Efficacy of scleral buckling for the treatment of rhegmatogenous retinal detachment using a novel foldable capsular buckle.

AIM: To evaluate the effectiveness and safety of scleral buckling for the treatment of rhegmatogenous retinal detachment (RRD) using a novel foldable capsular buckle (FCB). METHODS: This was a series of case observation studies. Eighteen patients (18 eyes) who visited our ophthalmology department between August 2020 and August 2022 and were treated for RRD with scleral buckling using FCB were included. The procedure was similar to conventional scleral buckling, while a balloon-like FCB was placed onto the retinal break with balanced salt solution filling for a broad, external indentation instead of the silicone buckle. The retinal reattachment rate, best corrected visual acuity (BCVA), intraocular pressure (IOP), refractive dioptre and astigmatism degree, and complications were evaluated and recorded. RESULTS: There were 7 males and 11 females aged 19-58y. The average time course of RRD was 12d, ranging from 7-20d. The retinal break was located in the superior quadrants in 8 eyes and in the inferior quadrants in 10 eyes, with macula-off detachments in 12 eyes. The patients were followed-up for at least 6mo. The final retinal reattachment rate was 100%. The BCVA was significantly improved compared with the baseline (P<0.05). There was no significant change in refractive dioptre or astigmatism degree at each follow-up (all P>0.05). Three patients had transiently high IOPs within one week after surgery. Mild diplopia occurred in 5 patients after surgery and then disappeared after the balloon fluid was removed. CONCLUSION: The success rate of FCB scleral buckling for RRD is satisfactory. This procedure can be expected to be applied in new, uncomplicated cases of RRD.

Alterations in gut microbiota contribute to cognitive deficits induced by chronic infection of Toxoplasma gondii.

Chronic infection with Toxoplasma gondii (T. gondii) emerges as a risk factor for neurodegenerative diseases in animals and humans. However, the underlying mechanisms are largely unknown. We aimed to investigate whether gut microbiota and its metabolites play a role in T. gondii-induced cognitive deficits. We found that T. gondii infection induced cognitive deficits in mice, which was characterized by synaptic ultrastructure impairment and neuroinflammation in the hippocampus. Moreover, the infection led to gut microbiota dysbiosis, barrier integrity impairment, and inflammation in the colon. Interestingly, broad-spectrum antibiotic ablation of gut microbiota attenuated the adverse effects of the parasitic infection on the cognitive function in mice; cognitive deficits and hippocampal pathological changes were transferred from the infected mice to control mice by fecal microbiota transplantation. In addition, the abundance of butyrate-producing bacteria and the production of serum butyrate were decreased in infected mice. Interestingly, dietary supplementation of butyrate ameliorated T. gondii-induced cognitive impairment in mice. Notably, compared to the healthy controls, decreased butyrate production was observed in the serum of human subjects with high levels of anti-T. gondii IgG. Overall, this study demonstrates that gut microbiota is a key regulator of T. gondii-induced cognitive impairment.

Correlation Between the Severity of Coronary Artery Disease and Retinal Artery Disease and the Therapeutic Effect of Captopril.

Objective: Investigate the Correlation Between the Severity of Coronary Artery Disease and Retinal Artery Disease, and assess the Efficacy of Angiotensin-Converting Enzyme Inhibitors (ACEIs) Application. Methods: One hundred patients diagnosed with primary hypertension at our hospital were chosen for the study. All patients underwent dual-source 64-layer spiral CT coronary angiography and fundus photography examination. Based on the extent of coronary artery stenosis, the patients were divided into Group A, Group B, Group C, and Group D. Results: In comparison with patients in Group A, individuals in Groups B, C, and D exhibited a notable increase in the severity of retinal artery stenosis and arteriovenous crossing signs (P < .05). Furthermore, the severity of retinal artery stenosis and arteriovenous crossing signs demonstrated an incremental trend with the severity of coronary artery stenosis (P < .05). The arteriovenous crossing sign exhibited a sensitivity of 47.87%, the specificity of 89.21%, positive predictive value of 89.76%, and the negative predictive value of 46.53% for predicting coronary artery stenosis. After treatment, the blood pressure levels of the patients, both systolic (SBP) and diastolic blood pressure (DBP) levels significantly decreased compared to before treatment. Conclusion: A significant positive correlation was observed between the severity of coronary artery lesions and retinal artery lesions. Assessing alterations in retinal blood vessels in hypertensive patients can effectively indicate the extent of coronary artery stenosis indirectly. Concerning medication, the antihypertensive drug captopril demonstrated the potential to alleviate the severity of coronary artery and retinal artery lesions in hypertensive patients. However, specific treatment methods should be tailored to individual patient circumstances.

