Shortfalls of free autologous internal limiting membrane transplantation for highly myopic refractory macular holes in a long term follow-up.

BACKGROUND: The aim of this study is to evaluate long-term anatomical and functional outcomes of autologous internal limiting membrane (ILM) transplantation in refractory highly myopic macular holes (HMMHs). METHODS: Retrospective interventional analysis of 13 eyes with refractory HMMH undergoing autologous ILM transplantation with gas tamponade. Best-corrected visual acuity (BCVA, Snellen), optical coherence tomography and fundus photography were scheduled at baseline and every follow-up visit (1, 3, 6, 12, 18, 24 months and the most recent). Preoperatively, we collected minimum linear diameter (MLD) and basal diameter (BD). Post-operatively, rates of external limiting membrane (ELM)/ellipsoid zone (EZ) restoration, excessive gliosis and subfoveal retinal pigmented epithelium (RPE) atrophy were evaluated. RESULTS: Average AXL was 31.45 ± 2.07 mm and mean follow-up was 47.2 ± 31.4 months. Anatomical success was reached in 7/13 eyes (54%), while 2 cases showed persisting HMMH, 2 cases had early recurrence and 2 cases late recurrence. BCVA went from 0.19 ± 0.18 to 0.22 ± 0.20 at final follow-up (p = 0.64), improving in 5/13 eyes (38%). One eye showed continuous ELM and EZ lines, while another eye showed an irregular ELM but no EZ. Post-operatively, 5 eyes (71%) developed progressive atrophy of the subfoveal RPE, while excessive gliosis was reported in 3 eyes (43%). Furthermore, one patient developed post-operative chronic macular edema-like changes in the perifoveal area. CONCLUSION: Autologous ILM transplantation showed controversial anatomical outcomes and and poor visual results in refractory HMMH. Moreover, progressive subfoveal patchy atrophy and excessive gliosis are possible post-operative complications.

Systemic inflammation, oxidative damage and neurocognition predict telomere length in a transdiagnostic sample stratified by global DNA methylation levels.

Epigenetic mechanisms contribute to the maintenance of both type 2 diabetes mellitus (T2DM) and psychiatric disorders. Emerging evidence suggests that molecular pathways and neurocognitive performance regulate epigenetic dynamics in these disorders. The current combined and transdiagnostic study investigated whether inflammatory, oxidative stress, adhesion molecule, neurocognitive and functional performance are significant predictors of telomere dynamics in a sample stratified by global DNA methylation levels. Peripheral blood inflammation, oxidative stress and adhesion molecule biomarkers and neurocognitive function were assessed twice over a 1-year period in 80 individuals, including 16 with schizophrenia (SZ), 16 with bipolar disorder (BD), 16 with major depressive disorder (MDD), 15 with T2DM, and 17 healthy controls (HCs). Leukocyte telomere length (LTL) was measured by qRT-PCR using deoxyribonucleic acid (DNA) extracted from peripheral blood samples. A posteriori, individuals were classified based on their global methylation score (GMS) at baseline into two groups: the below-average methylation (BM) and above-average methylation (AM) groups. Hierarchical and k-means clustering methods, mixed one-way analysis of variance and linear regression analyses were performed. Overall, the BM group showed a significantly higher leukocyte telomere length (LTL) than the AM group at both time points (p = 0.02; η2p = 0.06). Moreover, the BM group had significantly lower levels of tumor necrosis factor alpha (TNF-α) (p = 0.03; η2p = 0.06) and C-reactive protein (CRP) (p = 0.03; η2p = 0.06) than the AM group at the 1-year follow-up. Across all participants, the regression models showed that oxidative stress (reactive oxygen species [ROS]) (p = 0.04) and global cognitive score [GCS] (p = 0.02) were significantly negatively associated with LTL, whereas inflammatory (TNF-α) (p = 0.04), adhesion molecule biomarkers (inter cellular adhesion molecule [ICAM]) (p = 0.009), and intelligence quotient [IQ] (p = 0.03) were significantly positively associated with LTL. Moreover, the model predictive power was increased when tested in both groups separately, explaining 15.8% and 28.1% of the LTL variance at the 1-year follow-up for the AM and BM groups, respectively. Heterogeneous DNA methylation in individuals with T2DM and severe mental disorders seems to support the hypothesis that epigenetic dysregulation occurs in a transdiagnostic manner. Our results may help to elucidate the interplay between epigenetics, molecular processes and neurocognitive function in these disorders. DNA methylation and LTL are potential therapeutic targets for transdiagnostic interventions to decrease the risk of comorbidities.

