Predicting the cognitive impairment with multimodal ophthalmic imaging and artificial neural network for community screening.

BACKGROUND/AIMS: To investigate the comprehensive prediction ability for cognitive impairment in a general elder population using the combination of the multimodal ophthalmic imaging and artificial neural networks. METHODS: Patients with cognitive impairment and cognitively healthy individuals were recruited. All subjects underwent medical history, blood pressure measurement, the Montreal Cognitive Assessment, medical optometry, intraocular pressure and custom-built multimodal ophthalmic imaging, which integrated pupillary light reaction, multispectral imaging, laser speckle contrast imaging and retinal oximetry. Multidimensional parameters were analysed by Student's t-test. Logistic regression analysis and back-propagation neural network (BPNN) were used to identify the predictive capability for cognitive impairment. RESULTS: This study included 104 cognitive impairment patients (61.5% female; mean (SD) age, 68.3 (9.4) years), and 94 cognitively healthy age-matched and sex-matched subjects (56.4% female; mean (SD) age, 65.9 (7.6) years). The variation of most parameters including decreased pupil constriction amplitude (CA), relative CA, average constriction velocity, venous diameter, venous blood flow and increased centred retinal reflectance in 548 nm (RC548) in cognitive impairment was consistent with previous studies while the reduced flow acceleration index and oxygen metabolism were reported for the first time. Compared with the logistic regression model, BPNN had better predictive performance (accuracy: 0.91 vs 0.69; sensitivity: 93.3% vs 61.70%; specificity: 90.0% vs 68.66%). CONCLUSIONS: This study demonstrates retinal spectral signature alteration, neurodegeneration and angiopathy occur concurrently in cognitive impairment. The combination of multimodal ophthalmic imaging and BPNN can be a useful tool for predicting cognitive impairment with high performance for community screening.

Effects of fluorescent protein tdTomato on mouse retina.

Fluorescent proteins (FPs) have been widely used to investigate cellular and molecular interactions and trace biological events in many applications. Some of the FPs have been demonstrated to cause undesirable cellular damage by light-induced ROS production in vivo or in vitro. However, it remains unknown if one of the most popular FPs, tdTomato, has similar effects in neuronal cells. In this study, we discovered that tdTomato expression led to unexpected retinal dysfunction and ultrastructural defects in the transgenic mouse retina. The retinal dysfunction mainly manifested in the reduced photopic electroretinogram (ERG) responses and decreased contrast sensitivity in visual acuity, caused by mitochondrial damages characterized with cellular redistribution, morphological modifications and molecular profiling alterations. Taken together, our findings for the first time demonstrated the retinal dysfunction and ultrastructural defects in the retinas of tdTomato-transgenic mice, calling for a more careful design and interpretation of experiments involved in FPs.

Daily Low-Level Red Light for Spherical Equivalent Error and Axial Length in Children With Myopia: A Randomized Clinical Trial.

