The spike of acute angle closure after the epidemic downgrade of COVID-19 management: a hospital-based comparative study from China.

PURPOSE: To analyse and compare the clinical characteristics and treatment outcomes of patients with acute angle closure (AAC) who presented before the COVID-19 pandemic, during the COVID-19 management and after their downgrading. METHODS: Consecutive AAC patients were recruited from our hospital and divided into three groups: those treated before the COVID-19 pandemic (Group1), during the COVID-19 management (Group2) and after the management downgrade (Group3). The demographic variables, clinical characteristics, treatment methods and therapeutic outcomes of the groups were compared. RESULTS: When compared to Groups1 and 2, Group3 showed a significantly higher incidence of AAC (0.27%, P < 0.001), a longer time from symptoms to treatment (TST; 160.88 ± 137.05 h, P = 0.031) and worse uncorrected visual acuity (P = 0.009) at presentation. In Group3, 68.9% had a history of COVID-19 and 28.5% developed ocular symptoms of AAC after taking medication for COVID-19 symptoms. The average time from the onset of COVID-19 to the appearance of eye symptoms was 3.21 ± 4.00 days. CONCLUSIONS: The COVID-19 has had a multifaceted impact on the incidence of AAC. Therefore, it is crucial to strengthen health education on glaucoma, especially AAC. The prevention and timely treatment of AAC should be emphasised to combat global blindness.

13C-Stable isotope resolved metabolomics uncovers dynamic biochemical landscape of gut microbiome-host organ communications in mice.

BACKGROUND: Gut microbiome metabolites are important modulators of host health and disease. However, the overall metabolic potential of the gut microbiome and interactions with the host organs have been underexplored. RESULTS: Using stable isotope resolved metabolomics (SIRM) in mice orally gavaged with 13C-inulin (a tracer), we first observed dynamic enrichment of 13C-metabolites in cecum contents in the amino acids and short-chain fatty acid metabolism pathways. 13C labeled metabolites were subsequently profiled comparatively in plasma, liver, brain, and skeletal muscle collected at 6, 12, and 24 h after the tracer administration. Organ-specific and time-dependent 13C metabolite enrichments were observed. Carbons from the gut microbiome were preferably incorporated into choline metabolism and the glutamine-glutamate/GABA cycle in the liver and brain, respectively. A sex difference in 13C-lactate enrichment was observed in skeletal muscle, which highlights the sex effect on the interplay between gut microbiome and host organs. Choline was identified as an interorgan metabolite derived from the gut microbiome and fed the lipogenesis of phosphatidylcholine and lysophosphatidylcholine in host organs. In vitro and in silico studies revealed the de novo synthesis of choline in the human gut microbiome via the ethanolamine pathway, and Enterococcus faecalis was identified as a major choline synthesis species. These results revealed a previously underappreciated role for gut microorganisms in choline biosynthesis. CONCLUSIONS: Multicompartmental SIRM analyses provided new insights into the current understanding of dynamic interorgan metabolite transport between the gut microbiome and host at the whole-body level in mice. Moreover, this study singled out microbiota-derived metabolites that are potentially involved in the gut-liver, gut-brain, and gut-skeletal muscle axes. Video Abstract.

Raman Spectra of Electrified Si-Water Interfaces: First-Principles Simulations.

We investigate the Raman spectra of liquid water in contact with a semiconductor surface using first-principles molecular dynamics simulations. We focus on a hydrogenated silicon-water interface and compute the Raman spectra from time correlation functions of the polarizability. We establish a relationship between Raman spectral signatures and structural properties of the liquid at the interface, and we identify the vibrational impacts of an applied electric field. We show that negative bias leads to a reduction of the number of hydrogen bonds (HBs) formed between the surface and the topmost water layer and an enhancement of the HB interactions between water molecules. Instead, positive bias leads to an enhancement of both the HB interactions between water and the surface and between water molecules, creating a semi-ordered interfacial layer. Our work provides molecular-level insights into electrified semiconductor/water interfaces and the identification of specific structural features through Raman spectroscopy.

Inhibition of cGAS-STING pathway alleviates neuroinflammation-induced retinal ganglion cell death after ischemia/reperfusion injury.