Overexpression of forebrain PTP1B leads to synaptic and cognitive impairments in obesity.

Obesity has reached pandemic proportions and is a risk factor for neurodegenerative diseases, including Alzheimer's disease. Chronic inflammation is common in obese patients, but the mechanism between inflammation and cognitive impairment in obesity remains unclear. Accumulative evidence shows that protein-tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. We investigated the causal role of PTP1B in obesity-induced cognitive impairment and the beneficial effect of PTP1B inhibitors in counteracting impairments of cognition, neural morphology, and signaling. We showed that obese individuals had negative relationship between serum PTP1B levels and cognitive function. Furthermore, the PTP1B level in the forebrain increased in patients with neurodegenerative diseases and obese cognitive impairment mice with the expansion of white matter, neuroinflammation and brain atrophy. PTP1B globally or forebrain-specific knockout mice on an obesogenic high-fat diet showed enhanced cognition and improved synaptic ultrastructure and proteins in the forebrain. Specifically, deleting PTP1B in leptin receptor-expressing cells improved leptin synaptic signaling and increased BDNF expression in the forebrain of obese mice. Importantly, we found that various PTP1B allosteric inhibitors (e.g., MSI-1436, well-tolerated in Phase 1 and 1b clinical trials for obesity and type II diabetes) prevented these alterations, including improving cognition, neurite outgrowth, leptin synaptic signaling and BDNF in both obese cognitive impairment mice and a neural cell model of PTP1B overexpression. These findings suggest that increased forebrain PTP1B is associated with cognitive decline in obesity, whereas inhibition of PTP1B could be a promising strategy for preventing neurodegeneration induced by obesity.

Gut microbiota dysbiosis contributes to α-synuclein-related pathology associated with C/EBPß/AEP signaling activation in a mouse model of Parkinson's disease.

JOURNAL/nrgr/04.03/01300535-202409000-00042/figure1/v/2024-01-16T170235Z/r/image-tiff Parkinson's disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction. Gastrointestinal dysfunction can precede the onset of motor symptoms by several years. Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson's disease, whether it plays a causal role in motor dysfunction, and the mechanism underlying this potential effect, remain unknown. CCAAT/enhancer binding protein ß/asparagine endopeptidase (C/EBPß/AEP) signaling, activated by bacterial endotoxin, can promote α-synuclein transcription, thereby contributing to Parkinson's disease pathology. In this study, we aimed to investigate the role of the gut microbiota in C/EBPß/AEP signaling, α-synuclein-related pathology, and motor symptoms using a rotenone-induced mouse model of Parkinson's disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation. We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier, as well as activation of the C/EBP/AEP pathway, α-synuclein aggregation, and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits. However, treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics. Importantly, we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits, intestinal inflammation, and endotoxemia. Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits, intestinal inflammation, endotoxemia, and intestinal barrier impairment. These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits, C/EBPß/AEP signaling activation, and α-synuclein-related pathology in a rotenone-induced mouse model of Parkinson's disease. Additionally, our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson's disease.

Cross-species transmission and host range genes in poxviruses.

The persistent epidemic of human mpox, caused by mpox virus (MPXV), raises concerns about the future spread of MPXV and other poxviruses. MPXV is a typical zoonotic virus which can infect human and cause smallpox-like symptoms. MPXV belongs to the Poxviridae family, which has a relatively broad host range from arthropods to vertebrates. Cross-species transmission of poxviruses among different hosts has been frequently reported and resulted in numerous epidemics. Poxviruses have a complex linear double-strand DNA genome that encodes hundreds of proteins. Genes related to the host range of poxvirus are called host range genes (HRGs). This review briefly introduces the taxonomy, phylogeny and hosts of poxviruses, and then comprehensively summarizes the current knowledge about the cross-species transmission of poxviruses. In particular, the HRGs of poxvirus are described and their impacts on viral host range are discussed in depth. We hope that this review will provide a comprehensive perspective about the current progress of researches on cross-species transmission and HRG variation of poxviruses, serving as a valuable reference for academic studies and disease control in the future.