Importance: Treatments are needed to slow progression of or reduce incidence of myopia. Objective: To evaluate the efficacy and safety of daily 650-nm low-level red light (LLRL) for myopia treatment. Design, Setting, and Participants: Single-masked, randomized clinical trial at 1 site in China. Baseline measurements were completed from August to September 2021. Participants were children aged 6 to 12 years with spherical equivalent error (SER) of -6 diopters (D) to 3 D. Data were analyzed from March to July 2023. Interventions: Irradiation daily with 650-nm LLRL for 3 minutes twice daily 4 or more hours apart or no intervention. Main Outcomes and Measures: Primary outcomes were changes in cycloplegia SER and axial length (AL) at 6- and 12-month follow-up visits. Safety was assessed on masked fundus photograph evaluations. Results: A total of 336 children were randomly allocated into the LLRL group or control group in a 1:1 ratio. The control group contained 86 female patients (51.2%), and the treatment group contained 90 female patients (53.6%). The mean (SD) age, SER, and AL were 9.0 (1.9) years, -1.3 (1.5) D, and 23.8 (1.0) mm for all patients. A total of 161 (95.8%) in the LLRL group and 159 (94.6%) in the control group returned for the 6-month follow-up. A total of 157 (93.5%) in the LLRL group and 152 (90.5%) in the control group returned for the 12-month follow-up. Mean (SD) changes in SER were 0.15 (0.16) D and -0.26 (0.21) D for the LLRL group and the control group, respectively (difference, -0.41 D; 95% CI, -0.48 to -0.34 D; P < .001), at 6 months and 0.24 (0.27) D and -0.65 (0.33) D for the LLRL group and the control group, respectively (difference, -0.89 D; 95% CI, -0.95 to -0.83 D; P < .001), at 12 months. Mean (SD) changes in AL were -0.06 (0.08) mm and 0.13 (0.12) mm for the LLRL group and control group, respectively (difference, 0.19 mm; 95% CI, 0.16 to 0.22 mm; P < .001), at 6 months and -0.11 (0.10) mm and 0.26 (0.16) mm for the LLRL group and control group, respectively (difference, 0.37 mm; 95% CI, 0.34 to 0.40 mm; P < .001). Masked fundus photograph review did not identify retinal changes in either group. Conclusions and relevance: These findings suggest daily use of 650-nm LLRL for 1 year can slow progression of SER and AL without safety concerns identified. Confirmation of these findings at independent sites seems warranted, as well as determining whether these effects can be sustained with or without continued treatment and whether LLRL has any effect on pathological myopia. Trial Registration: ChiCTR2200058963.

From gut to brain: understanding the role of microbiota in inflammatory bowel disease.

With the proposal of the "biological-psychological-social" model, clinical decision-makers and researchers have paid more attention to the bidirectional interactive effects between psychological factors and diseases. The brain-gut-microbiota axis, as an important pathway for communication between the brain and the gut, plays an important role in the occurrence and development of inflammatory bowel disease. This article reviews the mechanism by which psychological disorders mediate inflammatory bowel disease by affecting the brain-gut-microbiota axis. Research progress on inflammatory bowel disease causing "comorbidities of mind and body" through the microbiota-gut-brain axis is also described. In addition, to meet the needs of individualized treatment, this article describes some nontraditional and easily overlooked treatment strategies that have led to new ideas for "psychosomatic treatment".

Modeling autosomal dominant retinitis pigmentosa by using patient-specific retinal organoids with a class-3 RHO mutation.

Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP) causes progressive vision loss and is potentially incurable, accounting for 25% of adRP cases. Studies on RHO-adRP mechanism were at large based on the biochemical and cellular properties, especially class-3. Nonetheless, the absence of an appropriate model for class-3 RHO-adRP has impeded comprehensive exploration. Here, induced pluripotent stem cells (iPSCs) were generated from a healthy control and two sibling RP patients with the same point mutation, c.403C>T (p.R135W). The first three-dimensional (3D) retinal organoid model of a class-3 RHO point mutation from patient-derived iPSCs was generated. Significant defects were observed in rod photoreceptors in terms of localization, morphology, transcriptional profiling and single cell resolution, to better understand the human disease resulting from RHO mutations from a developmental perspective. This first human model of class-3 RHO-adRP provides a representation of patient's retina in vitro and displays features of RHO-adRP retinal organoids relevant for therapeutic development.

The retinal oxygen metabolism and hemodynamics as a substitute for biochemical tests to predict nonproliferative diabetic retinopathy.

