Antibiotic-Induced Gut Microbiota Dysbiosis Modulates Host Transcriptome and m6A Epitranscriptome via Bile Acid Metabolism.

Gut microbiota can influence host gene expression and physiology through metabolites. Besides, the presence or absence of gut microbiome can reprogram host transcriptome and epitranscriptome as represented by N6-methyladenosine (m6A), the most abundant mammalian mRNA modification. However, which and how gut microbiota-derived metabolites reprogram host transcriptome and m6A epitranscriptome remain poorly understood. Here, investigation is conducted into how gut microbiota-derived metabolites impact host transcriptome and m6A epitranscriptome using multiple mouse models and multi-omics approaches. Various antibiotics-induced dysbiotic mice are established, followed by fecal microbiota transplantation (FMT) into germ-free mice, and the results show that bile acid metabolism is significantly altered along with the abundance change in bile acid-producing microbiota. Unbalanced gut microbiota and bile acids drastically change the host transcriptome and the m6A epitranscriptome in multiple tissues. Mechanistically, the expression of m6A writer proteins is regulated in animals treated with antibiotics and in cultured cells treated with bile acids, indicating a direct link between bile acid metabolism and m6A biology. Collectively, these results demonstrate that antibiotic-induced gut dysbiosis regulates the landscape of host transcriptome and m6A epitranscriptome via bile acid metabolism pathway. This work provides novel insights into the interplay between microbial metabolites and host gene expression.

Relationship between the intravascular enhancement sign on three-dimensional T1-weighted turbo spin echo and intraluminal thrombus in middle cerebral artery atherosclerosis.

PURPOSE: To investigate the association between the intravascular enhancement sign (IVES) and intraluminal thrombus (ILT) detected by high-resolution magnetic resonance vessel wall imaging (HR-VWI) in patients with middle cerebral artery (MCA) atherosclerosis. METHOD: The data of patients who underwent HR-VWI between May 2021 and May 2023, including clinical information, the number of IVES vessels, stenosis degree, ILT, plaque features on 3D T1-weighted turbo spin echo sequences, and signal intensity ratio (SIR) on 3D time-of-flight magnetic resonance angiography, were retrospectively analyzed. Correlation and logistic regression analyses were performed. RESULTS: A total of 194 MCA plaques were identified in 132 patients (103 [53 %] on the left). Atherosclerosis with, relative to without, ILT was associated with a higher incidence of ischemic events, higher plaque enhancement and stenosis degrees, more vessels with IVES, and lower remodeling ratio, lumen area, wall area, total vessel area, and SIR. Multivariate logistic regression analysis showed significant and independent associations of the number of IVES vessels (OR = 1.089; 95 % CI [1.013-1.170]; P = 0.020) and SIR (OR = 0.007; 95 % CI [0.0004-0.124]; P < 0.001) with ILT. The number of vessels with the IVES (AUC = 0.81, 95 % CI [0.75-0.87]; P < 0.001) and SIR (AUC = 0.88, 95 % CI [0.82-0.94]; P < 0.001) sufficiently diagnosed ILT, and the AUC of the combination of the IVES and SIR was 0.89 (95 % CI [0.84-0.94]; P < 0.001). CONCLUSION: The number of IVES vessels and SIR are independent risk factors for ILT. They may provide new monitoring targets for stroke prevention in patients with atherosclerotic stenosis.

Altered Resting-State Amygdalar Functional Connectivity in Primary Angle-Closure Glaucoma Patients.