A Multilayer Perceptron-Based Spherical Visual Compass Using Global Features.

This paper presents a visual compass method utilizing global features, specifically spherical moments. One of the primary challenges faced by photometric methods employing global features is the variation in the image caused by the appearance and disappearance of regions within the camera's field of view as it moves. Additionally, modeling the impact of translational motion on the values of global features poses a significant challenge, as it is dependent on scene depths, particularly for non-planar scenes. To address these issues, this paper combines the utilization of image masks to mitigate abrupt changes in global feature values and the application of neural networks to tackle the modeling challenge posed by translational motion. By employing masks at various locations within the image, multiple estimations of rotation corresponding to the motion of each selected region can be obtained. Our contribution lies in offering a rapid method for implementing numerous masks on the image with real-time inference speed, rendering it suitable for embedded robot applications. Extensive experiments have been conducted on both real-world and synthetic datasets generated using Blender. The results obtained validate the accuracy, robustness, and real-time performance of the proposed method compared to a state-of-the-art method.

The lincRNA JUNI regulates the stress-dependent induction of c-Jun, cellular migration and survival through the modulation of the DUSP14-JNK axis.

Cancer cells employ adaptive mechanisms to survive various stressors, including genotoxic drugs. Understanding the factors promoting survival is crucial for developing effective treatments. In this study, we unveil a previously unexplored long non-coding RNA, JUNI (JUN-DT, LINC01135), which is upregulated by genotoxic drugs through the activation of stress-activated MAPKs, JNK, and p38 and consequently exerts positive control over the expression of its adjacent gene product c-Jun, a well-known oncoprotein, which transduces signals to multiple transcriptional outputs. JUNI regulates cellular migration and has a crucial role in conferring cellular resistance to chemotherapeutic drugs or UV radiation. Depletion of JUNI markedly increases the sensitivity of cultured cells and spheroids to chemotherapeutic agents. We identified 57 proteins interacting with JUNI. The activity of one of them the MAPK phosphatase and inhibitor, DUSP14, is counteracted by JUNI, thereby, facilitating efficient JNK phosphorylation and c-Jun induction when cells are exposed to UV radiation. The antagonistic interplay with DUSP14 contributes not only to c-Jun induction but also augments the survival of UV-exposed cells. In summary, we introduce JUNI as a novel stress-inducible regulator of c-Jun, positioning it as a potential target for enhancing the sensitivity of cancer cells to chemotherapy.

Exploring miRNA-target gene pair detection in disease with coRmiT.

A wide range of approaches can be used to detect micro RNA (miRNA)-target gene pairs (mTPs) from expression data, differing in the ways the gene and miRNA expression profiles are calculated, combined and correlated. However, there is no clear consensus on which is the best approach across all datasets. Here, we have implemented multiple strategies and applied them to three distinct rare disease datasets that comprise smallRNA-Seq and RNA-Seq data obtained from the same samples, obtaining mTPs related to the disease pathology. All datasets were preprocessed using a standardized, freely available computational workflow, DEG_workflow. This workflow includes coRmiT, a method to compare multiple strategies for mTP detection. We used it to investigate the overlap of the detected mTPs with predicted and validated mTPs from 11 different databases. Results show that there is no clear best strategy for mTP detection applicable to all situations. We therefore propose the integration of the results of the different strategies by selecting the one with the highest odds ratio for each miRNA, as the optimal way to integrate the results. We applied this selection-integration method to the datasets and showed it to be robust to changes in the predicted and validated mTP databases. Our findings have important implications for miRNA analysis. coRmiT is implemented as part of the ExpHunterSuite Bioconductor package available from https://bioconductor.org/packages/ExpHunterSuite.

Validation of circulating histone detection by mass spectrometry for early diagnosis, prognosis, and management of critically ill septic patients.