Acute glaucoma is a vision-threatening disease characterized by a sudden elevation in intraocular pressure (IOP), followed by retinal ganglion cell (RGC) death. Cytosolic double-stranded DNA (dsDNA)-a damage-associated molecular pattern (DAMP) that triggers inflammation and immune responses-has been implicated in the pathogenesis of IOP-induced RGC death, but the underlying mechanism is not entirely clear. In this study, we investigated the effect of the inflammatory cascade on dsDNA recognition and examined the neuroprotective effect of the cyclic GMP-AMP (cGAMP) synthase (cGAS) antagonist A151 on a retinal ischemia/reperfusion (RIR) mouse model. Our findings reveal a novel mechanism of microglia-induced neuroinflammation-mediated RGC death associated with glaucomatous vision loss. We found that RIR injury facilitated the release of dsDNA, which initiated inflammatory responses by activating cGAS-stimulator of interferon genes (STING) pathway. Correspondingly, elevated expressions of cGAS and STING were found in retinal samples from human glaucoma donors. Furthermore, we found that deletion or inhibition of cGAS or STING in microglia transfected with poly(dA:dT) specifically decreased microglia activation and inflammation response. We also observed that A151 treatment promoted poly(dA:dT)--stimulated changes in polarization from the M1 to the M2 phenotype in microglia. Subsequently, A151 administered to mice effectively inhibited the cGAS-STING pathway, absent in melanoma 2 (AIM2) inflammasome and pyroptosis-related molecules. Furthermore, A151 administration significantly reduced neuroinflammation, ameliorated RGC death and RGC-related reductions in visual function. These findings provide a unique perspective on glaucomatous neuropathogenesis and suggest cGAS as an underlying target of retinal inflammation to provide a potential therapeutic for acute glaucoma.

Design and synthesis of broad-spectrum antimicrobial amphiphilic peptidomimetics to combat drug-resistance.

The gradual depletion of antibiotic discovery pipeline makes the antibiotic resistance a difficult clinical problem and a global health emergency. The membrane-active antimicrobial peptides (AMPs) attracted much attention due to a lower tendency to bacterial resistance than traditional antibiotics. However, some immanent drawbacks of AMPs may hamper their application in combating antibiotic resistance in the long run, such as susceptible to enzymatic degradation and low cell permeability. Herein, we report the design and synthesis of a novel series of amphiphilic peptidomimetics, from which we identified compounds that exhibited potent antimicrobial activity against a panel of clinically relevant Gram-positive and Gram-negative bacteria strains. The most potent compound 20 (SD-110-12) is able to kill intracellular bacterial pathogens and prevent the development of bacterial resistance under the tested conditions by targeting cell membranes. Additionally, compound 20 (SD-110-12) obtains good in vivo efficacy that is comparative to vancomycin by eradicating MRSA and suppressing inflammation in a mice infected skin wound model, demonstrating its promising therapeutic potential.

Rationally Designed Nonapeptides with Great Skin Photoprotective Effect through Producing Type 1 Collagen and Blocking the mTOR Pathway.

Ultraviolet (UV), as the most common environmental stress factor to human skin, causes redox imbalance and leads to photoaging and the development of cancer. In this work, we screened a nonapeptide (PWH) with good activities of antioxidant, promoting the secretion of type 1 collagen (COL-1) and repairing damaged skin from a series of rationally designed novel short peptides. PWH could alleviate UV-A-induced oxidative stress, restrain pro-inflammatory cytokine production, protect mitochondrial function, and maintain autophagy activity. We also first indicated that inhibiting the PI3K/AKT/mTOR signaling pathway and restoration of autophagy activity might delay the photoaging process in skin cells. Topical applications of PWH were further demonstrated to exhibit significant protection in full-wavelength UV-induced skin aging in mice models both in the prophylaxis and treatment way. In addition, given the good stability and without unwanted toxicity and anaphylaxis, PWH could be a promising candidate for cosmetics and pharmaceuticals.

Transition between Different Diffusion Modes of Individual Lipids during the Membrane-Specific Action of As-CATH4 Peptides.

