Intracellular Zn2+ promotes extracellular matrix remodeling in dexamethasone-treated trabecular meshwork.

Given the widespread application of glucocorticoids in ophthalmology, the associated elevation of intraocular pressure (IOP) has long been a vexing concern for clinicians, yet the underlying mechanisms remain inconclusive. Much of the discussion focuses on the extracellular matrix (ECM) of trabecular meshwork (TM). It is widely agreed that glucocorticoids impact the expression of matrix metalloproteinases (MMPs), leading to ECM deposition. Since Zn2+ is vital for MMPs, we explored its role in ECM alterations induced by dexamethasone (DEX). Our study revealed that in human TM cells treated with DEX, the level of intracellular Zn2+ significantly decreased, accompanied by impaired extracellular Zn2+ uptake. This correlated with changes in several Zrt-, Irt-related proteins (ZIPs) and metallothionein. ZIP8 knockdown impaired extracellular Zn2+ uptake, but Zn2+ chelation did not affect ZIP8 expression. Resembling DEX's effects, chelation of Zn2+ decreased MMP2 expression, increased the deposition of ECM proteins, and induced structural disarray of ECM. Conversely, supplementation of exogenous Zn2+ in DEX-treated cells ameliorated these outcomes. Notably, dietary zinc supplementation in mice significantly reduced DEX-induced IOP elevation and collagen content in TM, thereby rescuing the visual function of the mice. These findings underscore zinc's pivotal role in ECM regulation, providing a novel perspective on the pathogenesis of glaucoma.NEW & NOTEWORTHY Our study explores zinc's pivotal role in mitigating extracellular matrix dysregulation in the trabecular meshwork and glucocorticoid-induced ocular hypertension. We found that in human trabecular meshwork cells treated with dexamethasone, intracellular Zn2+ significantly decreased, accompanied by impaired extracellular Zn2+ uptake. Zinc supplementation rescues visual function by modulating extracellular matrix proteins and lowering intraocular pressure, offering a direction for further exploration in glaucoma management.

Unraveling power-law scaling through exponential cell division dynamics.

A primary objective of biology is the development of universal laws that define how organic form develops and how it evolves as a function of size, both ontogenetically and across evolutionary time. Scaling theory has been essential in reaching this goal by giving a complete perspective point, particularly in illuminating the fundamental biological features produced within scaling exponents defining families of equations. Nonetheless, the theoretical basis of the allometric equation within scaling theory are inadequately explained, particularly when it comes to establishing links between micro-level processes at the cellular level and macro-level phenomena. We proposed an unlimited cell bipartition, resulting in an exponential growth in cell numbers during an individual's lifespan, to bridge this conceptual gap between cellular processes and allometric scaling. The power-law scaling between body mass and organ weight was produced by the synchronous exponential increments and the allometric exponent is rate of logarithmic cell proliferation rate. Substituting organ weight for erythrocyte weight aided in the development of a power-law scaling relationship between body mass and metabolic rate. Furthermore, it is critical to understand how cell size affects the exponent in power-law scaling. We find that a bigger exponent will result from an increase in the average weight of organ cells or a decrease in the average weight of all cells. Furthermore, cell proliferation dynamics showed a complex exponential scaling between body mass and longevity, defying the previously reported power-law scaling. We discovered a quadratic link between longevity and logarithmic body mass. Notably, all of the parameters included in these relationships are explained by indices linked to cell division and embryonic development. This research adds to our understanding of the complex interaction between cellular processes and overarching scaling phenomena in biology.

Microbial contribution estimated by clumped isotopologues (13CH3D and 12CH2D2) characteristics in a CO2 enhanced coal bed methane reservoir.

