Probiotic LB101 alleviates dry eye in mice by suppressing matrix metalloproteinase-9 expression through the regulation of gut microbiota-involved NF-κB signaling.

Tear matrix metalloproteinase (MMP)-9 is an inflammatory signal in patients with dry eye (DE). In the present study, to understand the action mechanism of probiotic LB101 (Lactobacillus plantarum NK151 and Bifidobacterium bifidum NK175 [4:1] mix) against DE, we investigated its effect on tear amount and inflammatory marker expression levels in mice with unilateral exorbital lacrimal gland excision/atropine-benzalkonium chloride application (EB) or fecal microbiota transplantation from mice with EB (eFMT). Oral gavage of LB101 increased EB-suppressed tear amount and decreased EB-induced blinking number. Furthermore, LB101 decreased EB-induced TNF-α, IL-1ß, and MMP-9 expression, TNF-α+ and NF-κB+CD11c+ cell populations, and edema in the conjunctiva, while EB-suppressed IL-10 and occludin expression increased. LB101 also decreased EB-induced TNF-α and IL-1ß expression and NF-κB+CD11c+ cell population in the colon. eFMT also decreased tear amount and increased blinking number in the transplanted mice. eFMT increased TNF-α, IL-1ß, and MMP-9 expression and TNF-α+ and NF-κB+CD11c+ cell populations in the conjunctiva and TNF-α and IL-1ß expression and NF-κB+CD11c+ cell populations in the colon. Oral gavage of LB101 increased eFMT-suppressed tear amount and decreased eFMT-induced blinking number. Furthermore, LB101 decreased TNF-α, IL-1ß, and MMP-9 expression, TNF-α+ and NF-κB+CD11c+ cell populations, and edema in the conjunctiva and TNF-α and IL-1ß expression and NF-κB+CD11c+ cell population in the colon, while eFMT-suppressed IL-10 and occludin expression decreased. Furthermore, LB101 increased eFMT-suppressed Muribaculaceae, Prevotellaceae, and Lactobacillaceae populations in the gut microbiota, while eFMT-induced Bacteroidaceae population decreased. These findings suggest that DE may cause gut dysbiosis, which may be a risk factor for DE, and LB101 may alleviate DE with gut inflammation by suppressing the expression of MMP-9 and proinflammatory cytokines TNF-α and IL-1ß with the regulation of gut microbiota-involved NF-κB signaling.

Machine Learning of Cardiac Anatomy and the Risk of New-Onset Atrial Fibrillation After TAVR.

BACKGROUND: New-onset atrial fibrillation (NOAF) occurs in 5% to 15% of patients who undergo transfemoral transcatheter aortic valve replacement (TAVR). Cardiac imaging has been underutilized to predict NOAF following TAVR. OBJECTIVES: The objective of this analysis was to compare and assess standard, manual echocardiographic and cardiac computed tomography (cCT) measurements as well as machine learning-derived cCT measurements of left atrial volume index and epicardial adipose tissue as risk factors for NOAF following TAVR. METHODS: The study included 1,385 patients undergoing elective, transfemoral TAVR for severe, symptomatic aortic stenosis. Each patient had standard and machine learning-derived measurements of left atrial volume and epicardial adipose tissue from cardiac computed tomography. The outcome of interest was NOAF within 30 days following TAVR. We used a 2-step statistical model including random forest for variable importance ranking, followed by multivariable logistic regression for predictors of highest importance. Model discrimination was assessed by using the C-statistic to compare the performance of the models with and without imaging. RESULTS: Forty-seven (5.0%) of 935 patients without pre-existing atrial fibrillation (AF) experienced NOAF. Patients with pre-existing AF had the largest left atrial volume index at 76.3 ± 28.6 cm3/m2 followed by NOAF at 68.1 ± 26.6 cm3/m2 and then no AF at 57.0 ± 21.7 cm3/m2 (P < 0.001). Multivariable regression identified the following risk factors in association with NOAF: left atrial volume index ≥76 cm2 (OR: 2.538 [95% CI: 1.165-5.531]; P = 0.0191), body mass index <22 kg/m2 (OR: 4.064 [95% CI: 1.500-11.008]; P = 0.0058), EATv (OR: 1.007 [95% CI: 1.000-1.014]; P = 0.043), aortic annulus area ≥659 mm2 (OR: 6.621 [95% CI: 1.849-23.708]; P = 0.004), and sinotubular junction diameter ≥35 mm (OR: 3.891 [95% CI: 1.040-14.552]; P = 0.0435). The C-statistic of the model was 0.737, compared with 0.646 in a model that excluded imaging variables. CONCLUSIONS: Underlying cardiac structural differences derived from cardiac imaging may be useful in predicting NOAF following transfemoral TAVR, independent of other clinical risk factors.