A Bioinspired Gradient Design Strategy for Cellulose-Based Electromagnetic Wave Absorbing Structural Materials.

Cellulose nanofiber (CNF) possesses excellent intrinsic properties, and many CNF-based high-performance structural and functional materials have been developed recently. However, the coordination of the mechanical properties and functionality is still a considerable challenge. Here, a CNF-based structural material is developed by a bioinspired gradient structure design using hollow magnetite nanoparticles and the phosphorylation-modified CNF as building blocks, which simultaneously achieves a superior mechanical performance and electromagnetic wave absorption (EMA) ability. Benefiting from the gradient design, the flexural strength of the structural material reached ∼205 MPa. Meanwhile, gradient design improves impedance matching, contributing to the high EMA ability (-59.5 dB) and wide effective absorption width (5.20 GHz). Besides, a low coefficient of thermal expansion and stable storage modulus was demonstrated as the temperature changes. The excellent mechanical, thermal, and EMA performance exhibited great potential for application in stealth equipment and electromagnetic interference protecting electronic packaging materials.

Lineage classification and selective site identification of Orthoebolavirus zairense.

As the high pathogenic species of Filoviridae virus family, Orthoebolavirus zairense (EBOV) shows frequent outbreaks in human in recently years since its first emerging in 1976 in Democratic Republic of the Congo (COD), bringing ongoing risks and burden on public health safety. Here, the phylogenetic relationship among major outbreaks was analyzed. The results showed that EBOV isolates could be divided into four lineages according to spatial and temporal epidemics. Then, the positive selection sites (PSSs) were detected on all proteins of the EBOV, exhibiting lineage characteristic. Particularly, sites in GP and VP24 were identified to be significantly under positive selection, and partial of which were maintained in the latest isolates in 2021. GP and L were found to have high variability between lineages. Substitutions including F443L and F443S in GP, as well as F1610L and I1951V in L could be characteristic of the two large outbreaks in COD (2018) and West Africa (2014), respectively. Further, substitutions of significant PSSs in VP24 and L proteins were visualized for analysis of structural changes, which may affect EBOV pathogenesis. In summary, our results gains insights in genetic characteristic and adaptive evolution of EBOV, which could facilitate gene functional research against EBOV.

Probiotic Clostridium butyricum ameliorates cognitive impairment in obesity via the microbiota-gut-brain axis.

Obesity is a risk factor for cognitive dysfunction and neurodegenerative disease, including Alzheimer's disease (AD). The gut microbiota-brain axis is altered in obesity and linked to cognitive impairment and neurodegenerative disorders. Here, we targeted obesity-induced cognitive impairment by testing the impact of the probiotic Clostridium butyricum, which has previously shown beneficial effects on gut homeostasis and brain function. Firstly, we characterized and analyzed the gut microbial profiles of participants with obesity and the correlation between gut microbiota and cognitive scores. Then, using an obese mouse model induced by a Western-style diet (high-fat and fiber-deficient diet), the effects of Clostridium butyricum on the microbiota-gut-brain axis and hippocampal cognitive function were evaluated. Finally, fecal microbiota transplantation was performed to assess the functional link between Clostridium butyricum remodeling gut microbiota and hippocampal synaptic protein and cognitive behaviors. Our results showed that participants with obesity had gut microbiota dysbiosis characterized by an increase in phylum Proteobacteria and a decrease in Clostridium butyricum, which were closely associated with cognitive decline. In diet-induced obese mice, oral Clostridium butyricum supplementation significantly alleviated cognitive impairment, attenuated the deficit of hippocampal neurite outgrowth and synaptic ultrastructure, improved hippocampal transcriptome related to synapses and dendrites; a comparison of the effects of Clostridium butyricum in mice against human AD datasets revealed that many of the genes changes in AD were reversed by Clostridium butyricum; concurrently, Clostridium butyricum also prevented gut microbiota dysbiosis, colonic barrier impairment and inflammation, and attenuated endotoxemia. Importantly, fecal microbiota transplantation from donor-obese mice with Clostridium butyricum supplementation facilitated cognitive variables and colonic integrity compared with from donor obese mice, highlighting that Clostridium butyricum's impact on cognitive function is largely due to its ability to remodel gut microbiota. Our findings provide the first insights into the neuroprotective effects of Clostridium butyricum on obesity-associated cognitive impairments and neurodegeneration via the gut microbiota-gut-brain axis.

