Formación docente para la educación inclusiva en instituciones públicas del Quindío / Teacher training for inclusive education in public institutions of Quindío

La formación docente es esencial dentro del proceso de educación inclusiva permitiendo responder a la diversidad de los estudiantes a partir de estrategias que promuevan su aprendizaje y participación. Este estudio analiza la formación en inclusión de 253 docentes de instituciones públicas mediante el Cuestionario de Valoración Docente de la Inclusión Educativa (CEFI-R). Los resultados indican niveles bajos de formación en las dimensiones concepciones, apoyos y metodologías. Lo que sugiere que no existe una preparación integral del profesorado para la inclusión y los planes de formación deben abordar desde aspectos conceptuales hasta la implementación de ajustes en el aula. (AU)

Teacher training is essential within the inclusive education process, allowing students to respond to diversity through strategies that promote their learning and participation. This study analyzes the inclusion training of 253 teachers in public institutions, through the Cuestionario de Valoración Docente de la Inclusión Educativa (CEFI-R). The results indicate low levels of training in the conceptual dimensions, supports and methodologies. This suggests that there is no comprehensive preparation of teachers for inclusion and training plans should address conceptual aspects to the implementation of adjustments in the classroom. (AU)

Formación docente para la educación inclusiva en instituciones públicas del Quindío / Teacher training for inclusive education in public institutions of Quindío

La formación docente es esencial dentro del proceso de educación inclusiva permitiendo responder a la diversidad de los estudiantes a partir de estrategias que promuevan su aprendizaje y participación. Este estudio analiza la formación en inclusión de 253 docentes de instituciones públicas mediante el Cuestionario de Valoración Docente de la Inclusión Educativa (CEFI-R). Los resultados indican niveles bajos de formación en las dimensiones concepciones, apoyos y metodologías. Lo que sugiere que no existe una preparación integral del profesorado para la inclusión y los planes de formación deben abordar desde aspectos conceptuales hasta la implementación de ajustes en el aula. (AU)

Teacher training is essential within the inclusive education process, allowing students to respond to diversity through strategies that promote their learning and participation. This study analyzes the inclusion training of 253 teachers in public institutions, through the Cuestionario de Valoración Docente de la Inclusión Educativa (CEFI-R). The results indicate low levels of training in the conceptual dimensions, supports and methodologies. This suggests that there is no comprehensive preparation of teachers for inclusion and training plans should address conceptual aspects to the implementation of adjustments in the classroom. (AU)

Vaccines and monoclonal antibodies: new tools for malaria control.

SUMMARYMalaria remains one of the biggest health problems in the world. While significant reductions in malaria morbidity and mortality had been achieved from 2000 to 2015, the favorable trend has stalled, rather significant increases in malaria cases are seen in multiple areas. In 2022, there were 249 million estimated cases, and 608,000 malaria-related deaths, mostly in infants and children aged under 5 years, globally. Therefore, in addition to the expansion of existing anti-malarial control measures, it is critical to develop new tools, such as vaccines and monoclonal antibodies (mAbs), to fight malaria. In the last 2 years, the first and second malaria vaccines, both targeting Plasmodium falciparum circumsporozoite proteins (PfCSP), have been recommended by the World Health Organization to prevent P. falciparum malaria in children living in moderate to high transmission areas. While the approval of the two malaria vaccines is a considerable milestone in vaccine development, they have much room for improvement in efficacy and durability. In addition to the two approved vaccines, recent clinical trials with mAbs against PfCSP, blood-stage vaccines against P. falciparum or P. vivax, and transmission-blocking vaccine or mAb against P. falciparum have shown promising results. This review summarizes the development of the anti-PfCSP vaccines and mAbs, and recent topics in the blood- and transmission-blocking-stage vaccine candidates and mAbs. We further discuss issues of the current vaccines and the directions for the development of next-generation vaccines.

Survey of target site mutations linked with insecticide resistance in Italian populations of Aphis gossypii.