Predicting the occurrence of nonproliferative diabetic retinopathy (NPDR) using biochemical parameters is invasive, which limits large-scale clinical application. Noninvasive retinal oxygen metabolism and hemodynamics of 215 eyes from 73 age-matched healthy subjects, 90 diabetic patients without DR, 40 NPDR, and 12 DR with postpanretinal photocoagulation were measured with a custom-built multimodal retinal imaging device. Diabetic patients underwent biochemical examinations. Two logistic regression models were developed to predict NPDR using retinal and biochemical metrics, respectively. The predictive model 1 using retinal metrics incorporated male gender, insulin treatment condition, diastolic duration, resistance index, and oxygen extraction fraction presented a similar predictive power with model 2 using biochemical metrics incorporated diabetic duration, diastolic blood pressure, and glycated hemoglobin A1c (area under curve: 0.73 vs. 0.70; sensitivity: 76% vs. 68%; specificity: 64% vs. 62%). These results suggest that retinal oxygen metabolic and hemodynamic biomarkers may replace biochemical parameters to predict the occurrence of NPDR .

A Novel Grading System for Diffuse Chorioretinal Atrophy in Pathologic Myopia.

INTRODUCTION: This study aims to quantitatively assess diffuse chorioretinal atrophy (DCA) in pathologic myopia and establish a standardized classification system utilizing artificial intelligence. METHODS: A total of 202 patients underwent comprehensive examinations, and 338 eyes were included in the study. The methodology involved image preprocessing, sample labeling, employing deep learning segmentation models, measuring and calculating the area and density of DCA lesions. Lesion severity of DCA was graded using statistical methods, and grades were assigned to describe the morphology of corresponding fundus photographs. Hierarchical clustering was employed to categorize diffuse atrophy fundus into three groups based on the area and density of diffuse atrophy (G1, G2, G3), while high myopic fundus without diffuse atrophy was designated as G0. One-way analysis of variance (ANOVA) and nonparametric tests were conducted to assess the statistical association with different grades of DCA. RESULTS: On the basis of the area and density of DCA, the condition was classified into four grades: G0, G1 (0 < density ≤ 0.093), G2 (0.093 < density ≤ 0.245), and G3 (0.245 < density ≤ 0.712). Fundus photographs depicted a progressive enlargement of atrophic lesions, evolving from punctate-shaped to patchy with indistinct boundaries. DCA atrophy lesions exhibited a gradual shift in color from brown-yellow to yellow-white, originating from the temporal side of the optic disc and extending towards the macula, with severe cases exhibiting widespread distribution throughout the posterior pole. Patients with DCA were significantly older [34.00 (27.00, 48.00) vs 29.00 (26.00, 34.00) years], possessed a longer axial length (28.85 ± 1.57 vs 27.11 ± 1.01 mm), and exhibited a more myopic spherical equivalent [- 13.00 (- 16.00, - 10.50) vs - 9.09 ± 2.41 D] compared to those without DCA (G0) (all P < 0.001). In eyes with DCA, a trend emerged as grades increased from G1 to G3, showing associations with older age, longer axial length, deeper myopic spherical equivalent, larger area of parapapillary atrophy, and increased fundus tessellated density (all P < 0.001). CONCLUSIONS: The novel grading system for DCA, based on assessments of area and density, serves as a reliable measure for evaluating the severity of this condition, making it suitable for widespread application in the screening of pathologic myopia.

Genetic control of DNA methylation is largely shared across European and East Asian populations.

DNA methylation is an ideal trait to study the extent of the shared genetic control across ancestries, effectively providing hundreds of thousands of model molecular traits with large QTL effect sizes. We investigate cis DNAm QTLs in three European (n = 3701) and two East Asian (n = 2099) cohorts to quantify the similarities and differences in the genetic architecture across populations. We observe 80,394 associated mQTLs (62.2% of DNAm probes with significant mQTL) to be significant in both ancestries, while 28,925 mQTLs (22.4%) are identified in only a single ancestry. mQTL effect sizes are highly conserved across populations, with differences in mQTL discovery likely due to differences in allele frequency of associated variants and differing linkage disequilibrium between causal variants and assayed SNPs. This study highlights the overall similarity of genetic control across ancestries and the value of ancestral diversity in increasing the power to detect associations and enhancing fine mapping resolution.

Afferent renal denervation attenuates sympathetic over activation from the paraventricular nucleus in spontaneously hypertensive rats.

