound structure reveals critical interactions necessary for protospacer-adjacent motif recognition and R-loop formation. This work lays the foundation for a structural understanding of how DNA targeting by TniQ-Cascade leads to downstream recruitment of additional transposase proteins, and will guide protein engineering efforts to leverage this system for programmable DNA insertions in genome-engineering applications.

Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta-CoV that recently emerged as a human pathogen and is the causative agent of the COVID-19 pandemic. A molecular framework of how the virus manipulates host cellular machinery to facilitate infection remains unclear. Here, we focus on SARS-CoV-2 NSP1, which is proposed to be a virulence factor that inhibits protein synthesis by directly binding the human ribosome. We demonstrate biochemically that NSP1 inhibits translation of model human and SARS-CoV-2 messenger RNAs (mRNAs). NSP1 specifically binds to the small (40S) ribosomal subunit, which is required for translation inhibition. Using single-molecule fluorescence assays to monitor NSP1-40S subunit binding in real time, we determine that eukaryotic translation initiation factors (eIFs) allosterically modulate the interaction of NSP1 with ribosomal preinitiation complexes in the absence of mRNA. We further elucidate that NSP1 competes with RNA segments downstream of the start codon to bind the 40S subunit and that the protein is unable to associate rapidly with 80S ribosomes assembled on an mRNA. Collectively, our findings support a model where NSP1 proteins from viruses in at least two subgenera of beta-CoVs associate with the open head conformation of the 40S subunit to inhibit an early step of translation, by preventing accommodation of mRNA within the entry channel.

Diabetes and hypertension in elderly women: interactions between severity and failure to control inflammation.

Elderly women are more susceptible to the development of chronic non-communicable diseases. Among these, diabetes mellitus (DM) and systemic arterial hypertension (SAH) stand out. This work aimed to carry out an expanded study on the interactions of anthropometric, biochemical and inflammatory parameters associated with the risk of severity in elderly women with hypertension and diabetes. The study involved the evaluation of 126 elderly women with hypertension and diabetes mellitus. The women were divided according disease severity (low, moderate, high and very high). Anthropometric data were collected by bioimpedance analysis. The inflammatory and biochemical data were obtained from volunteer blood samples. Waist circumference, waist circumference/height ratio, and systolic and diastolic pressures increased with severity. Biochemical marker levels increased with risk of severity, except HDLc. In the very high risk group, there was a higher IL-1ß, IFN-γ and TNF-α production, however, lower IL-10 levels were observed. The very high risk group showed change values for the IL-10/IL-1ß, IL-10/IL-17 and IL-10/TNF-α ratios. The results showed to be extensively altered in the very high risk group, where the inflammatory profile loses its responsiveness. This is the first study that shows an expanded view of the different parameters evaluated in elderly women with hypertension and diabetes.

The Israeli acute paralysis virus IRES captures host ribosomes by mimicking a ribosomal state with hybrid tRNAs.

Colony collapse disorder (CCD) is a multi-faceted syndrome decimating bee populations worldwide, and a group of viruses of the widely distributed Dicistroviridae family have been identified as a causing agent of CCD. This family of viruses employs non-coding RNA sequences, called internal ribosomal entry sites (IRESs), to precisely exploit the host machinery for viral protein production. Using single-particle cryo-electron microscopy (cryo-EM), we have characterized how the IRES of Israeli acute paralysis virus (IAPV) intergenic region captures and redirects translating ribosomes toward viral RNA messages. We reconstituted two in vitro reactions targeting a pre-translocation and a post-translocation state of the IAPV-IRES in the ribosome, allowing us to identify six structures using image processing classification methods. From these, we reconstructed the trajectory of IAPV-IRES from the early small subunit recruitment to the final post-translocated state in the ribosome. An early commitment of IRES/ribosome complexes for global pre-translocation mimicry explains the high efficiency observed for this IRES. Efforts directed toward fighting CCD by targeting the IAPV-IRES using RNA-interference technology are underway, and the structural framework presented here may assist in further refining these approaches.

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.

BACKGROUND: Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited. METHODS: We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed. RESULTS: A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. CONCLUSIONS: Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.).

Undifferentiated and Dedifferentiated Metastatic Melanomas Masquerading as Soft Tissue Sarcomas: Mutational Signature Analysis and Immunotherapy Response.