Enhanced Nonradiative Charge Recombination in Microfiber-Based Bismuthene.

After the first report of a graphene-based passive mode-locking ultrafast fiber laser, two-dimensional materials as efficient saturable absorbers offer a new horizon in ultrafast fiber laser. However, the interactions on atomic scale between these two-dimensional materials and fiber and the fiber effect on the carrier dynamics have not been realized. To figure out the exact role of fiber and the carrier dynamics affected by the fiber substrate related to ultrafast photonics, bismuthene, a newly reported 2D quantum material used in a passive mode-locking fiber laser, deposited on α-quartz has been investigated. We surprisingly found that the α-quartz substrate can strongly accelerate the nonradiative electron-hole recombination of bismuthene in theory, and the transient absorption spectra of bismuthene on normal glass and α-quartz further verify the substrate effect on carrier dynamics of bismuthene. The discovery provides new thinking about substrate effect to regulate the performance of ultrafast mode-locking fiber lasers as well as ultrafast photonics.

Lipopolysaccharide-producing Veillonella infantium and Escherichia fergusonii cause vagus nerve-mediated cognitive impairment in mice.

Gut microbiota communicates bidirectionally with the brain through the nervous, immune, and endocrine systems of the gut. In our preliminary study, the fecal microbiota of volunteers with mild cognitive impairment (Fmci) exhibited a higher abundance of Escherichia fergusonii (NK2001), Veillonella infantium (NK2002), and Enterococcus faecium (NK2003) populations compared with those of healthy volunteers. Therefore, we examined the effects of Fmci, NK2001 (gram-negative), NK2002 (gram-negative-like), and NK2003 (gram-positive) on cognitive impairment-like behavior, neuroinflammation, and colitis in mice with or without antibiotics. Fmci transplantation increased cognitive impairment-like behavior, hippocampal tumor necrosis factor (TNF)-α expression, and the size of toll-like receptor (TLR)4+Iba1+, TLR2+Iba1+, and NF-κB+Iba1+ cell populations independent of antibiotic treatment. Oral gavage of NK2001, NK2002, or NK2003, which induced TNF-α expression in Caco-2 cells, significantly increased cognitive impairment-like behavior and hippocampal TNF-α expression and Iba1-positive cell populations and decreased brain-derived neurotrophic factor (BDNF) expression in mice. Celiac vagotomy significantly decreased NK2001- or NK2002-induced cognitive impairment-like behavior and hippocampal Iba1+ cell population and TNF-α expression and increased NK2001- or NK2002-suppressed hippocampal BDNF expression. However, NK2003-induced cognitive impairment-like behavior and hippocampal Iba1+ cell population and TNF-α expression were partially, but not significantly, attenuated by celiac vagotomy. Furthermore, celiac vagotomy did not affect NK2001-, NK2002-, or NK2003-induced lipopolysaccharide (LPS) levels in the blood and feces and TNF-α expression and NF-κB-positive cell population in the colon. In conclusion, LPS-producing NK2001 and NK2002 and LPS-nonproducing NK2003 may induce NF-κB-mediated neuroinflammation through the translocation of byproducts such as LPS and peptidoglycan into the brain through gut-blood/vagus nerve-brain and gut-blood-brain pathways, respectively, resulting in cognitive impairment.

Influence of Income, Education, and Medicaid Expansion on Palliative Care in Acute Myeloid Leukemia Using the National Cancer Database.