Atomically Precise Metal Nanocluster Photosystem: Electron Relay Boosts Photocatalytic Organic Transformation.

Atomically precise metal nanoclusters (NCs) demonstrate emerging potential as a new generation of photosensitizers in photoredox catalysis. However, metal NCs suffer from intrinsic poor instability, which leads to the loss of photosensitization effect and hampers their widespread applications in heterogeneous photocatalysis. Herein, we corroborate the design of a spatially directional charge transfer pathway over transition metal chalcogenide (TMC)-based heterostructures by way of a facile and efficient electrostatic self-assembly approach. Positively charged solid-state nonconjugated insulating polymer of poly(allylamine hydrochloride) (PAH) and negatively charged glutathione (GSH) capped metal NCs [Ag9@(GSH)6] as building blocks were controllably and highly ordered anchored on the TMC substrate. It was unveiled that owing to the appropriate energy level alignment and interface configuration, photogenerated electrons over metal NCs can directionally flow to the TMC substrate with the aid of PAH, which functions as an interfacial charge transfer mediator, and simultaneously holes migrate in the opposite direction, thereby collaboratively contributing to substantially boosted charge separation and prolonged charge lifetime. Benefiting from these merits, the thus self-assembled TMCs/PAH/metal NC heterostructure unfolds conspicuously enhanced photoactivity toward anaerobic selective photocatalytic reduction of nitroaromatics to amino derivatives under visible light irradiation. This work would significantly reinforce our fundamental understanding of the charge transfer characteristic of atomically precise metal NCs and the charge-withdrawing capability of solid insulating polymers for solar energy conversion.

Impaired mitophagosome-lysosome fusion mediates olanzapine-induced aging.

The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for treating patients with psychosis, including schizophrenia and bipolar disorder. Despite their effectiveness in treating positive and negative symptoms, prolonged exposure to APDs may lead to accelerated aging and cognitive decline, among other side effects. Here we report that dysfunctional mitophagy is a fundamental mechanism underlying accelerated aging induced by olanzapine, using in vitro and in vivo (Caenorhabditis elegans) models. We showed that the aberrant mitophagy caused by olanzapine was via blocking mitophagosome-lysosome fusion. Furthermore, olanzapine can induce mitochondrial damage and hyperfragmentation of the mitochondrial network. The mitophagosome-lysosome fusion in olanzapine-induced aging models can be restored by a mitophagy inducer, urolithin A, which alleviates defective mitophagy, mitochondrial damage, and fragmentation of the mitochondrial network. Moreover, the mitophagy inducer ameliorated behavioral changes induced by olanzapine, including shortened lifespan, and impaired health span, learning, and memory. These data indicate that olanzapine impairs mitophagy, leading to the shortened lifespan, impaired health span, and cognitive deficits. Furthermore, this study suggests the potential application of mitophagy inducers as therapeutic strategies to reverse APD-induced adverse effects associated with accelerated aging.

Prediction of mammalian virus cross-species transmission based on host proteins.