The distinction between undifferentiated melanoma (UM) or dedifferentiated melanoma (DM) from undifferentiated or unclassifiable sarcoma can be difficult and requires the careful correlation of clinical, pathologic, and genomic findings. In this study, we examined the utility of mutational signatures to identify patients with UM/DM with particular attention as to whether this distinction matters for treatment because the survival of patients with metastatic melanoma has dramatically improved with immunologic therapy, whereas durable responses are less frequent in sarcomas. We identified 19 cases of UM/DM that were initially reported as unclassified or undifferentiated malignant neoplasm or sarcoma and submitted for targeted next-generation sequencing analysis. These cases were confirmed as UM/DM by harboring melanoma driver mutations, UV signature, and high tumor mutation burden. One case of DM showed melanoma in situ. Meanwhile, 18 cases represented metastatic UM/DM. Eleven patients had a prior history of melanoma. Thirteen of 19 (68%) of the tumors were immunohistochemically completely negative for 4 melanocytic markers (S100, SOX10, HMB45, and MELAN-A). All cases harbored a dominant UV signature. Frequent driver mutations involved BRAF (26%), NRAS (32%), and NF1 (42%). In contrast, the control cohort of undifferentiated pleomorphic sarcomas (UPS) of deep soft tissue exhibited a dominant aging signature in 46.6% (7/15) without evidence of UV signature. The median tumor mutation burden for DM/UM vs UPS was 31.5 vs 7.0 mutations/Mb (P < .001). A favorable response to immune checkpoint inhibitor therapy was observed in 66.6% (12/18) of patients with UM/DM. Eight patients exhibited a complete response and were alive with no evidence of disease at the last follow-up (median 45.5 months). Our findings support the usefulness of the UV signature in discriminating DM/UM vs UPS. Furthermore, we present evidence suggesting that patients with DM/UM and UV signatures can benefit from immune checkpoint inhibitor therapy.

Association between Type of Fluid Received Prior to Enrollment, Type of Admission, and Effect of Balanced Crystalloid in Critically Ill Adults: A Secondary Exploratory Analysis of the BaSICS Clinical Trial.

Rationale: The effects of balanced crystalloid versus saline on clinical outcomes for ICU patients may be modified by the type of fluid that patients received for initial resuscitation and by the type of admission. Objectives: To assess whether the results of a randomized controlled trial could be affected by fluid use before enrollment and admission type. Methods: Secondary post hoc analysis of the BaSICS (Balanced Solution in Intensive Care Study) trial, which compared a balanced solution (Plasma-Lyte 148) with 0.9% saline in the ICU. Patients were categorized according to fluid use in the 24 hours before enrollment in four groups (balanced solutions only, 0.9% saline only, a mix of both, and no fluid before enrollment) and according to admission type (planned, unplanned with sepsis, and unplanned without sepsis). The association between 90-day mortality and the randomization group was assessed using a hierarchical logistic Bayesian model. Measurements and Main Results: A total of 10,520 patients were included. There was a low probability that the balanced solution was associated with improved 90-day mortality in the whole trial population (odds ratio [OR], 0.95; 89% credible interval [CrI], 0.66-10.51; probability of benefit, 0.58); however, probability of benefit was high for patients who received only balanced solutions before enrollment (regardless of admission type, OR, 0.78; 89% CrI, 0.56-1.03; probability of benefit, 0.92), mostly because of a benefit in unplanned admissions due to sepsis (OR, 0.70; 89% CrI, 0.50-0.97; probability of benefit, 0.96) and planned admissions (OR, 0.79; 89% CrI, 0.65-0.97; probability of benefit, 0.97). Conclusions: There is a high probability that balanced solution use in the ICU reduces 90-day mortality in patients who exclusively received balanced fluids before trial enrollment. Clinical trial registered with www.clinicaltrials.gov (NCT02875873).

A Pilot Randomized Controlled Trial (RCT) of Acceptance and Commitment Therapy Versus Cognitive Behavioral Therapy for Chronic Insomnia.

OBJECTIVE: To compare the effectiveness of protocols for acceptance and commitment therapy for insomnia (ACT-I) and cognitive behavioral therapy for insomnia (CBT-I) in adults. METHOD: Participants were 37 adults (74.3% women; M = 43.7 years, SD = 10.7) with chronic insomnia who were randomized to 6 weekly group sessions consisting of ACT-I (n = 19) or CBT-I (n = 18). The primary outcome measures were based on the Insomnia Severity Index (ISI) total score, a measure of insomnia complaints, and included the proportions of treatment responders (defined as a change in score of 8 points or more) and remitters (defined as a final score below 8). RESULTS: Both treatment modalities significantly reduced insomnia severity. Post-treatment, the proportion of treatment responders was higher in the CBT-I than the ACT-I (64.7% vs. 50.0%, respectively) group and six months later, ACT-I made further improvements whereas CBT-I had a reduced treatment response (58.8% vs. 55.6%, respectively). CBT-I was associated with a higher proportion of insomnia remission at post treatment. CONCLUSIONS: Both CBT-I and ACT-I are effective, with a higher proportion of insomnia remitters in CBT-I post-treatment. The different change trajectories for the two therapy groups provide insights into behavioral change via a cognitive versus contextual approach.