BACKGROUND: Glaucoma patients frequently present with depressive symptoms, the development of which is closely associated with amygdalar activity. However, no studies to date have documented glaucoma-related changes in the functional connectivity (FC) of the amygdala. Accordingly, resting-state functional magnetic resonance imaging (rs-fMRI) analyses were herein used to evaluate changes in amygdalar FC in primary angle-closure glaucoma (PACG) patients. METHODS: In total, this study enrolled 36 PACG patients and 33 healthy controls (HCs). Complete eye exams were conducted for all PACG patients. After the preprocessing of magnetic resonance imaging (MRI) data, the bilateral amygdala was selected as a seed point, followed by the comparison of resting-state FC between the PACG and HC groups. Then, those brain regions exhibiting significant differences between these groups were identified, and relationships between the FC coefficient values for these regions and clinical variables of interest were assessed. RESULTS: These analyses revealed that as compared to HC individuals, PACG patients exhibited reductions in FC between the amygdala and the cerebellum_8, vermis_4_5, anterior central gyrus, supplementary motor area, paracentral lobule, putamen, middle frontal gyrus, and posterior cingulate gyrus, while enhanced FC was detected between the right and left amygdala. No significant correlations between these changes in amygdalar any any disease-related clinical parameters or disease duration were noted. CONCLUSIONS: Patients with PACG exhibit extensive resting state abnormalities with respect to the FC between the amygdala and other regions of the brain, suggesting that dysregulated amygdalar FC may play a role in the pathophysiology of PACG.

Systematic assessment of transcriptomic and metabolic reprogramming by blue light exposure coupled with aging.

The prevalent use of light-emitting diodes (LEDs) has caused revolutionary changes in modern life, but the potential hazards to health of blue light are poorly understood. N6-methyladenosine (m6A) is the most prevalent posttranscriptional modification in eukaryotes and can modulate diverse physiological processes by regulating mRNA fate. Here, to understand the effects and molecular mechanisms of daily low-intensity blue light exposure (BLE) and ascertain whether m6A methylation plays a role in BLE-induced phenotypes, we constructed a series of Drosophila models under different durations of daily low-intensity BLE and obtained multiomics profiles. Our results revealed that BLE could induce transcriptomic, m6A epitranscriptomic, and metabolomic reprogramming in Drosophila along with aging process. Importantly, the m6A methylation sites enriched in the 5' untranslated regions (UTRs) of Drosophila transcripts showed strong age specificity and could be altered by BLE. We experimentally validated that aging-related gene Tor and circadian rhythm-related gene per were regulated by 5' UTR-enriched m6A methylation. Overall, our study provides a systematic assessment of m6A RNA methylome reprogramming by BLE and aging in Drosophila model.

The Design and Experimental Validation of a Biomimetic Stubble-Cutting Device Inspired by a Leaf-Cutting Ant's Mandibles.

Under the conditions of conservation tillage, the existence of the root-soil complex greatly increases the resistance and energy consumption of stubble-cutting blades, especially in Northeast China. In this research, the corn root-soil complex in Northeast China was selected as the research object. Based on the multi-toothed structure of the leaf-cutting ant's mandibles and the unique bite mode of its mandibles on leaves, a gear-tooth, double-disk, bionic stubble-cutting device (BSCD) was developed by using a combination of power cutting and passive cutting. The effects of rotary speed, tillage depth, and forward speed on the torque and power of the BSCD were analyzed using orthogonal tests, and the results showed that all of the factors had a large influence on the torque and power, in the order of tillage depth > rotary speed > forward speed. The performance of the BSCD and the traditional power straight blade (TPSB) was explored using comparative tests. It was found that the optimal stubble-cutting rate of the BSCD was 97.4%. Compared with the TPSB, the torque of the BSCD was reduced by 15.2-16.4%, and the power was reduced by 9.2-11.3%. The excellent performance of the BSCD was due to the multi-toothed structure of the cutting edge and the cutting mode.

The value of 3D T2-weighted SPACE sequence in the differential diagnosis of spinal arteriovenous fistula and acute transverse myelitis.