Most emerging viruses are spilled over from mammals. Understanding the mechanism of virus cross-species transmission and identifying zoonotic viruses before their emergence are critical for the prevention and control of newly emerging viruses. This study systematically investigated the host proteins associated with the cross-species transmission of mammalian viruses based on 1,271 pairs of virus-mammal interactions including 382 viruses from 33 viral families and 73 mammal species from 11 orders. Numerous host proteins were found to contribute to the cross-species transmission of mammalian viruses. Host proteins potentially contributing to virus cross-species transmission are specific to viral families, and few overlaps of such host proteins are observed in different viral families. Based on these host proteins, the random-forest (RF) models were built to predict the cross-species transmission potential of mammalian viruses. Moderate performance was obtained when using all viruses together. However, when modeling by viral family, the performance of the RF models varied much among viral families. In 13 viral families such as Flaviviridae, Retroviridae, and Poxviridae, the AUC of the RF model was greater than 0.8. Finally, the contribution of virus receptors to cross-species transmission was evaluated, and the virus receptor was found to have a minor effect in predicting the cross-species transmission of mammalian viruses. The study deepens our understanding of the mechanism of virus cross-species transmission and provides a framework for predicting the cross-species transmission of mammalian viruses. IMPORTANCE Emerging viruses pose serious threats to humans. Understanding the mechanism of virus cross-species transmission and identifying zoonotic viruses before their emergence are critical for the prevention and control of emerging viruses. This study systematically identified host factors associated with cross-species transmission of mammalian viruses and further built machine-learning models for predicting cross-species transmission of the viruses based on host factors including virus receptors. The study not only deepens our understanding of the mechanism of virus cross-species transmission but also provides a framework for predicting the cross-species transmission of mammalian viruses based on host factors.

Detection of Alpha- and Betacoronaviruses in Small Mammals in Western Yunnan Province, China.

The genetic diversity of coronaviruses (CoVs) is high, and their infection in animals has not yet been fully revealed. By RT-PCR detection of the partial RNA-dependent RNA polymerase (RdRp) gene of CoVs, we screened a total of 502 small mammals in the Dali and Nujiang prefectures of Western Yunnan Province, China. The number of overall CoV positives was 20, including ß-CoV (n = 13) and α-CoV (n = 7), with a 3.98% prevalence in rectal tissue samples. The identity of the partial RdRp genes obtained for 13 strains of ß-CoV was 83.42-99.23% at the nucleotide level, and it is worth noting that the two strains from Kachin red-backed voles showed high identity to BOV-36/IND/2015 from Indian bovines and DcCoV-HKU23 from dromedary camels (Camelus dromedarius) in Morocco; the nucleotide identity was between 97.86 and 98.33%. Similarly, the identity of the seven strains of α-CoV among the partial RdRp sequences was 94.00-99.18% at nucleotide levels. The viral load in different tissues was measured by quantitative RT-PCR (qRT-PCR). The average CoV viral load in small mammalian rectal tissue was 1.35 × 106 copies/g; differently, the mean CoV viral load in liver, heart, lung, spleen, and kidney tissue was from 0.97 × 103 to 3.95 × 103 copies/g, which revealed that CoV has extensive tropism in rectal tissue in small mammals (p < 0.0001). These results revealed the genetic diversity, epidemiology, and infective tropism of α-CoV and ß-CoV in small mammals from Dali and Nujiang, which deepens the comprehension of the retention and infection of coronavirus in natural hosts.

A Novel Methacryloyl Chitosan Hydrogel Microneedles Patch with Sustainable Drug Release Property for Effective Treatment of Psoriasis.

Psoriasis is a chronic and recurrent skin disease that often requires long-term treatment, and topical transdermal drug delivery can reduce systemic side effects. However, it is still a challenge in efficient transdermal drug delivery for psoriasis treatment due to low penetration efficiency of most drugs and the abnormal skin conditions of psoriasis patients. Here, a safe and effective methacryloyl chitosan hydrogel microneedles (CSMA hMNs) patch is developed and served as a sustained drug release platform for the treatment of psoriasis. By systematically optimizing the CSMA preparation, CSMA hMNs with excellent morphological characteristics and strong mechanical properties (0.7 N needle-1 ) are prepared with a concentration of only 3% (w/v) CSMA. As a proof-of-concept, methotrexate (MTX) and nicotinamide (NIC) are loaded into CSMA hMNs patch, which can produce a sustained drug release of 80% within 24 h in vitro. In vivo experiments demonstrated that the CSMA hMNs patch can effectively inhibit the skin thickening and spleen enlargement of psoriatic mice and has a good biosafety profile at sufficient therapeutic doses. This study provides a new idea for the preparation of hMN systems using modified CS or other biocompatible materials and offers an effective therapeutic option for psoriasis treatment.

