Rationale: Microvascular complication is a major cause of morbidity and mortality among the patients with diabetes. Pericyte dysfunction is the predominant pathological manifestation of microvascular complication. N 6 -methyladenosine (m 6 A) serves as the most prevalent modification in eukaryotic mRNAs. However, the role of m 6 A RNA modification in pericyte dysfunction is still unclear. Methods: Quantitative polymerase chain reactions and western blots were conducted to detect the change of m 6 A RNA modification in pericytes and mouse retinas following diabetic stress. MTT assay, transwell migration assay, caspase 3/7 activity assay, calcein-AM/propidium iodide (PI) staining, and TUNEL staining were conducted to determine the role of METTL3 in pericyte biology in vitro . Retinal trypsin digestion, vascular permeability assay, and IB4-NG2 double immunofluorescent staining were conducted to determine the role of METTL3 in retinal pericyte dysfunction and vascular complication. RNA sequencing, RNA pull-down assays and immunoblots were conducted to clarify the mechanism of METTL3-mediated pericyte dysfunction and vascular complication. Results: The levels of m 6 A RNA methylation were significantly up-regulated in pericytes and mouse retinas following diabetic stress, which were caused by increased expression of METTL3. METTL3 regulated the viability, proliferation, and differentiation of pericytes in vitro . Specific depletion of METTL3 in pericytes suppressed diabetes-induced pericyte dysfunction and vascular complication in vivo . METTL3 overexpression impaired pericyte function by repressing PKC-η, FAT4, and PDGFRA expression, which was mediated by YTHDF2-dependent mRNA decay. Conclusion: METTL3-mediated m 6 A methylation epigenetically regulates diabetes-induced pericyte dysfunction. METTL3-YTHDF2-PKC-η/FAT4/PDGFRA signaling axis could be therapeutically targeted for treating microvascular complications.

The afferent visual system may be affected by neuro-degeneration in amyotrophic lateral sclerosis (ALS) based on observations of visual function impairment and retinal inclusions on histopathology in ALS patients. To test the hypothesis that visual acuity is impaired in ALS, we compared three measures of visual acuity in ALS patients (n = 25) attending a multidisciplinary ALS clinic and age matched control subjects (n = 25). Bilateral monocular and binocular visual acuities were assessed using high contrast (black letters on white background) and low contrast (2.5%, 1.25% grey letters on white background) visual acuity charts under controlled lighting conditions following refraction. Binocular summation was calculated as the difference between binocular and best monocular acuity scores. There were no associations between binocular or monocular high contrast visual acuity or low contrast visual acuity and amyotrophic lateral sclerosis diagnosis (generalized estimating equation models accounting for age). Binocular summation was similar in both amyotrophic lateral sclerosis and control subjects. There was a small magnitude association between increased duration of ALS symptoms and reduced 1.25% low contrast visual acuity. This study does not confirm prior observations of impaired visual acuity in patients with amyotrophic lateral sclerosis and does not support this particular measure of visual function for use in broad scale assessment of visual pathway involvement in ALS patients.

Abnormalities of the inner and intermediate retinal structures in patients with amyotrophic lateral sclerosis (ALS) have been described using optical coherence tomography and histopathology. Colour vision is a potential marker of these structural changes. The purpose of this study is to test the hypothesis that colour vision impairment is associated with ALS. Monocular (right eye) colour vision was assessed in subjects with definite or probable ALS ( = 25, aged 50-80 years) and control ( = 21, aged 46-89 years) subjects with corrected near visual acuity of at least 20/40 using the L'Anthony D15 color test (desaturated), scored by c-index, a measure of diffuse colour discrimination. Of ALS subjects, 16/25 (64%) had impaired colour vision (c-index >1.8). Comparing with our normal subjects and accounting for age, 72% ( = 18) of ALS subjects had colour vision below the 50th percentile, 52% ( = 13) had colour vision below the 25th percentile, 24% ( = 6) had colour vision below the 10th percentile, and 8% ( = 2) had colour vision below the 2nd percentile. In multivariate models of ln(c-index) and age, the intercept was higher and the slope was flatter in ALS subjects, suggesting that colour vision deficits are more prominent in younger ALS patients. Diffuse colour discrimination deficits are detected in ALS subjects at younger ages than in control subjects. Further study is needed to confirm these findings and to determine if the ALS colour discrimination abnormalities correlate with structural markers of retinal involvement and ALS disease severity.

This case study demonstrates the safety and feasibility of long-term facilitatory and inhibitory tDCS on a single participant with ALS. This study serves as a guideline for implementing tDCS in future ALS trials.