OBJECTIVE: Spinal arteriovenous fistulas (SAVF) was often neglected and misdiagnosed as acute transverse myelitis (ATM) due to its insidious onset and non-specific clinical symptoms. This study aims to investigate the differential diagnostic value of high-resolution T2-weighted volumetric sequence (3D sampling perfection with application-optimized contrasts using different flip-angle evolutions [SPACE]) in patients with SAVF and ATM. METHODS: Retrospectively analyzed the clinical and radiological findings of 32 SDAVF patients and 32 ATM patients treated at our institutions from May 2018 to January 2023. They all underwent conventional spinal MRI and T2-SPACE examination, compared their performance in identifying lesions, to estimate the value of T2 SPACE sequence in the diagnosis of SAVF and ATM patients. RESULTS: The clue of cauda equina area change (CEAC) in conventional MRI and T2-SPACE sequences is specific for the diagnosis of SAVF. The diagnostic model composed of perimedullary flow voids (PFV) and CEAC has good diagnostic performance (AUCMRI = 0.95; AUCSPACE = 0.935). Compared with conventional MRI, the T2-SPACE sequence has a higher detection rate, sensitivity, and negative predictive value for PFV and CEAC in SAVF patients, but lower specificity and positive predictive value. In T2-SPACE images, there are significant differences in the distribution range, quadrant, and maximum diameter of PFV vessels between SAVF and ATM patients. Moreover, T2-SPACE sequence can determine the site of fistula in most SAVF patients preferably, and the inter-rater agreement was good in the assessment of the fistula. CONCLUSION: The CEAC is a new and useful clue for the diagnosis of thoracolumbar SAVF. And T2-SPACE sequence can more intuitively observe the lesions of SAVF, has good differential diagnostic value for SAVF and ATM patients.

Mechanosensitive ion channel gene survey suggests potential roles in primary open angle glaucoma.

Although glaucoma is a disease modulated by eye pressure, the mechanisms of pressure sensing in the eye are not well understood. Here, we investigated associations between mechanosensitive ion channel gene variants and primary open-angle glaucoma (POAG). Common (minor allele frequency > 5%) single nucleotide polymorphisms located within the genomic regions of 20 mechanosensitive ion channel genes in the K2P, TMEM63, PIEZO and TRP channel families were assessed using genotype data from the NEIGHBORHOOD consortium of 3853 cases and 33,480 controls. Rare (minor allele frequency < 1%) coding variants were assessed using exome array genotyping data for 2606 cases and 2606 controls. Association with POAG was analyzed using logistic regression adjusting for age and sex. Two rare PIEZO1 coding variants with protective effects were identified in the NEIGHBOR dataset: R1527H, (OR 0.17, P = 0.0018) and a variant that alters a canonical splice donor site, g.16-88737727-C-G Hg38 (OR 0.38, P = 0.02). Both variants showed similar effects in the UK Biobank and the R1527H also in the FinnGen database. Several common variants also reached study-specific thresholds for association in the NEIGHBORHOOD dataset. These results identify novel variants in several mechanosensitive channel genes that show associations with POAG, suggesting that these channels may be potential therapeutic targets.

Association of intravascular enhancement sign on 3D-T1W TSE with collateral status in middle cerebral artery occlusion stroke.

OBJECTIVE: The significance of the intravascular enhancement sign (IVES) on high-resolution magnetic resonance vascular wall imaging (HR-VWI) remains unclear. This study aimed to investigate the correlation between the IVES and collateral assessment derived from digital subtraction angiography (DSA). METHOD: A total of 75 patients with occlusion of the first segment of the middle cerebral artery (MCA) who underwent HR-VWI and DSA examinations at our research institution between November 2016 and February 2023 were included. The number of vessels with IVES, IVES-Alberta Stroke Program Early Computed Tomography Score (ASPECTS), American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) collateral grade, and DSA collateral blood flow grade were retrospectively evaluated. Correlations between these indicators were assessed using Spearman's correlation. RESULTS: Interrater agreement was good for the assessment of HR-VWI and DSA indicators. After adjustments for age, degree of wall enhancement, and hypertension, a multivariable ordinal logistic regression model identified both the number of IVES vessels (OR = 1.37; 95%CI [1.06-1.78]; P = 0.017) and IVES-ASPECTS (OR = 2.00; 95%CI [1.03-3.87]; P = 0.041) as independent predictors of ischemic stroke. In the patient group with acute ischemic stroke, we found weak correlations between the number of IVES vessels and the ASITN/SIR collateral grade (rho = -0.35; P = 0.002) and between the IVES-ASPECTS and ASITN/SIR collateral grade (rho = -0.27; P = 0.02). Moreover, there were strong correlations between the number of IVES vessels and the DSA collateral blood flow grade (rho = -0.74; P < 0.001) and between the IVES-ASPECTS and the DSA collateral blood flow grade (rho = -0.65; P < 0.001). The number of IVES vessels correlated strongly with the IVES-ASPECTS (rho = 0.92, P < 0.001). CONCLUSION: We find that the IVES is closely associated with sluggish collateral blood flow, which further confirms the hemodynamic mechanism underlying the IVES in MCA occlusion.