BACKGROUND: Aphis gossypii is a worldwide agricultural pest that cause high levels of economic losses by feeding and transmitting virus diseases. It is usually controlled by chemical insecticides, but this could lead to the selection of resistant populations. Several SNPs have been identified associated with insecticide resistance. Monitoring activities to detect the presence of such mutations in field populations can have an important role in insect pest management but, currently, no information on Italian strains is available. RESULTS: The presence of target site mutations conferring resistance to different insecticides was analysed in Italian field collected populations of A. gossypii with an allele specific approach (QSGG, Qualitative Sybr-Green Genotyping). Primers were designed to detect mutations in genes coding acetylcholinesterase (S431F), nicotinic acetylcholine receptor (R81T) and voltage gated sodium channel (M918L and L1014F). S431F was widespread but with high variability across populations. R81T was detected for the first time in Italy but only in 2 populations. The L1014F mutation (kdr) was not found, while in the samples showing the M918L two different nucleotidic substitutions were detected. Mutant allele frequencies were respectively 0.70 (S431), 0.31 (M918) and 0.02 (R81). Further analysis on the voltage gated sodium channel gene showed the presence of eight haplotypes and one nonsynonymous mutation in the gene coding region. CONCLUSION: Multiple target-site mutations were detected within Italian populations. The combinations of genotypes observed in certain locations could affect negatively the control of this pest. Preliminary insights on the genetic structure in the Italian populations of A. gossypii were acquired.

Key arginine residues in R2D2 dsRBD1 and dsRBD2 lead the siRNA recognition in Drosophila melanogaster RNAi pathway.

In Drosophila melanogaster, Dcr-2:R2D2 heterodimer binds to the 21 nucleotide siRNA duplex to form the R2D2/Dcr-2 Initiator (RDI) complex, which is critical for the initiation of siRNA-induced silencing complex (RISC) assembly. During RDI complex formation, R2D2, a protein that contains three dsRNA binding domains (dsRBD), senses two aspects of the siRNA: thermodynamically more stable end (asymmetry sensing) and the 5'-phosphate (5'-P) recognition. Despite several detailed studies to date, the molecular determinants arising from R2D2 for performing these two tasks remain elusive. In this study, we have performed structural, biophysical, and biochemical characterization of R2D2 dsRBDs. We found that the solution NMR-derived structure of R2D2 dsRBD1 yielded a canonical α1-ß1-ß2-ß3-α2 fold, wherein two arginine salt bridges provide additional stability to the R2D2 dsRBD1. Furthermore, we show that R2D2 dsRBD1 interacts with thermodynamically asymmetric siRNA duplex independent of its 5'-phosphorylation state, whereas R2D2 dsRBD2 prefers to interact with 5'-P siRNA duplex. The mutation of key arginine residues, R53 and R101, in concatenated dsRBDs of R2D2 results in a significant loss of siRNA duplex recognition. Our study deciphers the active roles of R2D2 dsRBDs by showing that dsRBD1 initiates siRNA recognition, whereas dsRBD2 senses 5'-phosphate as an authentic mark on functional siRNA.

Influence of Sodium Chloride on Human Bitter Taste Receptor Responses.

In the past, taste interactions between sodium chloride (NaCl) and bitter tastants were investigated in human sensory studies, and the suppression of bitterness by sodium was observed. It is currently not clear if this phenomenon occurs predominantly peripherally or centrally and if the effect is general or only particular bitter compounds are blocked. Therefore, the influence of NaCl at the receptor level was tested by functional expression assays using four out of ∼25 human bitter taste receptors together with prototypical agonists. It was observed that NaCl affected only the responses of particular bitter taste receptor-compound pairs, whereas other bitter responses remained unchanged upon variations of the sodium concentrations. Among the tested receptors, TAS2R16 showed a reduction in signaling in the presence of NaCl. This demonstrates that for some receptor-agonist pairs, NaCl reduces the activation at the receptor level, whereas central effects may dominate the NaCl-induced bitter taste inhibition for other substances.

Prospective Comparison of 68Ga-NeoB and 68Ga-PSMA-R2 PET/MRI in Patients with Biochemically Recurrent Prostate Cancer.

Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptors are both overexpressed in prostate cancer (PC) but may provide complementary information.68Ga-PSMA-R2 and 68Ga-NeoB (DOTA-p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH[CH2-CH(CH3)2]2) are novel PET radiopharmaceuticals that were developed for theranostic use. In this phase II imaging study, we assessed the feasibility, safety, and diagnostic performance of 68Ga-NeoB and 68Ga-PSMA-R2 PET/MRI for detection of biochemically recurrent PC. Methods: We prospectively enrolled 27 men with suspected biochemically recurrent PC after initial treatment but noncontributory conventional imaging results (negative or equivocal findings on MRI, CT, and/or bone scan). Participants underwent 68Ga-NeoB and 68Ga-PSMA-R2 PET/MRI within 2 wk in noncontrolled order. The SUVmax of putative PC lesions was measured and compared with a composite reference standard (histopathology, follow-up imaging, prostate-specific antigen change). The SUVmax and SUVmean of background organs were measured. Vital signs were recorded before injection of the radiopharmaceuticals and after the scans. Adverse events were recorded up to 72 h after each scan. Results: The prostate-specific antigen level at enrollment was 3.5 ± 3.9 ng/mL (range, 0.3-13.5 ng/mL). 68Ga-NeoB PET/MRI detected 31 lesions in 18 patients (66.7%), whereas 68Ga-PSMA-R2 identified 20 lesions in 15 participants (55.6%). 68Ga-NeoB PET/MRI showed higher sensitivity (85.7% vs. 71.4%), accuracy (88.9% vs. 77.8%), and negative predictive value (66.7% vs. 50.0%) than 68Ga-PSMA-R2, whereas specificity and positive predictive value were equally high (100.0% for both). In 6 patients, 68Ga-NeoB PET/MRI identified 14 lesions that were false-negative on 68Ga-PSMA-R2 PET/MRI. The mean lesion SUVmax was 6.6 ± 3.2 (range, 2.9-13.2) for 68Ga-NeoB and 4.4 ± 1.5 (range, 2.6-8.8) for 68Ga-PSMA-R2 (P = 0.019). Overall lower uptake was noted in tumors and background organs for 68Ga-PSMA-R2. There were no significant changes in vital signs before and after the scans. No adverse events were reported in the 72-h period after scans. Conclusion: 68Ga-NeoB and 68Ga-PSMA-R2 are safe for diagnostic imaging. 68Ga-NeoB PET/MRI showed better diagnostic performance than 68Ga-PSMA-R2. 68Ga-PSMA-R2 showed overall lower uptake, equally in background organs and tumors, and might therefore not be an ideal theranostic compound. Further evaluation in larger cohorts is needed to confirm our preliminary data.

Epidemiological variations and trends in glaucoma burden in the Belt and Road countries.

BACKGROUND: Analyzing the glaucoma burden in "Belt and Road" (B&R) countries based on age, gender, and risk factors from 1990 to 2019 in order to provide evidence for future prevention strategies. METHODS: We applied global burden of disease(GBD) 2019 to compare glaucoma prevalence and Years lived with disabilities (YLDs) from 1990 to 2019 in the B&R countries. Trends of disease burden between 1990 and 2019 were evaluated using the average annual percent change and the 95% uncertainty interval (UI) were reported. RESULTS: From 1990 to 2019, most B&R countries showed a downward trend in age-standardized prevalence and YLDs (all P < 0.05). Additionally, only the age-standardized YLDs in males of Pakistan has a 0.35% increase (95%CI:0.19,0.50,P < 0.001), and most B&R countries has a decline(all P < 0.05) in age-standardized YLDs in every 5 years age group after 45 years old except for Pakistan(45-79 years and > 85 years), Malaysia(75-84 years), Brunei Darussalam(45-49 years), Afghanistan(70-79 years). Finally, in all Central Asian countries, the age-standardized YLDs due to glaucoma caused by fasting hyperglycemia demonstrated have an increase between 1990 and 2019 (all P < 0.05), but Armenia and Mongolia have a decrease between 2010 and 2019 (all P < 0.05). CONCLUSION: The prevalence of glaucoma continues to pose a significant burden across regions, ages, and genders in countries along the "B&R". It is imperative for the "B&R" nations to enhance health cooperation in order to collaboratively tackle the challenges associated with glaucoma.