The effectiveness of Renal Denervation (RDN) in reducing blood pressure and systemic sympathetic activity in hypertensive patients has been established. However, the underlying central mechanism remains unknown. This study aimed to investigate the role of RDN in regulating cardiovascular function via the central Renin-Angiotensin System (RAS) pathway. Ten-week-old Spontaneously Hypertensive Rats (SHR) were subjected to Selective Afferent Renal Denervation (ADN) using capsaicin solution. We hypothesized that ADN would effectively reduce blood pressure and rebalance the RAS component of PVN in SHR. The experimental results show that ADN group exhibited significantly lower blood pressure, reduced systemic sympathetic activity, decreased chronic neuronal activation marker C-FOS expression in the paraventricular nucleus of hypothalamus (PVN), and improved arterial baroreflex function, compared with the Sham group. Furthermore, ACE and AT1 protein expression was reduced while ACE2 and MAS protein expression was increased in the PVN of SHR after ADN. These findings suggest that RDN may exert these beneficial effects through modulating the central RAS pathway.

pGM-CSF as an adjuvant in DNA vaccination against SARS-CoV-2.

The emergence of SARS-CoV-2 presents a significant global public health dilemma. Vaccination has long been recognized as the most effective means of preventing the spread of infectious diseases. DNA vaccines have attracted attention due to their safety profile, cost-effectiveness, and ease of production. This study aims to assess the efficacy of plasmid-encoding GM-CSF (pGM-CSF) as an adjuvant to augment the specific humoral and cellular immune response elicited by DNA vaccines based on the receptor-binding domain (RBD) antigen. Compared to the use of plasmid-encoded RBD (pRBD) alone, mice that were immunized with a combination of pRBD and pGM-CSF exhibited significantly elevated levels of RBD-specific antibody titers in serum, BALF, and nasal wash. Furthermore, these mice generated more potent neutralization antibodies against both the wild-type and Omicron pseudovirus, as well as the ancestral virus. In addition, pGM-CSF enhanced pRBD-induced CD4+ and CD8+ T cell responses and promoted central memory T cells storage in the spleen. At the same time, tissue-resident memory T (Trm) cells in the lung also increased significantly, and higher levels of specific responses were maintained 60 days post the final immunization. pGM-CSF may play an adjuvant role by promoting antigen expression, immune cells recruitment and GC B cell responses. In conclusion, pGM-CSF may be an effective adjuvant candidate for the DNA vaccines against SARS-CoV-2.

Ultrasensitive detection of tyrosinase with click reaction-combined dark-field imaging platform.

Tyrosinase (TYR) is an essential oxidase that is responsible for the regulation of multiple physiological processes and diseases. Achieving the trace and reliable detection of TYR in complex biological samples is of great significance for the diagnosis of TYR-related diseases, but which faces a great challenge. In this study, we developed an ingenious and powerful method for the ultrasensitive detection of TYR by click reaction-combined dark-field microscopy. This method begins with the formation of cuprous ions (Cu+) based on the reduction of copper ions (Cu2+) by ascorbic acid (AA). Subsequently, the formed Cu+ can catalyze the crosslinking between azide- and alkyne-functionalized gold nanoparticles, causing a significant red-shift in the scattering spectrum. However, AA can chelate with TYR, which inhibits the generation of Cu+ and subsequent click reaction, thus achieving TYR-controlled scattering spectral shift. The proposed sensing platform shows a good linear detection range of 0.01-0.8 U/L with a low detection limit of 0.003 U/L, which is three orders of magnitude lower than the best performance of TYR sensing probes reported to date. Most importantly, the strategy has the ability to reliably and accurately detect TYR in serum sample, suggesting its potential clinical application in diagnosing TYR-related diseases. This visual sensing platform offers promising prospects for future research in enzymatic analysis and biomedical diagnostics.

Closure Grading and Visual Outcome in Patients with Large Idiopathic Macular Holes: A Spectral-Domain Optical Coherence Tomography Observation.