BACKGROUND: As leading contributors to worldwide morbidity and mortality, sepsis and septic shock are considered a major global health concern. Proactive biomarker identification in patients with sepsis suspicion at any time remains a daunting challenge for hospitals. Despite great progress in the understanding of clinical and molecular aspects of sepsis, its definition, diagnosis, and treatment remain challenging, highlighting a need for new biomarkers with potential to improve critically ill patient management. In this study we validate a quantitative mass spectrometry method to measure circulating histone levels in plasma samples for the diagnosis and prognosis of sepsis and septic shock patients. METHODS: We used the mass spectrometry technique of multiple reaction monitoring to quantify circulating histones H2B and H3 in plasma from a monocenter cohort of critically ill patients admitted to an Intensive Care Unit (ICU) and evaluated its performance for the diagnosis and prognosis of sepsis and septic shock (SS). RESULTS: Our results highlight the potential of our test for early diagnosis of sepsis and SS. H2B levels above 121.40 ng/mL (IQR 446.70) were indicative of SS. The value of blood circulating histones to identify a subset of SS patients in a more severe stage with associated organ failure was also tested, revealing circulating levels of histones H2B above 435.61 ng/ml (IQR 2407.10) and H3 above 300.61 ng/ml (IQR 912.77) in septic shock patients with organ failure requiring invasive organ support therapies. Importantly, we found levels of H2B and H3 above 400.44 ng/mL (IQR 1335.54) and 258.25 (IQR 470.44), respectively in those patients who debut with disseminated intravascular coagulation (DIC). Finally, a receiver operating characteristic curve (ROC curve) demonstrated the prognostic value of circulating histone H3 to predict fatal outcomes and found for histone H3 an area under the curve (AUC) of 0.720 (CI 0.546-0.895) p < 0.016 on a positive test cut-off point at 486.84 ng/mL, showing a sensitivity of 66.7% and specificity of 73.9%. CONCLUSIONS: Circulating histones analyzed by MS can be used to diagnose SS and identify patients at high risk of suffering DIC and fatal outcome.

Age-Related microRNA Overexpression in Lafora Disease Male Mice Provides Links between Neuroinflammation and Oxidative Stress.

Lafora disease is a rare, fatal form of progressive myoclonus epilepsy characterized by continuous neurodegeneration with epileptic seizures, characterized by the intracellular accumulation of aberrant polyglucosan granules called Lafora bodies. Several works have provided numerous evidence of molecular and cellular alterations in neural tissue from experimental mouse models deficient in either laforin or malin, two proteins related to the disease. Oxidative stress, alterations in proteostasis, and deregulation of inflammatory signals are some of the molecular alterations underlying this condition in both KO animal models. Lafora bodies appear early in the animal's life, but many of the aforementioned molecular aberrant processes and the consequent neurological symptoms ensue only as animals age. Here, using small RNA-seq and quantitative PCR on brain extracts from laforin and malin KO male mice of different ages, we show that two different microRNA species, miR-155 and miR-146a, are overexpressed in an age-dependent manner. We also observed altered expression of putative target genes for each of the microRNAs studied in brain extracts. These results open the path for a detailed dissection of the molecular consequences of laforin and malin deficiency in brain tissue, as well as the potential role of miR-155 and miR-146a as specific biomarkers of disease progression in LD.

Modified perfluorocarbon liquid/internal limiting membrane interface staining in myopic macular hole retinal detachment.

PURPOSE: To demonstrate a modified technique of perfluorocarbon liquid (PFCL)/internal limiting membrane (ILM) interface staining in patients affected by macular hole retinal detachment (MHRD) in the setting of high myopia. METHODS: Two-surgeon retrospective case series and review of surgical videos with step-by-step technique analysis. RESULTS: Our modified technique was proficiently employed to treat 9 highly myopic patients affected by MHRD. Successful staining and peeling of the ILM with the creation of an inverted flap was achieved in all cases. A limited number of dye injections required to stain the ILM was noted. No subretinal dye migration or other intra- and postoperative complications were recorded. CONCLUSION: Modified PFCL/ILM interface staining is a surgically efficient technique potentially reducing the risk of iatrogenic damage, including the toxicity of vital dyes to the retinal pigment epithelium (RPE) in myopic MHRD.

Reflectance evaluation of eye fundus structures with a visible and near-infrared multispectral camera.

We examined the spectral reflectance of fundus structures in the visible and near-infrared (400-1300 nm) range for contributing to the medical diagnosis of fundus diseases. Spectral images of healthy eye fundus and other ocular diseases were acquired using a novel multispectral fundus camera. Reflectance metrics were computed based on contrast to analyze the spectral features. Significant differences were observed among the structures in healthy and diseased eye fundus. Specifically, near-infrared analysis allows imaging of deeper layers, such as the choroid, which, to date, has not been retrieved using traditional color fundus cameras. Pathological structures, which were hardly observable in color fundus images owing to metamerism, were also revealed by the developed multispectral fundus camera.