Human P2X7 receptor variants Gly150Arg and Arg276His polymorphisms have differential effects on risk association and cellular functions in pancreatic cancer.

BACKGROUND: The purinergic P2X7 receptor (P2X7R) plays an important role in the crosstalk between pancreatic stellate cells (PSCs) and cancer cells, thus promoting progression of pancreatic ductal adenocarcinoma (PDAC). Single nucleotide polymorphisms (SNPs) in the P2X7R have been reported for several cancers, but have not been explored in PDAC. MATERIALS AND METHODS: Blood samples from PDAC patients and controls were genotyped for 11 non-synonymous SNPs in P2X7R and a risk analysis was performed. Relevant P2X7R-SNP GFP variants were expressed in PSCs and cancer cells and their function was assayed in the following tests. Responses in Ca2+ were studied with Fura-2 and dye uptake with YO-PRO-1. Cell migration was monitored by fluorescence microscopy. Released cytokines were measured with MSD assay. RESULTS: Risk analysis showed that two SNPs 474G>A and 853G>A (rs28360447, rs7958316), that lead to the Gly150Arg and Arg276His variants, had a significant but opposite risk association with PDAC development, protecting against and predisposing to the disease, respectively. In vitro experiments performed on cancer cells and PSCs expressing the Gly150Arg variant showed reduced intracellular Ca2+ response, fluorescent dye uptake, and cell migration, while the Arg276His variant reduced dye uptake but displayed WT-like Ca2+ responses. As predicted, P2X7R was involved in cytokine release (IL-6, IL-1ß, IL-8, TNF-α), but the P2X7R inhibitors displayed varied effects. CONCLUSION: In conclusion, we provide evidence for the P2X7R SNPs association with PDAC and propose that they could be considered as potential biomarkers.

Centrifuger: lossless compression of microbial genomes for efficient and accurate metagenomic sequence classification.

Centrifuger is an efficient taxonomic classification method that compares sequencing reads against a microbial genome database. In Centrifuger, the Burrows-Wheeler transformed genome sequences are losslessly compressed using a novel scheme called run-block compression. Run-block compression achieves sublinear space complexity and is effective at compressing diverse microbial databases like RefSeq while supporting fast rank queries. Combining this compression method with other strategies for compacting the Ferragina-Manzini (FM) index, Centrifuger reduces the memory footprint by half compared to other FM-index-based approaches. Furthermore, the lossless compression and the unconstrained match length help Centrifuger achieve greater accuracy than competing methods at lower taxonomic levels.

Impact of resection margin on outcome in soft-tissue sarcomas of the extremities treated with limb-sparing surgery and postoperative radiotherapy.

BACKGROUND: The standard curative treatments for extremity soft tissue sarcoma (ESTS) include surgical resection with negative margins and perioperative radiotherapy. However, the optimal resection margin remains controversial. This study aimed to evaluate the outcomes in ESTS between microscopically positive margin (R1) and microscopically negative margin (R0) according to the Union for International Cancer Control (UICC) (R + 1 mm) classification. METHODS: Medical records of patients with localized ESTS who underwent primary limb-sparing surgery and postoperative radiotherapy between 2004 and 2015 were retrospectively reviewed. Patients were followed for at least 5 years or till local or distant recurrence was diagnosed during follow-up. Outcomes were local and distal recurrences and survival. RESULTS: A total of 52 patients were included in this study, in which 17 underwent R0 resection and 35 underwent R1 resection. No significant differences were observed in rates of local recurrence (11.4% vs. 35.3%, p = 0.062) or distant recurrence (40.0% vs. 41.18%, p = 0.935) between R0 and R1 groups. Multivariate analysis showed that distant recurrences was associated with a Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade (Grade III vs. I, adjusted hazard ratio (aHR): 12.53, 95% confidence interval (CI): 2.67-58.88, p = 0.001) and tumor location (lower vs. upper extremity, aHR: 0.23, 95% CI: 0.07-0.7, p = 0.01). Kaplan-Meier plots showed no significant differences in local (p = 0.444) or distant recurrent-free survival (p = 0.161) between R0 and R1 groups. CONCLUSIONS: R1 margins, when complemented by radiotherapy, did not significantly alter outcomes of ESTS as R0 margins. Further studies with more histopathological types and larger cohorts are necessary to highlight the path forward.