INTRODUCTION: So far, there has been no closure grade system synthesizing morphological and microstructural features for large idiopathic macular holes (IMHs) treated by vitrectomy and internal limiting membrane (ILM) peeling. This study aimed to propose a concise one and explore its relevance with visual acuity and the related preoperative factors. METHODS: Consecutive patients with large IMHs (minimum diameter >400 µm), undergoing vitrectomy and ILM peeling, obtaining primary closure and regularly followed-up were enrolled. Preoperative clinical charts and spectral-domain optical coherence tomography (SD-OCT) parameters were reviewed. SD-OCT images and best corrected visual acuity (BCVA) were assessed at 1, 4, and 10 months postoperatively. SD-OCT features at last visit were categorized by BCVA significance, and preoperative risk factors were analyzed. RESULTS: Sixty-eight eyes from 64 patients were enrolled. The 10-month postoperative SD-OCT images were categorized into closure grade 1, 2, and 3 with successively decreased BCVA (p < 0.001). During early follow-up, part of grades 2 and 3 could evolve into the upper grade, respectively, but grade 3 could never evolve into grade 1 and exhibited the least satisfactory long-term BCVA. Binary logistic regression showed that large minimum linear diameter (MLD) was a risk factor for grade 3 occurrence (p < 0.001), with a cutoff value of 625.5 µm from the receiver operating characteristic curve for MLD predicting grade 3 occurrence (p = 0.001). CONCLUSION: Long-term closure status of large IMHs could be categorized into three grades with BCVA significance. Large horizontal MLD is a risk factor for occurrence of grade 3 closure with unsatisfactory visual recovery.

Enhanced innate responses in microglia derived from retinoblastoma patient-specific iPSCs.

RB1 deficiency leads to retinoblastoma (Rb), the most prevalent intraocular malignancy. Tumor-associated macrophages (TAMs) are related to local inflammation disorder, particularly by increasing cytokines and immune escape. Microglia, the unique resident macrophages for retinal homeostasis, are the most important immune cells of Rb. However, whether RB1 deficiency affects microglial function remain unknown. In this study, microglia were successfully differentiated from Rb patient- derived human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs), and then we investigated the function of RB1 in microglia by live imaging phagocytosis assay, immunofluorescence, RNA-seq, qRT-PCR, ELISA and retina organoids/microglia co-culturing. RB1 was abundantly expressed in microglia and predominantly located in the nucleus. We then examined the phagocytosis ability and secretion function of iMGs in vitro. We found that RB1 deficiency did not affect the expression of microglia-specific markers or the phagocytic abilities of these cells by live-imaging. Upon LPS stimulation, RB1-deficient microglia displayed enhanced innate immune responses, as evidenced by activated MAPK signaling pathway and elevated expression of IL-6 and TNF-α at both mRNA and protein levels, compared to wildtype microglia. Furthermore, retinal structure disruption was observed when retinal organoids were co-cultured with RB1-deficient microglia, highlighting the potential contribution of microglia to Rb development and potential therapeutic strategies for retinoblastoma.

The Complement System and C4b-Binding Protein: A Focus on the Promise of C4BPα as a Biomarker to Predict Clopidogrel Resistance.

The complement system plays a dual role in the body, either as a first-line defense barrier when balanced between activation and inhibition or as a potential driver of complement-associated injury or diseases when unbalanced or over-activated. C4b-binding protein (C4BP) was the first circulating complement regulatory protein identified and it functions as an important complement inhibitor. C4BP can suppress the over-activation of complement components and prevent the complement system from attacking the host cells through the binding of complement cleavage products C4b and C3b, working in concert as a cofactor for factor I in the degradation of C4b and C3b, and consequently preventing or reducing the assembly of C3 convertase and C5 convertase, respectively. C4BP, particularly C4BP α-chain (C4BPα), exerts its unique inhibitory effects on complement activation and opsonization, systemic inflammation, and platelet activation and aggregation. It has long been acknowledged that crosstalk or interplay exists between the complement system and platelets. Our unpublished preliminary data suggest that circulating C4BPα exerts its antiplatelet effects through inhibition of both complement activity levels and complement-induced platelet reactivity. Plasma C4BPα levels appear to be significantly higher in patients sensitive to, rather than resistant to, clopidogrel, and we suggest that a plasma C4BPα measurement could be used to predict clopidogrel resistance in the clinical settings.