Territorial Strategy of Medical Units for Addressing the First Wave of the COVID-19 Pandemic in the Metropolitan Area of Mexico City: Analysis of Mobility, Accessibility and Marginalization.

BACKGROUND: The COVID-19 pandemic has caused an exponential increase in the demand for medical care worldwide. In Mexico, the COVID Medical Units (CMUs) conversion strategy was implemented. OBJECTIVE: To evaluate the CMU coverage strategy in the Mexico City Metropolitan Area (MCMA) by territory. MATERIALS: The CMU directory was used, as were COVID-19 infection and mobility statistics and Mexican 2020 census information at the urban geographic area scale. The degree of urban marginalization by geographic area was also considered. METHOD: Using descriptive statistics and the calculation of a CMU accessibility index, population aggregates were counted based on coverage radii. In addition, two regression models are proposed to explain (1) the territorial and temporal trend of COVID-19 infections in the MCMA and (2) the mobility of the COVID-infected population visiting medical units. RESULTS: The findings of the evaluation of the CMU strategy were (1) in the MCMA, COVID-19 followed a pattern of contagion from the urban center to the periphery; (2) given the growth in the number of cases and the overload of medical units, the population traveled greater distances to seek medical care; (3) after the CMU strategy was evaluated at the territory level, it was found that 9 out of 10 inhabitants had a CMU located approximately 7 km away; and (4) at the metropolitan level, the lowest level of accessibility to the CMU was recorded for the population with the highest levels of marginalization, i.e., those residing in the urban periphery.

Comparative Analysis of Chromatin-Delivered Biomarkers in the Monitoring of Sepsis and Septic Shock: A Pilot Study.

Sepsis management remains one of the most important challenges in modern clinical practice. Rapid progression from sepsis to septic shock is practically unpredictable, hence the critical need for sepsis biomarkers that can help clinicians in the management of patients to reduce the probability of a fatal outcome. Circulating nucleoproteins released during the inflammatory response to infection, including neutrophil extracellular traps, nucleosomes, and histones, and nuclear proteins like HMGB1, have been proposed as markers of disease progression since they are related to inflammation, oxidative stress, endothelial damage, and impairment of the coagulation response, among other pathological features. The aim of this work was to evaluate the actual potential for decision making/outcome prediction of the most commonly proposed chromatin-related biomarkers (i.e., nucleosomes, citrullinated H3, and HMGB1). To do this, we compared different ELISA measuring methods for quantifying plasma nucleoproteins in a cohort of critically ill patients diagnosed with sepsis or septic shock compared to nonseptic patients admitted to the intensive care unit (ICU), as well as to healthy subjects. Our results show that all studied biomarkers can be used to monitor sepsis progression, although they vary in their effectiveness to separate sepsis and septic shock patients. Our data suggest that HMGB1/citrullinated H3 determination in plasma is potentially the most promising clinical tool for the monitoring and stratification of septic patients.

IGF-1 Haploinsufficiency Causes Age-Related Chronic Cochlear Inflammation and Increases Noise-Induced Hearing Loss.

Insulin-like growth factor 1 (IGF-1) deficiency is an ultrarare syndromic human sensorineural deafness. Accordingly, IGF-1 is essential for the postnatal maturation of the cochlea and the correct wiring of hearing in mice. Less severe decreases in human IGF-1 levels have been associated with other hearing loss rare genetic syndromes, as well as with age-related hearing loss (ARHL). However, the underlying mechanisms linking IGF-1 haploinsufficiency with auditory pathology and ARHL have not been studied. Igf1-heterozygous mice express less Igf1 transcription and have 40% lower IGF-1 serum levels than wild-type mice. Along with ageing, IGF-1 levels decreased concomitantly with the increased expression of inflammatory cytokines, Tgfb1 and Il1b, but there was no associated hearing loss. However, noise exposure of these mice caused increased injury to sensory hair cells and irreversible hearing loss. Concomitantly, there was a significant alteration in the expression ratio of pro- and anti-inflammatory cytokines in Igf1+/- mice. Unbalanced inflammation led to the activation of the stress kinase JNK and the failure to activate AKT. Our data show that IGF-1 haploinsufficiency causes a chronic subclinical proinflammatory age-associated state and, consequently, greater susceptibility to stressors. This work provides the molecular bases to further understand hearing disorders linked to IGF-1 deficiency.