Association of intravascular enhancement sign detected on high-resolution vessel wall imaging with ischaemic events in middle cerebral artery occlusion.

PURPOSE: Patients with intracranial artery occlusion have high rates of ischaemic events and recurrence. Early identification of patients with high-risk factors is therefore beneficial for prevention. Here we assessed the association between the intravascular enhancement sign (IVES) on high-resolution vessel wall imaging (HR-VWI) and acute ischaemic stroke (AIS) in a population with middle cerebral artery (MCA) occlusion. METHOD: We retrospectively analysed the records of 106 patients with 111 MCA occlusions, including 60 with and 51 without AIS, who had undergone HR-VWI and computed tomography angiography (CTA) examinations from November 2016 to February 2023. Numbers of IVES vessels were counted and compared to the CTA findings. Statistical analyses of demographic and medical data were also performed. RESULTS: Occurrence rates and numbers of IVES vessels were significantly higher in the AIS than the non-AIS group (P < 0.05), and most vessels were detected on CTA. Numbers of vessels positively correlated with AIS occurrence (rho = 0.664; P < 0.0001). A multivariable ordinal logistic regression model adjusted for age, degree of wall enhancement, hypertension, and heart status identified the number of IVES vessels as an independent predictor for AIS (odds ratio = 1.6; 95% CI, 1.3-1.9; P < 0.0001). CONCLUSION: Number of IVES vessels is an independent risk factor for AIS events, and may represent poor cerebral blood flow status and collateral compensation level. It thus provides cerebral haemodynamic information for patients with MCA occlusion for clinical use.

Parameter Optimization and DEM Simulation of Bionic Sweep with Lower Abrasive Wear Characteristics.

High wear rates during the tillage process often result in significant financial losses and wasted farming seasons. In this paper, a bionic design was used to reduce tillage wear. Inspired by wear-resistant animals with ribbed structures, the bionic ribbed sweep (BRS) was designed by combining a ribbed unit with a conventional sweep (CS). BRSs with different parameters (width φ, height h, angle θ, and interval λ) were simulated and optimized using the DEM and RSM methods at a working depth of 60 mm to evaluate the magnitude and trends of three responses: tillage resistance (TR), number of contacts between the sweep and soil particles (CNSP), and Archard wear value (AW). The results showed that a protective layer could be created on the surface of the sweep with a ribbed structure to reduce abrasive wear. Analysis of variance proved that factors φ, θ, and λ had significant effects on AW, CNSP, and TR, while factor h was insignificant. An optimal solution was obtained using the desirability method, including 8.88 mm φ, 1.05 mm h, 3.01 mm λ, and 34.46° θ. Wear tests and simulations showed that wear loss could be effectively reduced at different speeds by the optimized BRS. It was found to be feasible to create a protective layer to reduce partial wear by optimizing the parameters of the ribbed unit.

Structural Mechanical Properties of 3D Printing Biomimetic Bone Replacement Materials.

One of the primary challenges in developing bone substitutes is to create scaffolds with mechanical properties that closely mimic those of regenerated tissue. Scaffolds that mimic the structure of natural cancellous bone are believed to have better environmental adaptability. In this study, we used the porosity and thickness of pig cancellous bone as biomimetic design parameters, and porosity and structural shape as differential indicators, to design a biomimetic bone beam scaffold. The mechanical properties of the designed bone beam model were tested using the finite element method (FEM). PCL/ß-TCP porous scaffolds were prepared using the FDM method, and their mechanical properties were tested. The FEM simulation results were compared and validated, and the effects of porosity and pore shape on the mechanical properties were analyzed. The results of this study indicate that the PCL/ß-TCP scaffold, prepared using FDM 3D printing technology for cancellous bone tissue engineering, has excellent integrity and stability. Predicting the structural stability using FEM is effective. The triangle pore structure has the most stability in both simulations and tests, followed by the rectangle and honeycomb shapes, and the diamond structure has the worst stability. Therefore, adjusting the porosity and pore shape can change the mechanical properties of the composite scaffold to meet the mechanical requirements of customized tissue engineering.