The revision and factor analytic evaluation of the German version of the depression literacy scale (D-Lit-R German).

BACKGROUND: Depression is a common mental health disorder and the second leading cause of disability worldwide. In people with depression, low depression literacy, which could be characterized by a poor recognition of depressive symptoms and less knowledge about the availability of treatment options, can hinder adequate therapy for depression. Nevertheless, questionnaires measuring depression literacy in Germany are rare. Consequently, for the present study, the German Depression Literacy Scale (D-Lit) has been revised and evaluated. METHODS: First, a team of clinical psychologists revised the D-Lit German scale. Next, cognitive interviews were conducted with patients with depression to improve the comprehensibility of the scale items. Our revision of the D-Lit-R German scale was then subjected to an anonymous online study. Finally, the data went through an exploratory factor analysis, and sociodemographic subgroup analyses were performed. RESULTS: N = 524 individuals (age 18-80) completed the D-Lit-R German scale and a questionnaire on their sociodemographic data. Cronbach´s alpha was estimated as α = .72, and McDonald's Omega (categorical) was estimated as ω = .77. The mean Item difficulty was M = .75 (SD = .15). An EFA was performed for a unidimensional model, a 5-factor-model and at last a 3-factor-model. The 5-factorial model showed a good model fit (χ2emp,WLSMV(131) = 92.424, p > .05; CFI = 1, RMSEA = 0, SRMR = .07) but was rejected since the content of the potential 5 factors could not be determined. The 3-factor model showed an arguable model fit. The Chi2 test was significant (χ2emp,WLSMV(168) = 199.912, p < .05), but the CFI and the RMSEA met an acceptable model fit (CFI = .990, RMSEA of .019, 90% CI[.003, .029]). Substantively, the three factors were defined as (1) Distractors and other symptoms, (2) Depressive symptoms, and (3) Pharmacological and psychotherapeutic depression treatment. Furthermore, there were significant differences in sum scores regarding the subgroup's gender, treatment for mental health problems, depression treatment, experience with depression, and different career fields. CONCLUSIONS: The D-Lit-R German scale is a time-efficient scale to assess some aspects of the depression literacy construct that can be easily applied. Since there was no perfect model fit, it is recommended to continue to revise the scale. Further evaluation studies could ask for knowledge of the etiological factors of depression. Future studies could then use this instrument to convey depression literacy. This instrument could assess the growth of knowledge after psychoeducational interventions in different settings. TRIAL REGISTRATION: This trial was preregistered at the platform osf.io ( https://osf.io/49xdh ). REGISTRATION NUMBER: https://doi.org/10.17605/OSF.IO/49XDH Date of registration: 28 April 2022.

ICH S1 prospective evaluation study: weight of evidence approach to predict outcome and value of 2-year rat carcinogenicity studies. A report from the regulatory authorities subgroup.