Long-range interdomain communications in eIF5B regulate GTP hydrolysis and translation initiation.

Translation initiation controls protein synthesis by regulating the delivery of the first aminoacyl-tRNA to messenger RNAs (mRNAs). In eukaryotes, initiation is sophisticated, requiring dozens of protein factors and 2 GTP-regulated steps. The GTPase eIF5B gates progression to elongation during the second GTP-regulated step. Using electron cryomicroscopy (cryo-EM), we imaged an in vitro initiation reaction which is set up with purified yeast components and designed to stall with eIF5B and a nonhydrolyzable GTP analog. A high-resolution reconstruction of a "dead-end" intermediate at 3.6 Šallowed us to visualize eIF5B in its ribosome-bound conformation. We identified a stretch of residues in eIF5B, located close to the γ-phosphate of GTP and centered around the universally conserved tyrosine 837 (Saccharomyces cerevisiae numbering), that contacts the catalytic histidine of eIF5B (H480). Site-directed mutagenesis confirmed the essential role that these residues play in regulating ribosome binding, GTP hydrolysis, and translation initiation both in vitro and in vivo. Our results illustrate how eIF5B transmits the presence of a properly delivered initiator aminoacyl-tRNA at the P site to the distant GTPase center through interdomain communications and underscore the importance of the multidomain architecture in translation factors to sense and communicate ribosomal states.

Influence of age and education on breast cancer awareness and knowledge among women in South Western Nigeria.

The rising incidence of breast cancer (BC) in sub-Saharan Africa is aggravated by poor prognosis. Health education and several screening methods, including breast self-examination (BSE), clinical breast-examination (CBE) and mammography, have been advanced to achieve early detection and reduction in its mortality rate. This study evaluated the level of awareness and knowledge of BC and BSE amongst female students and staff of six educational institutions in Ota, Southwest Nigeria. The participants, consisting of 917 (80.79%) students and 218 (19.21%) staff, aged between 13 and 60 years, were selected using a stratified random sampling technique and categorized into age groups [adolescents (13-19 years), young adults (21-40 years) and middle-aged adults (41-60 years)] and levels of education. Data was collected via questionnaires and analysed using Epi-info software and SPSS version 20. Frequencies, percentages, regression and correlation co-efficient were calculated and used to determine the levels of association between age groups and levels of education. Mean age of the participants was 21 ± 1.7 years; over 75% were adolescents. BC and BSE awareness was 94.80% and 65.11% respectively, with 7 (0.62%) having BC. The major sources of BC and BSE information were television, health workers and internet. The average BC knowledge score of the participants was 4.06 (40.57%); it was highest among young adults, 4.31 (43.07%), and least among the adolescents, 3.88 (38.78%). The same trend was observed for BSE practice among the age groups. There was a direct relationship between BC knowledge and levels of education; the postgraduates had the highest BC knowledge score of 4.49 (44.89%) while the secondary students had the least score of 3.82 (38.12%). Similar trend was observed for BSE practice and the levels of education. Paucity of BSE knowledge largely accounted for the low BSE practice among the adolescents and secondary students. The huge gap in BC knowledge and BSE practice underscores the need for a structured health education and screening programmes in Nigerian schools to enhance prevention and early detection of BC and other ailments. BSE is free, easy to perform, and able to detect BC at earlier stage. The practice should be encouraged alongside mammography to reduce the burden and mortality rate of BC in Nigeria.

Ribosome-dependent activation of stringent control.