The cell membrane permeabilization ability of immune defense antimicrobial peptides (AMPs) is widely applied in biomedicine. Although the mechanisms of peptide-membrane interactions have been widely investigated, analyses at the molecular level are still lacking. Herein, the membrane-specific action of a native AMP, As-CATH4, is investigated using a single-lipid tracking method in combination with live cell and model membrane assays conducted at different scales. The peptide-membrane interaction process is characterized by analyzing single-lipid diffusion behaviors. As-CATH4 exhibits potent antimicrobial activity through bacterial membrane permeabilization, with moderate cytotoxicity against mammalian cells. In-plane diffusion analyses of individual lipids show that the lipid molecules exhibit non-Gaussian and heterogeneous diffusion behaviors in both pristine and peptide-treated membranes, which can be decomposed into two Gaussian subgroups corresponding to normal- and slow-diffusive lipids. Assessment of the temporal evolution of these two diffusion modes of lipids reveal that the peptide action states of As-CATH4 include surface binding, transmembrane defect formation, and dynamic equilibrium. The action mechanisms of As-CATH4 at varying concentrations and against different membranes are distinguished. This work resolves the simultaneous mixed diffusion mechanisms of single lipids in biomimetic cell membranes, especially during dynamic membrane permeabilization by AMPs.

Overview and update on cytomegalovirus-associated anterior uveitis and glaucoma.

Cytomegalovirus anterior uveitis is the most common ocular inflammatory disease caused by cytomegalovirus infection. It mainly occurs in middle-aged males with competent immunologic function, and the incidence is higher in Asia. The clinical manifestations vary from Posner-Schlossman syndrome and corneal endotheliitis to Fuchs uveitis syndrome, and are often accompanied by intraocular hypertension. Secondary glaucoma is a potentially blinding ocular complication with a pathogenesis that includes complicated immunological factors, intraocular inflammation, different types of angle abnormalities, and the administration of steroids, which may result in physical discomfort and visual impairment. Diagnostic tests, such as the polymerase chain reaction, optical coherence tomography, ocular microscopy, and confocal microscopy, might help in identifying anterior uveitis caused by other viruses. Combinations of antiviral medications and anti-inflammatory agents are effective treatments. If pharmacological therapy cannot reduce intraocular pressure or slow the progression of glaucomatous optic neuropathy, surgical intervention is required as a last resort.

Analysis of macular microvasculature with optical coherence tomography angiography for migraine: A systematic review and meta-analysis.

Objective: This study aimed to evaluate the features of macular microvasculature with optical coherence tomography angiography (OCTA) among migraine patients. Methods: We systematically searched PubMed, Web of Science, Embase, and Cochrane Library for studies that evaluated the macular microvasculature of migraine patients. The weighted mean differences (WMDs) of the foveal avascular zone (FAZ), foveal superficial capillary plexus (SCP) vessel density (VD), parafoveal SCP VD, foveal deep capillary plexus (DCP) VD, and parafoveal DCP VD with 95% confidence intervals (CIs) among migraine with aura (MA) group, migraine without aura (MO) group, and healthy controls (HC) group were analyzed using a random-effect model. P < 0.05 was considered significant in statistical analyses. Publication bias was assessed using funnel plots and statistical tests (Egger's test and Begg's test). Results: Nine studies covering 675 individuals were enrolled in this meta-analysis ultimately. The FAZ of MA patients was not significantly different from HC (WMD = 0.04, 95% CI -0.00 to 0.09). However, the FAZ of MA was significantly larger than that of HC after correction of publication bias by trim and fill method (WMD = 1.03, 95% CI 0.99 to 1.08). The FAZ of MO patients was similar to that of HC (WMD = 0.03, 95% CI -0.00 to 0.07), while smaller than that of MA patients (WMD = 0.05, 95% CI 0.01 to 0.09). VD of the SCP, either in the foveal or parafoveal area, was not significantly different among the three groups. As for DCP, VD in MA patients was lower when compared with HC in the parafovea (WMD = -1.20, 95% CI -1.88 to -0.51). Conclusions: We found that there was a larger FAZ in MA compared with HC after adjusting for publication bias. The FAZ in MO was not significantly different from that in HC, but significantly lower than that in MA. There was no significant difference in either foveal or parafoveal VD of SCP among MA, MO, and HC participants, while the parafoveal VD of the DCP in MA was lower than that of the HC.

Case Report: The First Reported Concurrence of Wilson Disease and Bilateral Retinitis Pigmentosa.