Introduction: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) initiated a process in 2012 to revise the S1B Guideline "Testing for Carcinogenicity of Pharmaceuticals". Previous retrospective analysis indicated the importance of histopathological risk factors in chronic toxicity studies, evidence of endocrine perturbation, and positive genetic toxicology results as potentially predictive indicators of carcinogenic risk. In addition, a relationship between pharmacodynamic activity and carcinogenicity outcome in long-term rodent studies has been reported. It was postulated that these factors could be evaluated in a Weight-of-Evidence (WoE) approach to predict the outcome of a 2-year rat study. Methods: The ICH S1B(R1) Expert Working Group (EWG) conducted a Prospective Evaluation Study (PES) to determine the regulatory feasibility of this WoE approach. Drug Regulatory Authorities (DRAs) evaluated 49 Carcinogenicity Assessment Documents (CADs), which describe the WoE for submitted pharmaceutical compounds. Each compound was categorized into a carcinogenic risk category including a statement of the value of the 2-year rat study. The outcome of the completed 2-year rat studies was evaluated in relation to the prospective CAD to determine the accuracy of predictions. Results: Based on the results of the PES, the EWG concluded that the evaluation process for assessing human carcinogenic risk of pharmaceuticals described in ICH S1B could be expanded to include a WoE approach. Approximately 27% of 2-year rat studies could be avoided in cases where DRAs and sponsors unanimously agreed that such a study would not add value. Discussion: Key factors supporting a WoE assessment were identified: data that inform carcinogenic potential based on drug target biology and the primary pharmacologic mechanism of the parent compound and major human metabolites; results from secondary pharmacology screens for this compound and major human metabolites that inform carcinogenic risk; histopathology data from repeated-dose toxicity studies; evidence for hormonal perturbation; genotoxicity data; and evidence of immune modulation. The outcome of the PES indicates that a WoE approach can be used in place of conducting a 2-year rat study for some pharmaceuticals. These data were used by the ICH S1B(R1) EWG to write the R1 Addendum to the S1B Guideline published in August 2022.

Prognosis and therapeutic significance of IGF-1R-related signaling pathway gene signature in glioma.

Background: Glioma is the most common cancer of the central nervous system with poor therapeutic response and clinical prognosis. Insulin-like growth factor 1 receptor (IGF-1R) signaling is implicated in tumor development and progression and induces apoptosis of cancer cells following functional inhibition. However, the relationship between the IGF-1R-related signaling pathway genes and glioma prognosis or immunotherapy/chemotherapy is poorly understood. Methods: LASSO-Cox regression was employed to develop a 16-gene risk signature in the TCGA-GBMLGG cohort, and all patients with glioma were divided into low-risk and high-risk subgroups. The relationships between the risk signature and the tumor immune microenvironment (TIME), immunotherapy response, and chemotherapy response were then analyzed. Immunohistochemistry was used to evaluate the HSP90B1 level in clinical glioma tissue. Results: The gene risk signature yielded superior predictive efficacy in prognosis (5-year area under the curve: 0.875) and can therefore serve as an independent prognostic indicator in patients with glioma. The high-risk subgroup exhibited abundant immune infltration and elevated immune checkpoint gene expression within the TIME. Subsequent analysis revealed that patients in the high-risk subgroup benefited more from chemotherapy. Immunohistochemical analysis confirmed that HSP90B1 was overexpressed in glioma, with significantly higher levels observed in glioblastoma than in astrocytoma or oligodendrocytoma. Conclusion: The newly identified 16-gene risk signature demonstrates a robust predictive capacity for glioma prognosis and plays a pivotal role in the TIME, thereby offering valuable insights for the exploration of novel biomarkers and targeted therapeutics.

Circ_0044235 regulates the development of osteoarthritis by the modulation of miR-375/PIK3R3 axis.

BACKGROUND: Circular RNAs (circRNAs) play an important role in osteoarthritis (OA). However, the role of circRNA in OA is still unclear. Here, we explored the role and mechanism of circ_0044235 in OA. METHODS: CHON-001 cells were treated with IL-1ß to establish OA model in vitro. The levels of circ_0044235, miR-375 and phosphoinositide 3-kinase (PI3K) regulatory subunit 3 (PIK3R3) were detected by quantitative real-time PCR. Cell count kit-8 assay and flow cytometry assay were used to detect cell viability and apoptosis. The concentrations of inflammation factors were determined by enzyme-linked immunosorbent assay. Western blot was used to detect protein levels. The interaction between miR-375 and circ_0044235 or PIK3R3 was analyzed by dual-luciferase reporter assay and RNA immunoprecipitation assay. RESULTS: Circ_0044235 was significantly decreased in OA cartilage tissue and IL-1ß-treated CHON-001 cells. Overexpression of circ_0044235 promoted IL-1ß-stimulated CHON-001 cell viability and inhibited apoptosis, inflammation, and extracellular matrix (ECM) degradation. In mechanism analysis, circ_0044235 could act as a sponge for miR-375 and positively regulate PIK3R3 expression. In addition, miR-375 ameliorated the effect of circ_0044235 overexpression on IL-1ß-mediated CHON-001 cells injury. In addition, miR-375 inhibition mitigated IL-1ß-induced CHON-001 cell injury, while PIK3R3 silencing restored the effect. CONCLUSION: Circ_0044235 knockdown alleviated IL-1ß-induced chondrocytes injury by regulating miR-375/PIK3R3 axis, confirming that circ_0044235 might be a potential target for OA treatment.

Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis.

BACKGROUND: Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family. METHODS: The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep-/-. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS). RESULTS: Excessive production of reactive oxygen species (ROS) decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis. CONCLUSIONS: This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury.

Structural determinants for activation of the Tau kinase CDK5 by the serotonin receptor 5-HT7R.

BACKGROUND: Multiple neurodegenerative diseases are induced by the formation and deposition of protein aggregates. In particular, the microtubule-associated protein Tau leads to the development of so-called tauopathies characterized by the aggregation of hyperphosphorylated Tau within neurons. We recently showed that the constitutive activity of the serotonin receptor 7 (5-HT7R) is required for Tau hyperphosphorylation and aggregation through activation of the cyclin-dependent kinase 5 (CDK5). We also demonstrated physical interaction between 5-HT7R and CDK5 at the plasma membrane suggesting that the 5-HT7R/CDK5 complex is an integral part of the signaling network involved in Tau-mediated pathology. METHODS: Using biochemical, microscopic, molecular biological, computational and AI-based approaches, we investigated structural requirements for the formation of 5-HT7R/CDK5 complex. RESULTS: We demonstrated that 5-HT7R domains responsible for coupling to Gs proteins are not involved in receptor interaction with CDK5. We also created a structural model of the 5-HT7R/CDK5 complex and refined the interaction interface. The model predicted two conserved phenylalanine residues, F278 and F281, within the third intracellular loop of 5-HT7R to be potentially important for complex formation. While site-directed mutagenesis of these residues did not influence Gs protein-mediated receptor signaling, replacement of both phenylalanines by alanine residues significantly reduced 5-HT7R/CDK5 interaction and receptor-mediated CDK5 activation, leading to reduced Tau hyperphosphorylation and aggregation. Molecular dynamics simulations of 5-HT7R/CDK5 complex for wild-type and receptor mutants confirmed binding interface stability of the initial model. CONCLUSIONS: Our results provide a structural basis for the development of novel drugs targeting the 5-HT7R/CDK5 interaction interface for the selective treatment of Tau-related disorders, including frontotemporal dementia and Alzheimer's disease.

GbyE: an integrated tool for genome widely association study and genome selection based on genetic by environmental interaction.

BACKGROUND: The growth and development of organism were dependent on the effect of genetic, environment, and their interaction. In recent decades, lots of candidate additive genetic markers and genes had been detected by using genome-widely association study (GWAS). However, restricted to computing power and practical tool, the interactive effect of markers and genes were not revealed clearly. And utilization of these interactive markers is difficult in the breeding and prediction, such as genome selection (GS). RESULTS: Through the Power-FDR curve, the GbyE algorithm can detect more significant genetic loci at different levels of genetic correlation and heritability, especially at low heritability levels. The additive effect of GbyE exhibits high significance on certain chromosomes, while the interactive effect detects more significant sites on other chromosomes, which were not detected in the first two parts. In prediction accuracy testing, in most cases of heritability and genetic correlation, the majority of prediction accuracy of GbyE is significantly higher than that of the mean method, regardless of whether the rrBLUP model or BGLR model is used for statistics. The GbyE algorithm improves the prediction accuracy of the three Bayesian models BRR, BayesA, and BayesLASSO using information from genetic by environmental interaction (G × E) and increases the prediction accuracy by 9.4%, 9.1%, and 11%, respectively, relative to the Mean value method. The GbyE algorithm is significantly superior to the mean method in the absence of a single environment, regardless of the combination of heritability and genetic correlation, especially in the case of high genetic correlation and heritability. CONCLUSIONS: Therefore, this study constructed a new genotype design model program (GbyE) for GWAS and GS using Kronecker product. which was able to clearly estimate the additive and interactive effects separately. The results showed that GbyE can provide higher statistical power for the GWAS and more prediction accuracy of the GS models. In addition, GbyE gives varying degrees of improvement of prediction accuracy in three Bayesian models (BRR, BayesA, and BayesCpi). Whatever the phenotype were missed in the single environment or multiple environments, the GbyE also makes better prediction for inference population set. This study helps us understand the interactive relationship between genomic and environment in the complex traits. The GbyE source code is available at the GitHub website ( https://github.com/liu-xinrui/GbyE ).