In order to survive, bacteria continually sense, and respond to, environmental fluctuations. Stringent control represents a key bacterial stress response to nutrient starvation that leads to rapid and comprehensive reprogramming of metabolic and transcriptional patterns. In general, transcription of genes for growth and proliferation is downregulated, while those important for survival and virulence are upregulated. Amino acid starvation is sensed by depletion of the aminoacylated tRNA pools, and this results in accumulation of ribosomes stalled with non-aminoacylated (uncharged) tRNA in the ribosomal A site. RelA is recruited to stalled ribosomes and activated to synthesize a hyperphosphorylated guanosine analogue, (p)ppGpp, which acts as a pleiotropic secondary messenger. However, structural information about how RelA recognizes stalled ribosomes and discriminates against aminoacylated tRNAs is missing. Here we present the cryo-electron microscopy structure of RelA bound to the bacterial ribosome stalled with uncharged tRNA. The structure reveals that RelA utilizes a distinct binding site compared to the translational factors, with a multi-domain architecture that wraps around a highly distorted A-site tRNA. The TGS (ThrRS, GTPase and SpoT) domain of RelA binds the CCA tail to orient the free 3' hydroxyl group of the terminal adenosine towards a ß-strand, such that an aminoacylated tRNA at this position would be sterically precluded. The structure supports a model in which association of RelA with the ribosome suppresses auto-inhibition to activate synthesis of (p)ppGpp and initiate the stringent response. Since stringent control is responsible for the survival of pathogenic bacteria under stress conditions, and contributes to chronic infections and antibiotic tolerance, RelA represents a good target for the development of novel antibacterial therapeutics.

Physical activity reduces intradermal bacterial load in a murine model submitted to forced swim training - a pilot study.

Regular exercise is beneficial to health. This study evaluated the effects of moderate and intense physical exercise modalities on intradermal infection by Staphylococcus aureus in a murine model. Mice that practiced moderate exercise had lower bacterial load on lymph nodes and less inflammatory infiltrate in dermis. They presented greater weight, however, less amount of epididymal fat: the weight was increased while they had fat diminished. A positive correlation was observed between lipid content and bacterial load in mice trained at moderate intensity. Animals that were under high intensity exercises presented superior bacterial load on the lymph nodes, increased neutrophil count and circulating lymphocytes, and had leukocyte recruitment to the dermis augmented, when compared to the ones in moderate exercise. These findings suggest that moderate physical activity modulates the immune response in dermal infection caused by S. aureus in a murine model.

Tectocerebellar dysraphia and occipital encephalocele associated with trisomy X: case report and review of the literature.

INTRODUCTION: Tectocerebellar dysraphia (TCD) is a rare sporadic malformation associated with severe neurodevelopmental morbidity and high infant mortality. The presence of other ciliopathies worsens the prognosis. Joubert syndrome (JS) is a ciliopathy associated with gene mutations, consisting of midbrain and cerebellum malformations, markedly lack fiber decussation at the level of the pontomesencephalic junction. CASE REPORT: We report the case of a child who was born term with occipital encephalocele (OE), diagnosed with TCD and JS spectrum through computed tomography (CT), magnetic resonance (MR), diffuse tensor imaging (DTI), and clinical findings. She had the OE surgically corrected after spontaneous rupture on the second day after delivery. She developed postoperative ventriculitis, meningitis, and hydrocephalus, successfully treated with intravenous antibiotics and cysto-ventriculostomy, cysto-cisternostomy, third ventriculostomy, and choroid plexus coagulation. G-band karyotyping showed 47, XXX, in all analyzed cells (trisomy X). The infant was followed up for 18 months, presenting, so far, a relatively good outcome. CONCLUSION: This is the first case reported in the literature of the association of TCD/OE/JS spectrum (JSS) with trisomy X (XXX).

Gender-related differences in the modulation of anthropometric, biochemical, and immune markers by physical activity in hypertensive and diabetic individuals.

Systemic arterial hypertension (SAH) and type 2 diabetes mellitus (T2DM) compose the two major noncommunicable chronic inflammatory diseases. Physical activity has been shown as a promising complementary approach to control the systemic inflammation. However, it is still unclear whether this modulation is gender-dependent. The objective of this study was evaluate the gender-related influence of physical activity on the inflammatory response and biochemical profile of individuals with SAH and T2DM. An international physical activity questionnaire was applied to 376 individuals diagnosed with SAH and T2DM in order to access their exercises routine and was evaluated the influence of physical activity in biochemical, anthropometrical, and immunological markers involved in these disorders in men and women. Even though active individuals have exhibited lower serum levels of IL-1ß, IFN-γ, TNF-α, and IL-17A, the ratios between IL-10 and all inflammatory cytokines were higher in men than in women. Physically active individuals also demonstrated increased HDL/LDL and HDL/VLDL ratios. Moreover, multiple correlations revealed that in active women both IL-10 and TNF-α serum levels positively correlate with fasting glucose levels, and were negatively associated with HDL levels. Our findings suggest that gender-related differences dictate a distinct crosstalk between inflammatory and biochemical markers in physically active individuals.