Palliative care is integral to symptom management, and we examined its relationship with income, education, and Medicaid expansion in acute myeloid leukemia. This was a retrospective cross-sectional study using the National Cancer Database that included patients with acute myeloid and monocytic leukemias > 18 years of age treated at Commission on Cancer facilities from 2004 to 2016. Univariate and multivariate models were adjusted for demographic variables and facility characteristics. There were 124,988 patients, but only 106,495 had palliative care data, and of this 4111 (3%) received palliative care. The most educated had the highest odds of receiving palliative care (odds ratio, OR 1.23, 95% CI 1.08-1.41; P = 0.002), but the highest income bracket (≥ $63,333) had the lowest odds (OR 0.82, 95% CI 0.72-0.93; P = 0.003). Residence in states with Medicaid expansion (January 2014 onward) had greater palliative care utilization. Palliative care use was associated with higher education but underutilized with higher incomes. Increased access with Medicaid expansion suggests the importance of public insurance.

IL-6 expression-suppressing Lactobacillus reuteri strains alleviate gut microbiota-induced anxiety and depression in mice.

Fecal microbiota transplantation from patients with depression/inflammatory bowel disease (PDI) causes depression with gut inflammation in mice. Here, we investigated the effects of six Lactobacillus reuteri strains on brain-derived neurotropic factor (BDNF), serotonin, and interleukin (IL)-6 expression in neuronal or macrophage cells and PDI fecal microbiota-cultured microbiota (PcM)-induced depression in mice. Of these strains, L6 most potently increased BDNF and serotonin levels in corticosterone-stimulated SH-SY5Y and PC12 cells, followed by L3. L6 most potently decreased IL-6 expression in lipopolysaccharide (LPS)-stimulated macrophages. When L1 (weakest in vitro), L3, and L6 were orally administered in mice with PcM-induced depression, L6 most potently suppressed depression-like behaviors and hippocampal TNF-α and IL-6 expression and increased hippocampal serotonin, BDNF, 5HT7, GABAARα1, and GABABR1b expression, followed by L3 and L1. L6 also suppressed TNF-α and IL-6 expression in the colon. BDNF or serotonin levels in corticosterone-stimulated neuronal cells were negatively correlated with depression-related biomarkers in PcM-transplanted mice, while IL-6 levels in LPS-stimulated macrophage were positively correlated. These findings suggest that IL-6 expression-suppressing and BDNF/serotonin expression-inducing LBPs in vitro, particularly L6, may alleviate gut microbiota-involved depression with colitis in vivo.

Using machine learning to enhance prediction of atrial fibrillation recurrence after catheter ablation.

Background: Traditional risk scores for recurrent atrial fibrillation (AF) following catheter ablation utilize readily available clinical and echocardiographic variables and yet have limited discriminatory capacity. Use of data from cardiac imaging and deep learning may help improve accuracy and prediction of recurrent AF after ablation. Methods: We evaluated patients with symptomatic, drug-refractory AF undergoing catheter ablation. All patients underwent pre-ablation cardiac computed tomography (cCT). LAVi was computed using a deep-learning algorithm. In a two-step analysis, random survival forest (RSF) was used to generate prognostic models with variables of highest importance, followed by Cox proportional hazard regression analysis of the selected variables. Events of interest included early and late recurrence. Results: Among 653 patients undergoing AF ablation, the most important factors associated with late recurrence by RSF analysis at 24 (+/-18) months follow-up included LAVi and early recurrence. In total, 5 covariates were identified as independent predictors of late recurrence: LAVi (HR per mL/m2 1.01 [1.01-1.02]; p < .001), early recurrence (HR 2.42 [1.90-3.09]; p < .001), statin use (HR 1.38 [1.09-1.75]; p = .007), beta-blocker use (HR 1.29 [1.01-1.65]; p = .043), and adjunctive cavotricuspid isthmus ablation [HR 0.74 (0.57-0.96); p = .02]. Survival analysis demonstrated that patients with both LAVi >66.7 mL/m2 and early recurrence had the highest risk of late recurrence risk compared with those with LAVi <66.7 mL/m2 and no early recurrence (HR 4.52 [3.36-6.08], p < .001). Conclusions: Machine learning-derived, full volumetric LAVi from cCT is the most important pre-procedural risk factor for late AF recurrence following catheter ablation. The combination of increased LAVi and early recurrence confers more than a four-fold increased risk of late recurrence.