Background: Wilson disease (WD) and retinitis pigmentosa (RP) are common genetic disorders in clinical practice, however, the concurrence of WD and RP has never been reported before. WD occurs due to mutations that cause copper metabolic abnormalities; in turn, change in copper metabolism has been suggested to be related with RP. Here, we report the first case of concurrent WD and bilateral RP, and investigate possible pathogenesis to illuminate whether the two genetic disorders are causality or coincidence. Case Presentation: The patient was a 43-year-old Chinese female diagnosed with WD 12 years ago. She had suffered from night blindness since childhood and faced diminution of bilateral vision within 10 years, for which she was referred to our Eye Center during hospitalization for routine copper excretion treatment. The ceruloplasmin, skull magnetic resonance imaging (MRI), and abdominal ultrasound results accorded with hepatolenticular degeneration. Ocular examinations revealed corneal Kayser-Fleischer (K-F) ring, sunflower-like cataract, retinal osteocyte-like pigmentation, bilateral atrophy of outer retina, cystoid macular edema (CME), and tubular vision in both eyes. Phacoemulsification combined with intraocular lens implantation was performed in the right and left eye, but there was limited improvement in her visual acuity. Whole exome sequencing (WES) detected a deleterious homozygous mutation in the ATP7B gene related to WD, and a homozygous mutation in the CNGA1 gene very likely to cause RP. Conclusions: We reported the first case of concurrent WD and RP. WES detected two pathogenic gene mutations, ATP7B and CNGA1. Though we cannot completely rule out a causal effect of WD-related abnormal copper metabolism with RP, we speculate that the two gene mutations lead to the coincidence of the two genetic disorders, respectively.

Photoelectron spectra of water and simple aqueous solutions at extreme conditions.

Determining the electronic structure of aqueous solutions at extreme conditions is an important step towards understanding chemical bonding and reactions in water under pressure (P) and at high temperature (T). We present calculations of the photoelectron spectra of water and a simple solution of NaCl under pressure at conditions relevant to the Earth's interior (11 GPa and 1000 K). We combine first-principles and deep-potential molecular dynamics with electronic structure calculations with dielectric-dependent hybrid functionals. These functionals are defined with a fraction of exact exchange determined from the dielectric constant of the liquid computed in extreme conditions. We find a broadening of the spectra relative to ambient conditions, particularly prominent in the merging of the two main peaks below the onset of the spectra. Furthermore we find an overall red shift at high pressure and temperature, which is however not constant over the whole energy range and varies between 1.1 and 2.4 eV. Our results also show that the anion energy levels are closer to the valence band maximum of the liquid than at ambient conditions, indicating that as P and T are increased, the defect levels of Cl- and OH- in water may eventually lie below the valence band maximum of water. Finally, we characterize the ionization potential of hydrated species deriving from rapid water dissociation, e.g. hydrated hydroxide and hydronium, and we elucidate the electronic states associated with proton transfer events at high pressure. Our results represent a first, important step in predicting the electronic properties of solutions in super-critical conditions.

USP13: Multiple Functions and Target Inhibition.

As a deubiquitination (DUB) enzyme, ubiquitin-specific protease 13 (USP13) is involved in a myriad of cellular processes, such as mitochondrial energy metabolism, autophagy, DNA damage response, and endoplasmic reticulum-associated degradation (ERAD), by regulating the deubiquitination of diverse key substrate proteins. Thus, dysregulation of USP13 can give rise to the occurrence and development of plenty of diseases, in particular malignant tumors. Given its implications in the stabilization of disease-related proteins and oncology targets, considerable efforts have been committed to the discovery of inhibitors targeting USP13. Here, we summarize an overview of the recent advances of the structure, function of USP13, and its relations to diseases, as well as discovery and development of inhibitors, aiming to provide the theoretical basis for investigation of the molecular mechanism of USP13 action and further development of more potent druggable inhibitors.

USP30: Structure, Emerging Physiological Role, and Target Inhibition.

Ubiquitin-specific protease 30 (USP30) is a deubiquitinating enzyme (DUB) belonging to the USP subfamily, which was found localized in the mitochondrial outer membrane and peroxisomes owing to its unique transmembrane domain. Structural study revealed that USP30 employed a unique catalytic triad and molecular architecture to preferentially cleave the Lys6 linked ubiquitin chains. USP30 plays an essential role in several cellular events, such as the PINK1/Parkin-mediated mitophagy, pexophagy, BAX/BAK-dependent apoptosis, and IKKß-USP30-ACLY-regulated lipogenesis/tumorigenesis, and is tightly regulated by post-translational modification including phosphorylation and mono-ubiquitination. Dysregulation of USP30 is associated with a range of physiological disorders, such as neurodegenerative disease, hepatocellular carcinoma, pulmonary disorders, and peroxisome biogenesis disorders. Nowadays, scientists and many biopharmaceutical companies are making much effort to explore USP30 inhibitors including natural compounds, phenylalanine derivatives, N-cyano pyrrolidines, benzosulphonamide, and other compounds. For the treatment of pulmonary disorders, the study in Mission Therapeutics of USP30 inhibitor is already in the pre-clinical stage. In this review, we will summarize the current knowledge of the structure, regulation, emerging physiological role, and target inhibition of USP30, hoping to prompt further investigation and understanding of it.