Enhancing assisted diagnostic accuracy in scalp psoriasis: A Multi-Network Fusion Object Detection Framework for dermoscopic pattern diagnosis.

BACKGROUND: Dermoscopy is a common method of scalp psoriasis diagnosis, and several artificial intelligence techniques have been used to assist dermoscopy in the diagnosis of nail fungus disease, the most commonly used being the convolutional neural network algorithm; however, convolutional neural networks are only the most basic algorithm, and the use of object detection algorithms to assist dermoscopy in the diagnosis of scalp psoriasis has not been reported. OBJECTIVES: Establishment of a dermoscopic modality diagnostic framework for scalp psoriasis based on object detection technology and image enhancement to improve diagnostic efficiency and accuracy. METHODS: We analyzed the dermoscopic patterns of scalp psoriasis diagnosed at 72nd Group army hospital of PLA from January 1, 2020 to December 31, 2021, and selected scalp seborrheic dermatitis as a control group. Based on dermoscopic images and major dermoscopic patterns of scalp psoriasis and scalp seborrheic dermatitis, we investigated a multi-network fusion object detection framework based on the object detection technique Faster R-CNN and the image enhancement technique contrast limited adaptive histogram equalization (CLAHE), for assisting in the diagnosis of scalp psoriasis and scalp seborrheic dermatitis, as well as to differentiate the major dermoscopic patterns of the two diseases. The diagnostic performance of the multi-network fusion object detection framework was compared with that between dermatologists. RESULTS: A total of 1876 dermoscopic images were collected, including 1218 for scalp psoriasis versus 658 for scalp seborrheic dermatitis. Based on these images, training and testing are performed using a multi-network fusion object detection framework. The results showed that the test accuracy, specificity, sensitivity, and Youden index for the diagnosis of scalp psoriasis was: 91.0%, 89.5%, 91.0%, and 0.805, and for the main dermoscopic patterns of scalp psoriasis and scalp seborrheic dermatitis, the diagnostic results were: 89.9%, 97.7%, 89.9%, and 0.876. Comparing the diagnostic results with those of five dermatologists, the fusion framework performs better than the dermatologists' diagnoses. CONCLUSIONS: Studies have shown some differences in dermoscopic patterns between scalp psoriasis and scalp seborrheic dermatitis. The proposed multi-network fusion object detection framework has higher diagnostic performance for scalp psoriasis than for dermatologists.

Turnover of PPP1R15A mRNA encoding GADD34 controls responsiveness and adaptation to cellular stress.

The integrated stress response (ISR) is a key cellular signaling pathway activated by environmental alterations that represses protein synthesis to restore homeostasis. To prevent sustained damage, the ISR is counteracted by the upregulation of growth arrest and DNA damage-inducible 34 (GADD34), a stress-induced regulatory subunit of protein phosphatase 1 that mediates translation reactivation and stress recovery. Here, we uncover a novel ISR regulatory mechanism that post-transcriptionally controls the stability of PPP1R15A mRNA encoding GADD34. We establish that the 3' untranslated region of PPP1R15A mRNA contains an active AU-rich element (ARE) recognized by proteins of the ZFP36 family, promoting its rapid decay under normal conditions and stabilization for efficient expression of GADD34 in response to stress. We identify the tight temporal control of PPP1R15A mRNA turnover as a component of the transient ISR memory, which sets the threshold for cellular responsiveness and mediates adaptation to repeated stress conditions.