Bifidobacterium bifidum and Lactobacillus paracasei alleviate sarcopenia and cognitive impairment in aged mice by regulating gut microbiota-mediated AKT, NF-κB, and FOXO3a signaling pathways.

Sarcopenia is closely associated with gut dysbiosis. Probiotics alleviate gut dysbiosis. Therefore, we selected probiotics Lactobacillus paracasei P62 (Lp) and Bifidobacterium bifidum P61 (Bb), which suppressed muscle RING-finger protein-1 (MuRF1) expression and NF-κB activation in C2C12 cells, and examined their effects on muscle mass loss and dysfunction in aged mice. Oral administration of Lp, Bb, or their mix (LB) increased grip strength and treadmill running distance and time. They significantly increased muscle weight in aged mice. They also increased AKT activation, PGC1α, SIRT1, and myosin heavy chain (MyHC) expression, MyHC-positive cell population, and cell size in the gastrocnemius (GA) muscle, while FOXO3a and NF-κB activation, MuRF1, muscle atrophy F-box, and p16 expression, and NF-κB+CD11c+ cell population decreased. Furthermore, they reduced cognitive impairment-like behavior, IL-6 expression, FOXO3a activation, and NF-κB-positive cell population in the hippocampus, GA, and colon, while hippocampal brain-derived neurotropic factor expression increased. They shifted gut microbiota composition in aged mice: they increased Akkermansiaceae and Bacteroidaceae populations, which were positively correlated with total muscle weight and MyHC expression, and decreased Odoribacteraceae and Deferribacteriaceae populations, which were positively correlated with MuRF1 and IL-6 expression. LB alleviated sarcopenia- and cognitive impairment-like symptoms more potently than Lp or Bb alone. Based on these findings, probiotics, particularly Lp, Bb, and LB, can alleviate aging-dependent sarcopenia and cognitive impairment by regulating gut microbiota-mediated AKT, NF-κB, and/or FOXO3a signaling pathways.

The What and Who of Dietary Lignans in Human Health: Special Attention to Estrogen Effects and Safety Evaluation.

Lignans are a group of phenolic compounds found in plant-based diets. The human body can obtain lignans through diet, which are then metabolized into enterolignans. The enterolignans have been linked to several health benefits, including anticancer, anti-inflammatory, antioxidant effects, and estrogen effects. This review explores the relationship between the estrogenic effects of lignans and health. This review not only considers the estrogen-like activity of lignans but also discusses the safe dosage of lignans at different life stages. In addition, this review also identified other types of bioactive compounds that can act synergistically with lignans to promote health. Studies have shown that lignan administration during pregnancy and lactation reduces the risk of breast cancer in offspring. Further studies are needed to investigate the estrogenic safety effects of lignan on pregnant women and children. Whether lignans combine with other nutrients in complex food substrates to produce synergistic effects remains to be investigated. This review provides a basis for future studies on the safe dose of lignan and recommended dietary intake of lignan. We believe that the acquired as discussed here has implications for developing dietary therapies that can promote host nutrition and modulate estrogenic diseases.

Comparative Study on the Absorption and Metabolism of Pinoresinol and Pinoresinol-4-O-ß-D-Glucopyranoside in Mice.

SCOPE: Lignans are a group of phenolic compounds commonly found in plants, often in the form of glycosides. This study investigates the differences in the digestion, absorption, and metabolism of lignans and their glucosides using pinoresinol (PIN) and pinoresinol-4-O-ß-D-glucopyranoside (PMG). METHODS AND RESULTS: After oral administration mice PIN and PMG with a dose of 0.1 µmol kg-1 . The results showed that the stomach and small intestine rapidly absorbe PIN and PMG in their prototype form. After oral administration of 0.25 h, serum levels of PIN and PMG reach peak values of 61.14 and 52.97 ng mL-1 , respectively. This indicates a faster PIN absorption rate than PMG, likely due to the glycosides attach to the parent compound, with concentrations of 1574.14 and 876.75 ng g-1 , respectively. Pharmacokinetic analysis reveals that PIN has a greater area under the curve and a longer half-life than PMG in serum and liver. Moreover, mice in the PIN group exhibit higher metabolite levels in the serum and liver compared to those in the PMG group. CONCLUSION: The deglycosylation process that occurs during the pickling of white radish facilitates the absorption and metabolism of the lignans fraction in the body.