Probing the electronic properties of the electrified silicon/water interface by combining simulations and experiments.

Silicon (Si) is broadly used in electrochemical and photoelectrochemical devices, where the capacitive and Faradaic reactions at the Si/water interfaces are critical for signal transduction or noise generation. However, probing the electrified Si/water interface at the microscopic level remains a challenging task. Here we focus on hydrogenated Si surfaces in contact with water, relevant to transient electronics and photoelectrochemical modulation of biological cells and tissues. We show that by carrying out first-principles molecular dynamics simulations of the Si(100)/water interface in the presence of an electric field we can realistically correlate the computed flat-band potential and tunneling current images at the interface with experimentally measured capacitive and Faradaic currents. Specifically, we validate our simulations in the presence of bias by performing pulsed chronoamperometry measurements on Si wafers in solution. Consistent with prior experiments, our measurements and simulations indicate the presence of voltage-dependent capacitive currents at the interface. We also find that Faradaic currents are weakly dependent on the applied bias, which we relate to surface defects present in newly prepared samples.

Advanced Materials for Energy-Water Systems: The Central Role of Water/Solid Interfaces in Adsorption, Reactivity, and Transport.

The structure, chemistry, and charge of interfaces between materials and aqueous fluids play a central role in determining properties and performance of numerous water systems. Sensors, membranes, sorbents, and heterogeneous catalysts almost uniformly rely on specific interactions between their surfaces and components dissolved or suspended in the water-and often the water molecules themselves-to detect and mitigate contaminants. Deleterious processes in these systems such as fouling, scaling (inorganic deposits), and corrosion are also governed by interfacial phenomena. Despite the importance of these interfaces, much remains to be learned about their multiscale interactions. Developing a deeper understanding of the molecular- and mesoscale phenomena at water/solid interfaces will be essential to driving innovation to address grand challenges in supplying sufficient fit-for-purpose water in the future. In this Review, we examine the current state of knowledge surrounding adsorption, reactivity, and transport in several key classes of water/solid interfaces, drawing on a synergistic combination of theory, simulation, and experiments, and provide an outlook for prioritizing strategic research directions.

Tumor-Infiltrating Lymphocytes in Colorectal Cancer: The Fundamental Indication and Application on Immunotherapy.

The clinical success of immunotherapy has revolutionized the treatment of cancer patients, bringing renewed attention to tumor-infiltrating lymphocytes (TILs) of various cancer types. Immune checkpoint blockade is effective in patients with mismatched repair defects and high microsatellite instability (dMMR-MSI-H) in metastatic colorectal cancer (CRC), leading the FDA to accelerate the approval of two programmed cell death 1 (PD-1) blocking antibodies, pembrolizumab and nivolumab, for treatment of dMMR-MSI-H cancers. In contrast, patients with proficient mismatch repair and low levels of microsatellite stability or microsatellite instability (pMMR-MSI-L/MSS) typically have low tumor-infiltrating lymphocytes and have shown unsatisfied responses to the immune checkpoint inhibitor. Different TILs environments reflect different responses to immunotherapy, highlighting the complexity of the underlying tumor-immune interaction. Profiling of TILs fundamental Indication would shed light on the mechanisms of cancer-immune evasion, thus providing opportunities for the development of novel therapeutic strategies. In this review, we summarize phenotypic diversities of TILs and their connections with prognosis in CRC and provide insights into the subsets-specific nature of TILs with different MSI status. We also discuss current clinical immunotherapy approaches based on TILs as well as promising directions for future expansion, and highlight existing clinical data supporting its use.

Transmission properties of periodically sparse patterned microring resonators.

By using the transfer matrix method, we analyze the optical properties of periodically sparse patterned microring resonators in the resonator-waveguide system. The dispersion relation of a periodically sparse patterned microring is investigated theoretically. Two kinds of modes supported by the periodically sparse patterned microring resonators, traveling modes and stationary modes, are found. We also derive the reflectivity of the microring resonator side-coupled to a waveguide and find that just the stationary modes lead to total reflections. Traveling modes do not reflect, which can be used to extend free spectral range. All the transmission properties are confirmed by the finite-difference time-domain method numerically.