Comparison of the efficacy and safety of ultrasonic cycloplasty vs valve implantation and anti-VEGF for the treatment of fundus disease-related neovascular glaucoma.

AIM: To compare the clinical efficacy and safety of ultrasonic cycloplasty (UCP) vs Ahmed glaucoma drainage valve implantation (ADV) in addition to intravitreal anti-vascular endothelial growth factor (VEGF) for treatment of fundus disease-related neovascular glaucoma (NVG). METHODS: A total of 43 patients (45 eyes) with NVG secondary to fundus diseases underwent anti-VEGF combined with UCP or ADV from August 2020 to March 2022 were enrolled in this retrospective cohort study. Of them, 14 patients (15 eyes) were treated with both UCP and anti-VEGF as the UCP group and 29 patients (30 eyes) treated with both ADV and anti-VEGF as the ADV group. The success of the treatment was defined as intraocular pressure (IOP) between 11-20 mm Hg with or without using IOP-lowering drugs. IOP measurement, IOP lowering drugs at baseline and follow-ups period and complications were recorded. RESULTS: The average age was 63.03±9.95 and 52.27±12.89y in ADV and UCP groups, respectively (P=1.947). The fundus pathology included proliferative diabetic retinopathy in 42 eyes and retinal vein occlusion in 3 eyes. All eyes in both groups achieved successful treatment at 3mo. While the success rate was 90.0% (27/30) in the ADV group and 86.7% (13/15) in the UCP group at the last follow-up of 6mo (P>0.05). IOP was significantly lower with reduction of drug use than the baseline in both groups (both P<0.05). And the ADV group needed fewer anti-glaucoma drops than the UCP group from 1d to 3mo. The comfort scores of patients in the ADV group were significantly lower than those in the UCP group in the first week after the operation (P<0.05). CONCLUSION: UCP is an alternative to the ADV with the same efficacy but non-invasive for the treatment of NVG.

The Skeletal Muscle Transcriptome Profile of Elderly Men with Metabolic Syndrome Based on Weighted Gene Co-Expression Network Analysis.

INTRODUCTION: This study aimed to understand the transcriptome characteristics of the skeletal muscle of elderly (EL) men with metabolic syndrome (MS) and to find the hub genes and insight into the molecular mechanisms of skeletal muscle in the occurrence and development of MS. METHODS: In this study, the limma package of R software was used to analyze the differentially expressed genes in the skeletal muscle of healthy young (YO) adult men, healthy EL men, and EL men diagnosed with MS (SX) for at least 10 years. Bioinformatics methods, such as GO enrichment analysis, KEGG enrichment analysis, and gene interaction network analysis, were used to explore the biological functions of differentially expressed genes, and weighted gene coexpression network analysis (WGCNA) was used to cluster differentially expressed genes into modules. RESULTS: Among the YO group, EL group, and SX group, 65 co-differentially expressed genes were found maybe regulated by age factor and MS factor. Those co-differentially expressed genes were enriched into 25 biological process terms and 3 KEGG pathways. Based on the WGCNA results, a total of five modules were identified. Fifteen hub genes may play an essential role in regulating the function of skeletal muscle of EL men with MS. CONCLUSIONS: 65 differentially expressed genes and 5 modules may regulate the function of skeletal muscle of EL men with MS, among which fifteen hub genes may play an essential role in the occurrence and development of MS.

Butyrate ameliorates quinolinic acid-induced cognitive decline in obesity models.

Obesity is a risk factor for neurodegenerative disease associated with cognitive dysfunction, including Alzheimer's disease. Low-grade inflammation is common in obesity, but the mechanism between inflammation and cognitive impairment in obesity is unclear. Accumulative evidence shows that quinolinic acid (QA), a neuroinflammatory neurotoxin, is involved in the pathogenesis of neurodegenerative processes. We investigated the role of QA in obesity-induced cognitive impairment and the beneficial effect of butyrate in counteracting impairments of cognition, neural morphology, and signaling. We show that in human obesity, there was a negative relationship between serum QA levels and cognitive function and decreased cortical gray matter. Diet-induced obese mice had increased QA levels in the cortex associated with cognitive impairment. At single-cell resolution, we confirmed that QA impaired neurons, altered the dendritic spine's intracellular signal, and reduced brain-derived neurotrophic factor (BDNF) levels. Using Caenorhabditis elegans models, QA induced dopaminergic and glutamatergic neuron lesions. Importantly, the gut microbiota metabolite butyrate was able to counteract those alterations, including cognitive impairment, neuronal spine loss, and BDNF reduction in both in vivo and in vitro studies. Finally, we show that butyrate prevented QA-induced BDNF reductions by epigenetic enhancement of H3K18ac at BDNF promoters. These findings suggest that increased QA is associated with cognitive decline in obesity and that butyrate alleviates neurodegeneration.