First report of Root rot in Cerasus subhirtella Caused by Fusarium solani and Fusarium oxysporum in China.

Cerasus subhirtella (Miq.) Sok. is a widely used ornamental tree in urban areas around China and has a high ornamental value. From 2018 to 2020, a root rot disease was observed in C. subhirtella in Meitan County, Weng'an County, and Guiyang city of Guizhou, China (106.71 E, 26.57 N). Diseased C. subhirtella trees exhibited wilting with leaf chlorosis accompanied by brown to black root discoloration. In an area of 100 ha in total, with disease incidence ranging from 60 to 80%. Six symptomatic plants with root rot were randomly collected from three locations where disease symptoms were observed for pathogen isolation. Fifty fragments of diseased roots (5×5mm) were disinfected in 3% sodium hypochlorite for 30 s and 75% alcohol for 60 s, rinsed three times in sterile distilled water, plated on potato dextrose agar (PDA; BoWei, Shanghai), and incubated at 28 °C in the dark for 7 days. Eighteen isolates were purified by single spore culturing. Typical Fusarium spp. colonies were obtained from all root samples. On PDA, the colonies showed white and the hyphae were dense, while the colony of isolate YH15 showed pale yellow on the back, radial growth and produced chlamydospores. The macrospores (YH15) were straight to subarcuate, measured 15.3 to 25.1 × 2.5 to 6.2 µm (n=50). The microconidia (YH26) were ellipsoid to ovoid, measured 8.6 to 12.7 × 1.6 to 5.1 µm (n=50). These morphological characteristics were consistent with Fusarium spp., as described recently in Vitullo et al. (2014). To confirm the morphological diagnosis, genomic DNA from the isolates was extracted. The internal transcribed spacer (ITS) (White et al, 1990) region of rDNA and a ß-tubulin (Varga et al, 2011) gene fragment were amplified with the primers ITS1/ITS4 and Bt2a/Bt2b, respectively, and were subsequently sequenced. Maximum likelihood analysis was carried out using MEGA 11.0. BLAST analysis revealed that the ITS and ß-tubulin sequences of isolate YH15 were 100% homologous with F. oxysporum, and the isolate YH26 had a 99.69~100% homology with F. solani. Sequences of isolate YH15 and YH26 were deposited in GenBank (ITS: OQ363005 and OQ363049; ß-tubulin: OQ398187 and OQ398180). The isolate YH15 was thus identified as F. oxysporum by the morphological characteristics and sequences analysis, and the isolate YH26 was identified as F. solani. A reconstructed phylogenetic tree also confirmed their phylogenetic position. The healthy 2-year-old C. subhirtella plants grown in autoclaved acid yellow soil were used for the pathogenicity tests. Then, 50 mL of conidial suspension (2.0×105 conidia/mL, in medium) of 7-day-old isolates YH15 and YH26 were gently applied to the soil in each of the 10 pots as the treatment. A sterilized fungal culture matrix (PDB; BoWei, Shanghai) was applied to each of 10 pots as a control. All pots (30 cm high, 25 cm upper diameter, 15 cm base diameter) were placed in a greenhouse (25 °C, 12 h photoperiod). After 30 days of inoculation, all plants inoculated with the isolates showed wilting symptoms, and the roots showed light-brown to dark-brown lesions. No symptoms were observed in the controls. The pathogen was reisolated from all symptomatic roots and identified as F. oxysporum and F. solani as described above. The pathogenicity test was repeated twice with similar results. Although this fungus was previously reported to cause root disease in many hosts (Li et al., 2020; Gibert et al., 2022), this is the first report of F. oxysporum and F. solani causing root rot in C. subhirtella in China.