Carbon capture and storage (CCS) of CO2 is a key technology for substantially mitigating global greenhouse gas emissions. Determining the biogeochemical processes in host rocks after CO2 injection informs the viability of carbon storage as a long-term sink for CO2, the complexity of reservoir CH4 cycling, as well as the direct and indirect environmental impacts of this strategy. The doubly substituted ('clumped') isotopologues of methane (13CH3D and 12CH2D2) provide novel insights into methane origins and post-generation processing. Here, we report the chemical compositions of hydrocarbons (C1/C2+ molecular ratios), and methane bulk and clumped isotopes (δ13C, δD, Δ13CH3D and Δ12CH2D2) of a CO2 enhanced coal bed methane recovery (CO2-ECBM) area in Qinshui basin, China and is an analogue for carbon capture and storage. The clumped isotopologue compositions observed in the study area are generally consistent with a range of temperatures spanning 73 to 193 °C. The range in apparent temperature and correlations among clumped and bulk isotopic indices are best explained by mixing between a high maturity thermogenic methane (high in δ13C and δD, with a clumped isotope composition equilibrated near ∼249 °C) and biogenic methane formed or processed in the reservoir (low in δ13C and δD, with a clumped isotope composition equilibrated near 16-27 °C). We hypothesize that the biogenic endmember may result from slow methanogenesis and/or anaerobic oxidation of methane (AOM). This study demonstrates that the potential of methane clumped isotope approach to identify in situ microbial metabolic processes and their association with carbon cycling in CO2-ECBM area, improving our understanding of biogeochemical mechanisms in analogous geological reservoirs.

Effects of environmental feedback on species with finite population.

In an unchanging environment, natural selection always selects species with high fitness. In this study, we build a co-evolutionary system to study the interaction between stochasticity in finite populations and environmental feedback. Positive feedback between species and environment is detrimental to the invasion success, whereas negative feedback is beneficial to invasion since feedback makes population size important enough to revise natural selection's preference. In competition scenario, positive and negative feedback will benefit the initially inferior species. When selection intensity is high, negative feedback may even cause natural selection to favor the initially inferior species. All of these effects are caused by feedback that allows the initially inferior species to have greater fitness than the initially dominant species. Our results emphasize that the effects of stochasticity in evolutionary path can be reinforced by feedback with environment and then reverse the preference of natural selection.

Reduced Zn2+ promotes retinal ganglion cells survival and optic nerve regeneration after injury through inhibiting autophagy mediated by ROS/Nrf2.

The molecular mechanism of how reduced mobile zinc (Zn2+) affected retinal ganglion cell (RGC) survival and optic nerve regeneration after optic nerve crush (ONC) injury remains unclear. Here, we used conditionally knocked out ZnT-3 in the amacrine cells (ACs) of mice (CKO) in order to explore the role of reactive oxygen species (ROS), nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) and autophagy in the protection of RGCs and axon regeneration after ONC injury. We found that reduced Zn2+ can promote RGC survival and axonal regeneration by decreasing ROS, activating Nrf2, and inhibiting autophagy. Additionally, autophagy after ONC is regulated by ROS and Nrf2. Visual function in mice after ONC injury was partially recovered through the reduction of Zn2+, achieved by using a Zn2+ specific chelator N,N,N',N'-tetrakis-(2-Pyridylmethyl) ethylenediamine (TPEN) or through CKO mice. Overall, our data reveal the crosstalk between Zn2+, ROS, Nrf2 and autophagy following ONC injury. This study verified that TPEN or knocking out ZnT-3 in ACs is a promising therapeutic option for the treatment of optic nerve damage and elucidated the postsynaptic molecular mechanism of Zn2+-triggered damage to RGCs after ONC injury.

Selective deletion of zinc transporter 3 in amacrine cells promotes retinal ganglion cell survival and optic nerve regeneration after injury.

Vision depends on accurate signal conduction from the retina to the brain through the optic nerve, an important part of the central nervous system that consists of bundles of axons originating from retinal ganglion cells. The mammalian optic nerve, an important part of the central nervous system, cannot regenerate once it is injured, leading to permanent vision loss. To date, there is no clinical treatment that can regenerate the optic nerve and restore vision. Our previous study found that the mobile zinc (Zn2+) level increased rapidly after optic nerve injury in the retina, specifically in the vesicles of the inner plexiform layer. Furthermore, chelating Zn2+ significantly promoted axonal regeneration with a long-term effect. In this study, we conditionally knocked out zinc transporter 3 (ZnT3) in amacrine cells or retinal ganglion cells to construct two transgenic mouse lines (VGATCreZnT3fl/fl and VGLUT2CreZnT3fl/fl, respectively). We obtained direct evidence that the rapidly increased mobile Zn2+ in response to injury was from amacrine cells. We also found that selective deletion of ZnT3 in amacrine cells promoted retinal ganglion cell survival and axonal regeneration after optic nerve crush injury, improved retinal ganglion cell function, and promoted vision recovery. Sequencing analysis of reginal ganglion cells revealed that inhibiting the release of presynaptic Zn2+ affected the transcription of key genes related to the survival of retinal ganglion cells in postsynaptic neurons, regulated the synaptic connection between amacrine cells and retinal ganglion cells, and affected the fate of retinal ganglion cells. These results suggest that amacrine cells release Zn2+ to trigger transcriptomic changes related to neuronal growth and survival in reginal ganglion cells, thereby influencing the synaptic plasticity of retinal networks. These results make the theory of zinc-dependent retinal ganglion cell death more accurate and complete and provide new insights into the complex interactions between retinal cell networks.