Dimethyl itaconate ameliorates cognitive impairment induced by a high-fat diet via the gut-brain axis in mice.

BACKGROUND: Gut homeostasis, including intestinal immunity and microbiome, is essential for cognitive function via the gut-brain axis. This axis is altered in high-fat diet (HFD)-induced cognitive impairment and is closely associated with neurodegenerative diseases. Dimethyl itaconate (DI) is an itaconate derivative and has recently attracted extensive interest due to its anti-inflammatory effect. This study investigated whether intraperitoneal administration of DI improves the gut-brain axis and prevents cognitive deficits in HF diet-fed mice. RESULTS: DI effectively attenuated HFD-induced cognitive decline in behavioral tests of object location, novel object recognition, and nesting building, concurrent with the improvement of hippocampal RNA transcription profiles of genes associated with cognition and synaptic plasticity. In agreement, DI reduced the damage of synaptic ultrastructure and deficit of proteins (BDNF, SYN, and PSD95), the microglial activation, and neuroinflammation in the HFD-fed mice. In the colon, DI significantly lowered macrophage infiltration and the expression of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) in mice on the HF diet, while upregulating the expression of immune homeostasis-related cytokines (IL-22, IL-23) and antimicrobial peptide Reg3γ. Moreover, DI alleviated HFD-induced gut barrier impairments, including elevation of colonic mucus thickness and expression of tight junction proteins (zonula occludens-1, occludin). Notably, HFD-induced microbiome alteration was improved by DI supplementation, characterized by the increase of propionate- and butyrate-producing bacteria. Correspondingly, DI increased the levels of propionate and butyrate in the serum of HFD mice. Intriguingly, fecal microbiome transplantation from DI-treated HF mice facilitated cognitive variables compared with HF mice, including higher cognitive indexes in behavior tests and optimization of hippocampal synaptic ultrastructure. These results highlight the gut microbiota is necessary for the effects of DI in improving cognitive impairment. CONCLUSIONS: The present study provides the first evidence that DI improves cognition and brain function with significant beneficial effects via the gut-brain axis, suggesting that DI may serve as a novel drug for treating obesity-associated neurodegenerative diseases. Video Abstract.

Key mutations in the spike protein of SARS-CoV-2 affecting neutralization resistance and viral internalization.

To control the ongoing COVID-19 pandemic, a variety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have been developed. However, the rapid mutations of SARS-CoV-2 spike (S) protein may reduce the protective efficacy of the existing vaccines which is mainly determined by the level of neutralizing antibodies targeting S. In this study, we screened prevalent S mutations and constructed 124 pseudotyped lentiviral particles carrying these mutants. We challenged these pseudoviruses with sera vaccinated by Sinovac CoronaVac and ZF2001 vaccines, two popular vaccines designed for the initial strain of SARS-CoV-2, and then systematically assessed the susceptivity of these SARS-CoV-2 variants to the immune sera of vaccines. As a result, 14 S mutants (H146Y, V320I + S477N, V382L, K444R, L455F + S477N, L452M + F486L, F486L, Y508H, P521R, A626S, S477N + S698L, A701V, S477N + T778I, E1144Q) were found to be significantly resistant to neutralization, indicating reduced protective efficacy of the vaccines against these SARS-CoV-2 variants. In addition, F486L and Y508H significantly enhanced the utilization of human angiotensin-converting enzyme 2, suggesting a potentially elevated infectivity of these two mutants. In conclusion, our results show that some prevalent S mutations of SARS-CoV-2 reduced the protective efficacy of current vaccines and enhance the infectivity of the virus, indicating the necessity of vaccine renewal and providing direction for the development of new vaccines.