A Bionic Venus Flytrap Soft Microrobot Driven by Multiphysics for Intelligent Transportation.

With the continuous integration of material science and bionic technology, as well as increasing requirements for the operation of robots in complex environments, researchers continue to develop bionic intelligent microrobots, the development of which will cause a great revolution in daily life and productivity. In this study, we propose a bionic flower based on the PNIPAM-PEGDA bilayer structure. PNIPAM is temperature-responsive and solvent-responsive, thus acting as an active layer, while PEGDA does not change significantly in response to a change in temperature and solvent, thus acting as a rigid layer. The bilayer flower is closed in cold water and gradually opens under laser illumination. In addition, the flower gradually opens after injecting ethanol into the water. When the volume of ethanol exceeds the volume of water, the flower opens completely. In addition, we propose a bionic Venus flytrap soft microrobot with a bilayer structure. The robot is temperature-responsive and can reversibly transform from a 2D sheet to a 3D tubular structure. It is normally in a closed state in both cold (T < 32 °C) and hot water (T > 32 °C), and can be used to load and transport objects to the target position (magnetic field strength < 1 T).

Alleviation of Cognitive Impairment-like Behaviors, Neuroinflammation, Colitis, and Gut Dysbiosis in 5xFAD Transgenic and Aged Mice by Lactobacillus mucosae and Bifidobacterium longum.

Neuropsychiatric disorders including Alzheimer's disease (AD) may cause gut inflammation and dysbiosis. Gut inflammation-suppressing probiotics alleviate neuropsychiatric disorders. Herein, to understand whether anti-inflammatory probiotics Lactobacillus mucosae NK41 and Bifidobacterium longum NK46, which suppressed tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated macrophages, could alleviate cognitive impairment, we first examined their effects on cognitive function, gut inflammation, and gut microbiota composition in 5xFAD-transgenic mice. Oral administration of NK41 or NK46 decreased cognitive impairment-like behaviors, hippocampal amyloid-ß (Aß), TNF-α and interleukin (IL)-1ß expression, hippocampal NF-κB+Iba1+ cell population, and Aß accumulation, while hippocampal brain-derived neurotropic factor (BDNF) and IL-10 expression and BDNF+NeuN+ cell population increased. They also decreased TNF-α and IL-1ß expression and NF-κB+CD11c+ cell population in the colon. They also reduced fecal and blood LPS levels and gut Proteobacteria and Verrucomicrobia populations (including Akkkermansiaceae), which are positively associated with hippocampal TNF-α and fecal LPS levels and negatively correlated with hippocampal BDNF level. However, they increased Odoribactericeae, which positively correlated with BDNF expression level and TNF-α to IL-10 expression ratio. The combination of NK41 and NK46 (4:1, NKc), which potently inhibited TNF-α expression in LPS-stimulated macrophages, additively alleviated cognitive impairment-like behaviors in 5xFAD-transgenic or aged mice. NKc increased hippocampal BDNF+NeuN+ cell population and BDNF expression in 5xFAD-transgenic or aged mice, while hippocampal TNF-α and IL-1ß expression decreased. NKc also decreased TNF-α and IL-1ß expression in the colon and LPS levels in the blood and feces. These findings suggest that gut bacteria and its product LPS may be closely connected with occurrence of cognitive impairment and neuroinflammation and the combination of NK41 and NK46 can additively alleviate cognitive impairment and neuroinflammation by inducing NF-κB-suppressed BDNF expression and suppressing LPS-producing gut bacteria.

Optical absorption of bismuthene with a single vacancy: first-principle calculations.

The exceptional mechanical, electronic, topological, and optical properties, make bismuthene an ideal candidate for various applications in ultrafast saturation absorption and spintronics. Despite the extensive research efforts devoted to synthesizing this material, the introduction of defects, which can significantly affect its properties, remains a substantial obstacle. In this study, we investigate the transition dipole moment and joint density of states of bismuthene with/without single vacancy defect via energy band theory and interband transition theory. It is demonstrated that the existence of the single defect enhances the dipole transition and joint density of states at lower photon energies, ultimately resulting in an additional absorption peak in the absorption spectrum. Our results suggest that the manipulation of defects in bismuthene has enormous potential for improving the optoelectronic properties of this material.