Rationale and protocol paper for the Asia Pacific Network for inherited eye diseases.

PURPOSE: There are major gaps in our knowledge of hereditary ocular conditions in the Asia-Pacific population, which comprises approximately 60% of the world's population. Therefore, a concerted regional effort is urgently needed to close this critical knowledge gap and apply precision medicine technology to improve the quality of lives of these patients in the Asia-Pacific region. DESIGN: Multi-national, multi-center collaborative network. METHODS: The Research Standing Committee of the Asia-Pacific Academy of Ophthalmology and the Asia-Pacific Society of Eye Genetics fostered this research collaboration, which brings together renowned institutions and experts for inherited eye diseases in the Asia-Pacific region. The immediate priority of the network will be inherited retinal diseases (IRDs), where there is a lack of detailed characterization of these conditions and in the number of established registries. RESULTS: The network comprises 55 members from 35 centers, spanning 12 countries and regions, including Australia, China, India, Indonesia, Japan, South Korea, Malaysia, Nepal, Philippines, Singapore, Taiwan, and Thailand. The steering committee comprises ophthalmologists with experience in consortia for eye diseases in the Asia-Pacific region, leading ophthalmologists and vision scientists in the field of IRDs internationally, and ophthalmic geneticists. CONCLUSIONS: The Asia Pacific Inherited Eye Disease (APIED) network aims to (1) improve genotyping capabilities and expertise to increase early and accurate genetic diagnosis of IRDs, (2) harmonise deep phenotyping practices and utilization of ontological terms, and (3) establish high-quality, multi-user, federated disease registries that will facilitate patient care, genetic counseling, and research of IRDs regionally and internationally.

RNA fusion in human retinal development.

Chimeric RNAs have been found in both cancerous and healthy human cells. They have regulatory effects on human stem/progenitor cell differentiation, stemness maintenance, and central nervous system development. However, whether they are present in human retinal cells and their physiological functions in the retinal development remain unknown. Based on the human embryonic stem cell-derived retinal organoids (ROs) spanning from days 0 to 120, we present the expression atlas of chimeric RNAs throughout the developing ROs. We confirmed the existence of some common chimeric RNAs and also discovered many novel chimeric RNAs during retinal development. We focused on CTNNBIP1-CLSTN1 (CTCL) whose downregulation caused precocious neuronal differentiation and a marked reduction of neural progenitors in human cerebral organoids. CTCL is universally present in human retinas, ROs, and retinal cell lines, and its loss-of-function biases the progenitor cells toward retinal pigment epithelial cell fate at the expense of retinal cells. Together, this work provides a landscape of chimeric RNAs and reveals evidence for their critical role in human retinal development.

Foveal Microstructure and Visual Outcomes after Pars Plana Vitrectomy in Patients with Different Types of Epiretinal Membrane Foveoschisis.