Stimulant-like subjective effects of alcohol are not related to resting-state connectivity in healthy men.

Individual differences in subjective, stimulant-like effects of alcohol are associated with the risk of developing alcohol use disorder. Specifically, individuals who experience more pronounced stimulant-like effects from alcohol are more likely to continue and escalate their usage. The neural basis for these individual differences in subjective response is not yet known. Using a within-subject design, 27 healthy male social drinkers completed three fMRI scans after ingesting a placebo, 0.4 and 0.8 g/kg alcohol, in a randomized order under double-blind conditions. Subjective stimulant effects of alcohol were assessed at regular intervals during each session. Seed-based and regional homogeneity analyses were conducted to evaluate changes in resting-state functional connectivity in relation to the stimulant effect of alcohol. Results indicated that 0.4 g/kg alcohol increased the connectivity to thalamus, and 0.8 g/kg alcohol decreased the connectivity to ventral anterior insula, primarily from the superior parietal lobule. Both doses reduced regional homogeneity in the superior parietal lobule but without an exact overlap with clusters showing connectivity changes in the seed-based analyses. The self-reported stimulant effect of alcohol was not significantly related to changes in seed-based connectivity or regional homogeneity. These findings suggest that alcohol-induced stimulation effects are not related to these indices of neural activity.

Alleviating early demyelination in ischaemia/reperfusion by inhibiting sphingosine-1-phosphate receptor 2 could protect visual function from impairment.

Retinal ischaemia/reperfusion (I/R) injury is a common cause of retinal ganglion cell (RGC) apoptosis and axonal degeneration, resulting in irreversible visual impairment. However, there are no available neuroprotective and neurorestorative therapies for retinal I/R injury, and more effective therapeutic approaches are needed. The role of the myelin sheath of the optic nerve after retinal I/R remains unknown. Here, we report that demyelination of the optic nerve is an early pathological feature of retinal I/R and identify sphingosine-1-phosphate receptor 2 (S1PR2) as a therapeutic target for alleviating demyelination in a model of retinal I/R caused by rapid changes in intraocular pressure. Targeting the myelin sheath via S1PR2 protected RGCs and visual function. In our experiment, we observed early damage to the myelin sheath and persistent demyelination accompanied by S1PR2 overexpression after injury. Blockade of S1PR2 by the pharmacological inhibitor JTE-013 reversed demyelination, increased the number of oligodendrocytes, and inhibited microglial activation, contributing to the survival of RGCs and alleviating axonal damage. Finally, we evaluated the postoperative recovery of visual function by recording visual evoked potentials and assessing the quantitative optomotor response. In conclusion, this study is the first to reveal that alleviating demyelination by inhibiting S1PR2 overexpression may be a therapeutic strategy for retinal I/R-related visual impairment.

Development and validation of the 40-item Glaucoma Visual Functioning Questionnaire.