Screening of Bifidobacteria with Probiotic Potential from Healthy Infant Feces by Using 2'-Fucosyllactose.

Using 2'-fucosyllactose (2'-FL) as the sole carbon source can be an efficient way to screen bifidobacteria with superior probiotic capabilities since 2'-FL is a key element in promoting the growth of intestinal bifidobacteria in newborns. This approach was used in this work to screen eight bifidobacteria strains, including one strain of Bifidobacterium longum subsp. infantis BI_Y46 and seven strains of Bifidobacterium bifidum (BB_Y10, BB_Y30, BB_Y39, BB_S40, BB_H4, BB_H5 and BB_H22). Studies on their probiotic properties showed that BI_Y46 had a unique morphology with pilus-like structure, a high resistance to bile salt stimulation and a potent inhibitory action on Escherichia coli ATCC 25922. Similarly, BB_H5 and BB_H22 produced more extracellular polysaccharides and had a higher protein content than other strains. In contrast, BB_Y22 displayed considerable auto-aggregation activity and a high resistance to bile salt stimulation. Interestingly, BB_Y39 with weak self-aggregation ability and acid resistance had very excellent bile salt tolerance, extracellular polysaccharides (EPS) production and bacteriostatic ability. In conclusion, 2'-FL was used as sole carbon source to identify eight bifidobacteria with excellent probiotic properties.

GWAS on retinal vasculometry phenotypes.

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10-108), 2 loci with arteriolar width (rs12969347, p = 3.30×10-09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa.

Electrical responses from human retinal cone pathways associate with a common genetic polymorphism implicated in myopia.

Myopia is the commonest visual impairment. Several genetic loci confer risk, but mechanisms by which they do this are unknown. Retinal signals drive eye growth, and myopia usually results from an excessively long eye. The common variant most strongly associated with myopia is near the GJD2 gene, encoding connexin-36, which forms retinal gap junctions. Light-evoked responses of retinal neurons can be recorded noninvasively as the electroretinogram (ERG). We analyzed these responses from 186 adult twin volunteers who had been genotyped at this locus. Participants underwent detailed ERG recordings incorporating international standard stimuli as well as experimental protocols aiming to separate dark-adapted rod- and cone-driven responses. A mixed linear model was used to explore association between allelic dosage at the locus and international standard ERG parameters after adjustment for age, sex, and family structure. Significant associations were found for parameters of light-adapted, but not dark-adapted, responses. Further investigation of isolated rod- and cone-driven ERGs confirmed associations with cone-driven, but not rod-driven, a-wave amplitudes. Comparison with responses to similar experimental stimuli from a patient with a prior central retinal artery occlusion, and from two patients with selective loss of ON-bipolar cell signals, was consistent with the associated parameters being derived from signals from cone-driven OFF-bipolar cells. Analysis of single-cell transcriptome data revealed strongest GJD2 expression in cone photoreceptors; bipolar cell expression appeared strongest in OFF-bipolar cells and weakest in rod-driven ON-bipolar cells. Our findings support a potential role for altered signaling in cone-driven OFF pathways in myopia development.

Genetic Determinants of Intraocular Pressure.

Intraocular pressure (IOP) is the cardinal and only modifiable risk factor for glaucoma, the leading cause of irreparable blindness worldwide. Twin and family studies estimate the heritability of IOP to be 40-70%, and linkage studies for IOP have identified numerous loci. Mutations in MYOC can cause markedly elevated IOP and aggressive glaucoma often requiring surgical intervention. However, the majority of the genetic basis for raised IOP and glaucoma in populations is complex, and recent large genome-wide association studies (GWASs) have identified over 100 common variants that contribute to IOP variation. In combination, these loci are predictive for primary open-angle glaucoma in independent populations, achieving an area under the receiver operating characteristic curve of 76% for high-pressure primary open-angle glaucoma; this suggests the possibility of targeted screening in the future. Additionally, GWAS findings have identified important biological pathways underlying IOP regulation, including lymphangiogenesis and lipid metabolism, providing novel targets for new therapies.