INTRODUCTION: The aim of this study was to evaluate the clinical characteristics and surgical outcomes of the epiretinal membrane foveoschisis (ERM-FS) with different morphological types. METHODS: This retrospective observational study reviewed 44 consecutive ERM-FS patients who underwent ERM surgery. According to the optical coherence tomography images, ERM-FS was classified into three groups: group A, FS crossed the fovea with the foveola elevated; group B, FS located at the foveal edges with a near-normal central foveal point thickness; and group C, FS with undermined foveal edges with a near-normal central foveal point thickness. RESULTS: There were 10 eyes in group A, 20 eyes in group B, and 14 eyes in group C. Preoperatively, eyes in group A had the best best-corrected visual acuity (BCVA), the thickest central foveal point thickness, and the highest ellipsoid zone (EZ) intact rate among the three groups. After surgery, a resolution of foveoschisis was observed in 40.0%, 45.0%, and 50.0% of the eyes in group A, group B, and group C (p = 0.928), respectively. BCVA was significantly improved postoperatively. Although there was no significant difference in BCVA among the three groups at 1 month postoperatively, BCVA of group A was the best at 4 and 10 months. Correlation analysis indicated that the type of ERM-FS, baseline BCVA, central foveal point thickness, and postoperative EZ continuity (all p < 0.05) were important factors for the final BCVA. CONCLUSIONS: The damage to the retinal structure and visual function was milder in group A ERM-FS. Our study emphasized the necessity of OCT-based subtyping in patients with ERM-FS.

A global perspective: characteristics of infertility-related randomized clinical trials.

BACKGROUND: Infertility is a prevalent global condition, and emerging reproductive technologies may enhance its evaluation and treatment. Understanding the current features of randomized clinical trials in infertility is crucial for improving study design and ensuring the translation of results for patient benefits. OBJECTIVES: To investigate the primary characteristics of randomized clinical trials related to infertility and areas where require improvement. MATERIALS AND METHODS: We conducted a search on the International Clinical Trials Registry platform for eligible infertility trials between 2003 and 2022. The distribution ratio of various characteristics uploaded by infertility-related studies on the platform was analyzed and compared according to sex and registration year. RESULTS: Out of the total trials, 85.3% (1,906) included only women, 8.6% (192) included only men, and 6.1% (136) included couples. The majority of retrieved trials followed a parallel arm design (91.0%) and were non-industry-funded (92.2%), with a median planned sample size of 131 patients (interquartile range 75-270). Among these trials, 54.5% (1,217) were conducted in Asia. The most common primary purpose of infertility-related trials was treatment (88.8%), with over half of the investigated interventions focusing on medication (57.9%). DISCUSSION: Asia is the leading region for research, and the drug therapy is still widely used and updated. However, support care for infertile couples has also received some preference. Areas that require improvement and promotion include addressing male infertility and focusing on underserved regions like Africa. The results also highlight deficiencies in trial registration and masking methods, emphasizing the need for better regulation and facilitation of infertility trials in the post-COVID-19 era. CONCLUSION: Based on the current status of infertility RCT studies, greater attention should be paid to infertile men and populations in underdeveloped regions like Africa in future studies, together with a standardized registration and implementation procedures.

Auto-suppression of Tet dioxygenases protects the mouse oocyte genome from oxidative demethylation.

DNA cytosine methylation plays a vital role in repressing retrotransposons, and such derepression is linked with developmental failure, tumorigenesis and aging. DNA methylation patterns are formed by precisely regulated actions of DNA methylation writers (DNA methyltransferases) and erasers (TET, ten-eleven translocation dioxygenases). However, the mechanisms underlying target-specific oxidation of 5mC by TET dioxygenases remain largely unexplored. Here we show that a large low-complexity domain (LCD), located in the catalytic part of Tet enzymes, negatively regulates the dioxygenase activity. Recombinant Tet3 lacking LCD is shown to be hyperactive in converting 5mC into oxidized species in vitro. Endogenous expression of the hyperactive Tet3 mutant in mouse oocytes results in genome-wide 5mC oxidation. Notably, the occurrence of aberrant 5mC oxidation correlates with a consequent loss of the repressive histone mark H3K9me3 at ERVK retrotransposons. The erosion of both 5mC and H3K9me3 causes ERVK derepression along with upregulation of their neighboring genes, potentially leading to the impairment of oocyte development. These findings suggest that Tet dioxygenases use an intrinsic auto-regulatory mechanism to tightly regulate their enzymatic activity, thus achieving spatiotemporal specificity of methylome reprogramming, and highlight the importance of methylome integrity for development.