AIMS: To evaluate the psychometric properties of a newly designed questionnaire, the 40-item Glaucoma Visual Functioning Questionnaire (GVFQ-40), in a Chinese sample to capture the visual ability of patients with glaucomatous vision impairment in five domains. METHODS: Eighty-four glaucoma suspects (controls) and 270 glaucoma patients were recruited from the Glaucoma Clinic at Zhongshan Ophthalmic Centre in this cross-sectional, observational study. All subjects completed two questionnaires during routine clinical visits: the GVFQ-40 and the validated National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25). The discriminant, criterion-related and construct validity of the GVFQ-40 were assessed. A subset of subjects completed the GVFQ-40 twice, with an interval of 7-21 days, to determine test-retest reliability. RESULTS: Domain-specific and total GVFQ-40 scores were significantly higher (worse visual ability) in glaucoma patients than in controls (all p<0.001). All pairwise subgroup comparisons were statistically significant except for the 'mobility' domain comparison between the mild visual field loss and control groups (p=0.189). Significant differences between these two groups were observed in only 2 of the 12 dimensions on the NEI VFQ-25. The GVFQ-40 results demonstrated strong correlations with better-eye mean deviation and Visual Field Index (glaucoma severity measures). Exploratory factor analysis tended to confirm a three-domain structure. Test-retest intraclass correlation coefficients were higher than 0.927 for domain-specific and total GVFQ-40 scores. CONCLUSIONS: The GVFQ-40 possesses good validity and reliability. It can be used to evaluate the impact of glaucomatous damage on visual ability and has potential in the evaluation of intervention efficacy. TRIAL REGISTRATION NUMBER: NCT04722861.

Increased Mobile Zinc Regulates Retinal Ganglion Cell Survival via Activating Mitochondrial OMA1 and Integrated Stress Response.

Retinal ganglion cells (RGCs), the projection neurons of the eye, are irreversibly lost once the optic nerve is injured, which is a critical mechanism of glaucoma. Mobile zinc (Zn2+) levels rapidly increase in retinal interneuron amacrine cells and Zn2+ is then transferred to RGCs via the Zn2+ transporter protein ZnT-3, triggering RGC loss in optic nerve injury. Zn2+ chelation and ZnT-3 deletion promote long-term RGC survival. However, the downstream signaling pathways of Zn2+ in RGCs remains unknown. Here, we show that increased levels of Zn2+ upregulate the expression and activity of mitochondrial zinc metallopeptidase OMA1 in the retina, leading to the cleavage of DELE1 and activation of cytosolic eIF2α kinase PKR, triggering the integrated stress response (ISR) in RGCs. Our study identified OMA1 and ISR as the downstream molecular mechanisms of retinal Zn2+ and potential targets for preventing the progression of Zn2+-associated neuronal damage.

In situ-crosslinked hydrogel-induced experimental glaucoma model with persistent ocular hypertension and neurodegeneration.

A reliable animal model providing chronic and persistent ocular hypertension and characteristic neurodegeneration is essential to recapitulate human glaucoma and understand the underlying pathophysiological mechanisms behind this disease. Many approaches have been tried to establish persistently elevated intraocular pressure (IOP), while no efficient model and no systematic evaluation has been widely accepted yet. Herein, we developed a novel approach to reliably induce persistent IOP elevation using an injectable hydrogel formulated by hyperbranched macromolecular poly(ethylene glycol) (HB-PEG) and thiolated hyaluronic acid (HA-SH) under physiological conditions and established a systematic system for model evaluation. By formulation screening, an appropriate hydrogel with proper mechanical property, non-swelling profile and cytocompatibility was selected for further experiment. By intracameral injection, a persistent IOP elevation over 50% above baseline was obtained and it led to progressive retinal ganglion cell loss and ganglion cell complex thickness reduction. The evaluation of the efficacy of the model was thoroughly analyzed by whole-mounts retina immunostaining, optical coherence tomography, and hematoxylin-eosin staining for histological changes and by electroretinography for visual function changes. The N35-P50 amplitude of the pattern electroretinography and the N2-P2 amplitude of the flash visual-evoked potential were decreased, while the scotopic electroretinography showed no statistically significant changes. The in situ-forming HB-PEG/HA-SH hydrogel system could be an appropriate strategy for developing a reliable experimental glaucoma model without any confounding factors. We expect this model would be conducive to the development of neuroprotective and neuro-regenerative therapies.

A systematic and comprehensive analysis of colorectal squamous cell carcinoma: Implication for diagnosis and treatment.