Bainitic Ferrite Plate Thickness Evolution in Two Nanostructured Steels.

Bainitic ferrite plate thickness evolution during isothermal transformation was followed at the same holding temperatures in two nanostructured steels containing (in wt.%) 1C-2Si and 0.4C-3Si. A dynamic picture of how the bainitic transformation evolves was obtained from the characterization of the microstructure present at room temperature after full and partial transformation at 300 and 350 °C. The continuous change during transformation of relevant parameters influencing the final scale of the microstructure, YS of austenite, driving force of the transformation and evolution of the transformation rate has been tracked, and these variations have been correlated to the evolution of the bainitic ferrite plate. Instead of the expected refinement of the plate predicted by existing theory and models, this study revealed a thickening of the bainitic ferrite plate thickness as the transformation progresses, which is partially explained by changes in the transformation rate through the whole decomposition of austenite into bainitic ferrite.

Gene expression analysis method integration and co-expression module detection applied to rare glucide metabolism disorders using ExpHunterSuite.

High-throughput gene expression analysis is widely used. However, analysis is not straightforward. Multiple approaches should be applied and methods to combine their results implemented and investigated. We present methodology for the comprehensive analysis of expression data, including co-expression module detection and result integration via data-fusion, threshold based methods, and a Naïve Bayes classifier trained on simulated data. Application to rare-disease model datasets confirms existing knowledge related to immune cell infiltration and suggest novel hypotheses including the role of calcium channels. Application to simulated and spike-in experiments shows that combining multiple methods using consensus and classifiers leads to optimal results. ExpHunter Suite is implemented as an R/Bioconductor package available from https://bioconductor.org/packages/ExpHunterSuite . It can be applied to model and non-model organisms and can be run modularly in R; it can also be run from the command line, allowing scalability with large datasets. Code and reports for the studies are available from https://github.com/fmjabato/ExpHunterSuiteExamples .

Oxidative Stress and Rare Diseases: From Molecular Crossroads to Therapeutic Avenues.

Writing an editorial about rare diseases can become a messy subject from the biological perspective [...].

Oxidative stress-mediated alterations in histone post-translational modifications.

Epigenetic regulation of gene expression provides a finely tuned response capacity for cells when undergoing environmental changes. However, in the context of human physiology or disease, any cellular imbalance that modulates homeostasis has the potential to trigger molecular changes that result either in physiological adaptation to a new situation or pathological conditions. These effects are partly due to alterations in the functionality of epigenetic regulators, which cause long-term and often heritable changes in cell lineages. As such, free radicals resulting from unbalanced/extended oxidative stress have been proved to act as modulators of epigenetic agents, resulting in alterations of the epigenetic landscape. In the present review we will focus on the particular effect that oxidative stress and free radicals produce in histone post-translational modifications that contribute to altering the histone code and, consequently, gene expression. The pathological consequences of the changes in this epigenetic layer of regulation of gene expression are thoroughly evidenced by data gathered in many physiological adaptive processes and in human diseases that range from age-related neurodegenerative pathologies to cancer, and that include respiratory syndromes, infertility, and systemic inflammatory conditions like sepsis.

Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich's Ataxia.

The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich's ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.

Dilatometric and Microstructural Study of Martensite Tempering in 4% Mn Steel.

This paper presents the results of martensite tempering resistance in 4% Mn steel. The material was quenched and tempered at 350 °C for 15, 30, and 60 min. The analysis of the quenching and tempering was carried out using dilatometric and microstructural approaches. The phase composition was assessed using X-ray diffraction. The Ms temperature and tempering progress were simulated using JMatPro software. The dilatometric analysis revealed a small decrease in the relative change in length (RCL) during tempering. This decrease was connected to the precipitation kinetics of cementite within the martensite laths. The microstructure investigation using a scanning electron microscope showed a very small amount of carbides, even for the longest tempering time. This showed the high tempering resistance of the martensite in medium-Mn steels. The hardness results showed an insignificant decrease in the hardness depending on the tempering time, which confirmed the high tempering resistance of martensite.