Lactobacillus casei and Its Supplement Alleviate Stress-Induced Depression and Anxiety in Mice by the Regulation of BDNF Expression and NF-κB Activation.

Stress-induced depression and anxiety (DA) are closely connected to gastrointestinal inflammation and dysbiosis, which can suppress brain-derived neurotrophic factor (BDNF) in the brain. Herein, we isolated the BDNF expression-inducing probiotics Lactobacillus casei HY2782 and Bifidobacterium lactis HY8002 in lipopolysaccharide-stimulated SH-SY5Y cells. Then, we investigated the effects of HY2782, HY8002, anti-inflammatory L-theanine, and their supplement (PfS, probiotics-fermented L-theanine-containing supplement) on DA in mice exposed to restraint stress (RS) or the fecal microbiota of patients with inflammatory bowel disease and depression (FMd). Oral administration of HY2782, HY8002, or L-theanine alleviated RS-induced DA-like behaviors. They also decreased RS-induced hippocampal interleukin (IL)-1ß and IL-6 levels, as well as NF-κB-positive cell numbers, blood corticosterone level, and colonic IL-1ß and IL-6 levels and NF-κB-positive cell numbers. L-theanine more potently suppressed DA-like behaviors and inflammation-related marker levels than probiotics. However, these probiotics more potently increased RS-suppressed hippocampal BDNF level and BDNF+NeuN+ cell numbers than L-theanine. Furthermore, HY2782 and HY8002 suppressed RS-increased Proteobacteria and Verrucomicrobia populations in gut microbiota. In particular, they increased Lachnospiraceae and Lactobacillacease populations, which are closely positively associated with hippocampal BDNF expression, and suppressed Sutterellaceae, Helicobacteriaceae, Akkermansiaceae, and Enterobacteriaceae populations, which are closely positively associated with hippocampal IL-1ß expression. HY2782 and HY8002 potently alleviated FMd-induced DA-like behaviors and increased FMd-suppressed BDNF, serotonin levels, and BDNF-positive neuronal cell numbers in the brain. They alleviated blood corticosterone level and colonic IL-1ß α and IL-6 levels. However, L-theanine weakly, but not significantly, alleviated FMd-induced DA-like behaviors and gut inflammation. BDNF expression-inducing probiotic (HY2782, HY8002, Streptococcus thermophilus, and Lactobacillus acidophilus)-fermented and anti-inflammatory L-theanine-containing supplement PfS alleviated DA-like behaviors, inflammation-related biomarker levels, and gut dysbiosis more than probiotics or L-theanine. Based on these findings, a combination of BDNF expression-inducing probiotics with anti-inflammatory L-theanine may additively or synergistically alleviate DA and gut dysbiosis by regulating gut microbiota-mediated inflammation and BDNF expression, thereby being beneficial for DA.

Hospital facility characteristics and socioeconomic factors on outcomes and treatment in patients with multiple myeloma: National Cancer Database analysis.

Previous studies have shown that socioeconomic factors play an important role in multiple myeloma (MM) health outcomes. We postulated that the type of treatment facilities and their volume of cases also affect overall survival, utilization of various therapies including palliative care services in newly diagnosed MM. Using the National Cancer Database (NCDB), we analyzed 174,551 newly diagnosed MM participants from across the country. We found that at high volume facility centers (over 90th percentile of new patient volume from 2004 to 2016), the median overall survival (OS) was 62.3 months versus 35.3 months at lower volume facilities (p <0.001). Similarly, high volume academic cancer centers had an improved median OS of 66.4 months (65.3-67.4 CI) versus 39.2 months (37.9-40.4 months CI) in lower volume academic centers (p <0.001). The odds of utilizing chemotherapy, immunotherapy, and autologous transplants were higher in academic cancer centers compared to community cancer centers, after adjusting for demographic and socioeconomic factors (OR 1.10, 1.23, and 2.06 respectively, all with p<0.001). There was significantly decreased odds of receiving palliative care (OR 0.89, 95% CI 0.85-0.93) in high volume facilities compared to low volume. Palliative care services were more frequently utilized at integrated network cancers and comprehensive community cancer centers compared to community cancer centers, with similar odds of receiving palliative care between community and academic facility types. Our results likely reflect increased provider experience and resources in higher volume and academic facilities. This highlights the need to integrate resources and improve access to community programs.

Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxia.

Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.

Spectrum of clonal hematopoiesis in VEXAS syndrome.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic autoinflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 patients with VEXAS for CH in their peripheral blood (PB) and correlated the findings with clinical outcomes in 77 of them. UBA1mut were most common at hot spot p.M41 (median variant allele frequency [VAF] = 75%). Typical CH mutations cooccurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mut was the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed 2 major patterns: with either typical CH preceding UBA1mut selection in a clone (pattern 1) or occurring as an UBA1mut subclone or in independent clones (pattern 2). VAF in the PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.

Association of Incident Cardiovascular Disease With Time Course and Cumulative Exposure to Multiple Risk Factors.

BACKGROUND: The quantitative relationship of incident cardiovascular disease (CVD) to lifetime cumulative risk factor exposure is not well understood. OBJECTIVES: Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we examined the quantitative associations of cumulative exposure over time to multiple, simultaneously operating risk factors with CVD incidence and the incidence of its components. METHODS: Regression models were developed quantifying the influence of the time course and severity of multiple CVD risk factors, operating simultaneously, on risk of incident CVD. The outcomes were incident CVD and the incidence of its components: coronary heart disease, stroke, and congestive heart failure. RESULTS: Our study included 4,958 asymptomatic adults enrolled in CARDIA from 1985 to 1986 (ages 18 to 30 years) who were followed for 30 years. Risk of incident CVD depends on the time course and severity of a series of independent risk factors, the impact of which is mediated by their effects on individual CVD components after age 40 years. Cumulative exposure (AUC vs time) to low-density lipoprotein cholesterol and triglycerides was independently associated with risk of incident CVD. Of the blood pressure variables, areas under the mean arterial pressure vs time curve and the pulse pressure vs time curve were strongly and independently associated with incident CVD risk. CONCLUSIONS: The quantitative description of the link between risk factors and CVD informs the construction of individualized CVD mitigation strategies, design of primary prevention trials, and assessment of public health impact of risk factor-based interventions.

Alleviation of Porphyromonas gingivalis or Its Extracellular Vesicles Provoked Periodontitis and Cognitive Impairment by Lactobacillus pentosus NK357 and Bifidobacterium bifidum NK391.

Porphyromonas gingivalis (PG) is closely involved in the outbreak of periodontitis and cognitive impairment (CI). Herein, we examined the effects of anti-inflammatory Lactobacillus pentosus NK357 and Bifidobacterium bifidum NK391 on PG- or its extracellular vesicles (pEVs)-induced periodontitis and CI in mice. Oral administration of NK357 or NK391 significantly decreased PG-induced tumor necrosis factor (TNF)-α, receptor activator of nuclear factors κB (RANK), and RANK ligand (RANKL) expression, gingipain (GP)+lipopolysaccharide (LPS)+ and NF-κB+CD11c+ populations, and PG 16S rDNA level in the periodontal tissue. Their treatments also suppressed PG-induced CI -like behaviors, TNF-α expression and NF-κB-positive immune cells in the hippocampus and colon, while PG-suppressed hippocampal BDNF and N-methyl-D-aspartate receptor (NMDAR) expression increased. The combination of NK357 and NK391 additively alleviated PG- or pEVs-induced periodontitis, neuroinflammation, CI-like behaviors, colitis, and gut microbiota dysbiosis and increased PG- or pEVs-suppressed BDNF and NMDAR expression in the hippocampus. In conclusion, NK357 and NK391 may alleviate periodontitis and dementia by regulating NF-κB, RANKL/RANK, and BDNF-NMDAR signaling and gut microbiota.