BACKGROUND: This study was aimed at establishing a nomogram for survival prediction of Colorectal squamous cell carcinoma (CSCC), understanding the molecular pathogenesis, exploring a better treatment, and predicting the potential therapeutic agents. METHODS: Surveillance, Epidemiology, and End Results (SEER) database was used to obtained CSCC patients and the nomogram was performed. Propensity score matching (PSM), Kaplan-Meier analysis, subgroup analysis, and interaction test were used to explore the better treatment strategy for CSCC. Bioinformatics were used to explore the molecular mechanism and potential therapeutic drugs of CSCC. RESULTS: A total of 3949 CSCC patients were studied. The nomogram was constructed and evaluated to have a good performance. We found that the radiotherapy had a better effect than surgery, and the difference between radiotherapy and combined therapy was not significant. 821 differentially expressed genes in CSCC were obtained from GSE6988 dataset. DNA damage repair, mismatch repair, and cell cycle pathways might contribute to CSCC occurrence as indicated by KEGGpathway and GSEA analysis. Transcription factors analysis revealed that TP63 and STAT1 may have an important role in occurrence and development of CSCC. 1607 potential drugs against CSCC were found using the CMAP database, and molecular docking was carried out to show the binding energy between TP63 and drugs. CONCLUSIONS: A good prognosis nomogram was constructed for CSCC. We also have a better understanding of the underlying molecular mechanisms of occurrence and development of CSCC and predicted potential therapeutic drugs, providing a theoretical basis for the treatment of CSCC.

Real-time facial emotion recognition deficits across the psychosis spectrum: A B-SNIP Study.

Affective and non-affective psychotic disorders are associated with variable levels of impairment in affective processing, but this domain typically has been examined via presentation of static facial images. We compared performance on a dynamic facial expression identification task across six emotions (sad, fear, surprise, disgust, anger, happy) in individuals with psychotic disorders (bipolar with psychotic features [PBD] = 113, schizoaffective [SAD] = 163, schizophrenia [SZ] = 181) and healthy controls (HC; n = 236) derived from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). These same individuals with psychotic disorders were also grouped by B-SNIP-derived Biotype (Biotype 1 [B1] = 115, Biotype 2 [B2] = 132, Biotype 3 [B3] = 158), derived from a cluster analysis applied to a large biomarker panel that did not include the current data. Irrespective of the depicted emotion, groups differed in accuracy of emotion identification (P < 0.0001). The SZ group demonstrated lower accuracy versus HC and PBD groups; the SAD group was less accurate than the HC group (Ps < 0.02). Similar overall group differences were evident in speed of identifying emotional expressions. Controlling for general cognitive ability did not eliminate most group differences on accuracy but eliminated almost all group differences on reaction time for emotion identification. Results from the Biotype groups indicated that B1 and B2 had more severe deficits in emotion recognition than HC and B3, meanwhile B3 did not show significant deficits. In sum, this characterization of facial emotion recognition deficits adds to our emerging understanding of social/emotional deficits across the psychosis spectrum.

Acute effects of alcohol on resting-state functional connectivity in healthy young men.

Alcohol abuse and dependence remain significant public health issues, and yet the brain circuits that are involved in the rewarding effects of alcohol are poorly understood. One promising way to study the effects of alcohol on neural activity is to examine its effects on functional connectivity between brain areas involved in reward and other functions. Here, we compared the effects of two doses of alcohol (0.4 and 0.8 g/kg) to placebo on resting-state functional connectivity in brain circuits related to reward in 19 healthy young men without histories of alcohol problems. The higher, but not the lower, dose of alcohol, significantly increased connectivity from reward-related regions to sensory and motor cortex, and between seeds associated with cognitive control. Contrary to expectation, alcohol did not significantly change connectivity for the ventral striatum at either dose. These findings reveal unrecognized effects of alcohol on connectivity from reward-related regions to visual and sensory cortical areas.

Bidirectional Synthesis of Di- tert-butyl (2 S,6 S,8 S)- and (2 R,6 R,8 R)-1,7-Diazaspiro[5.5]undecane-2,8-dicarboxylate and Related Spirodiamines.

Efficient syntheses of both enantiomers of a spirodiamine diester from (l)- and (d)-aspartic acid are described. The key transformation was the conversion of Boc-protected tert-butyl aspartate into the derived aldehyde, two-directional Horner-Wadsworth-Emmons olefination, hydrogenation, and selective acid-catalyzed Boc-deprotection and spirocyclization. An alternative, two-directional approach to derivatives of 1,7-diazaspiro[5.5]undecane is described.