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There is increasing evidence that inducing neuronal mitophagy can be used as a therapeutic intervention for Alzheimer’s disease. Here, we screen a library of 2024 FDA-approved drugs or drug candidates, revealing UMI-77 as an unexpected mitophagy activator. UMI-77 is an established BH3-mimetic for MCL-1 and was developed to induce apoptosis in cancer cells. We found that at sub-lethal doses, UMI-77 potently induces mitophagy, independent of apoptosis. Our mechanistic studies discovered that MCL-1 is a mitophagy receptor and directly binds to LC3A. Finally, we found that UMI-77 can induce mitophagy in vivo and that it effectively reverses molecular and behavioral phenotypes in the APP/PS1 mouse model of Alzheimer’s disease. Our findings shed light on the mechanisms of mitophagy, reveal that MCL-1 is a mitophagy receptor that can be targeted to induce mitophagy, and identify MCL-1 as a drug target for therapeutic intervention in Alzheimer’s disease. Previous work suggests that mitophagy in neurons is could be therapeutic in Alzheimer’s disease (AD). Here, the authors screen a library of drugs and identify UMI-77, a mitophagy inducer with beneficial effects in an AD mouse model, by binding MCL-1, which they identify as a mitophagy receptor.

Background Heart failure (HF) is a leading cause of hospitalization and mortality for older chronic kidney disease (CKD) patients. However, the epidemiological data is scarce. We aimed to determine the prevalence of left ventricular (LV) dysfunction and HF, and to explore the risk factors for HF among those patients. Methods This is a cross-sectional analysis of the China Hypertension Survey conducted between October 2012 and December 2015. A total of 5, 808 participants aged ≥ 65 years were included in the analysis. Self-reported history of HF and any other cardiovascular diseases was acquired. 2-D and Doppler echocardiography were used to assess LV dysfunction. CKD was defined as either estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m2 or urinary albumin to creatinine ratio (ACR) ≥ 30 mg/g. Results Among CKD patients aged ≥ 65 years, the weighted prevalence of HF, heart failure with preserved ejection fraction (HFpEF), heart failure with mid-range ejection fraction (HFmrEF), and heart failure with reduced ejection fraction (HFrEF) was 4.8%, 2.5%, 0.8%, and 1.7%, respectively. The weighted prevalence of HF was 5.0% in patients with eGFR < 60 mL/min per 1.73 m2, and was 5.9% in patients with ACR ≥ 30 mg/g. The prevalence of LV systolic dysfunction was 3.1%, and while it was 8.9% for moderate/severe diastolic dysfunction. Multivariate analysis showed that smoking was significantly associated with the risk of HF. Furthermore, age, smoking, and residents in rural areas were significantly associated with a risk of LV diastolic dysfunction. Conclusions The prevalence of HF and LV dysfunction was high in older patients with CKD, suggesting that particular strategies will be required.

We perform a systematic study on the local and global spin polarization of $\Lambda$ and $\overline{\Lambda}$ hyperons in relativistic heavy-ion collisions at beam energy scan energies via the (3+1)-dimensional CLVisc hydrodynamics model with AMPT and SMASH initial conditions. Following the quantum kinetic theory, we decompose the polarization vector as the parts induced by thermal vorticity, shear tensor and the spin Hall effect (SHE). We find that the polarization induced by SHE and the total polarization strongly depends on the initial conditions. At $7.7$GeV, SHE gives a sizeable contribution and even flips the sign of the local polarization along the beam direction for AMPT initial condition, which is not observed for SMASH initial condition. Meanwhile, the local polarization along the out-of-plane direction induced by SHE with AMPT initial condition does not always increase with decreasing collision energies. Next, we find that the polarization along the beam direction is sensitive to the baryon diffusion coefficient, but the local polarization along the out-of-plane direction is not. Our results for the global polarization of $\Lambda$ and $\overline{\Lambda}$ agree well with the STAR data. Interestingly, the global polarization of $\overline{\Lambda}$ is not always larger than that of $\Lambda$ due to various competing effects. Our findings are helpful for understanding the polarization phenomenon and the detailed structure of quark-gluon plasma in relativistic heavy-ion collisions., Comment: 13 pages, 8 figures

AIM: To conduct a Meta-analysis pooling randomized controlled trials (RCTs) to compare hydrophobic with hydrophilic acrylic intraocular lenses in terms of posterior capsule opacification (PCO) development. METHODS: Electronic databases including PubMed, Embase, and the Cochrane Library were queried from their starting till January 2020. RCTs investigating the impact of hydrophobic versus hydrophilic acrylic intraocular lenses on PCO were considered eligible in this study. The pooled effect estimates were calculated using the random-effects model. RESULTS: Thirteen RCTs comprising of 939 patients (1263 eyes) were covered in this study. Patients with hydrophobic acrylic intraocular lenses had a lower PCO score than those with a hydrophilic acrylic intraocular lenses [standard mean difference: -1.80; 95% confidence interval (CI): -2.62 to -0.98; P

Asthma is a multifactorial disorder characterized by the airway chronic inflammation, hyper-responsiveness (AHR), remodeling, and reversible obstruction. Although asthma is known as a heterogeneous group of diseases with various clinical manifestations, recent studies suggest that more than half of the clinical cases are ‘‘T helper type 2 (Th2)-high’’ type, whose pathogenesis is driven by Th2 responses to an inhaled allergen from the environmental exposures. The intensity and duration of inflammatory responses to inhaled allergens largely depend on the balance between effector and regulatory cells, but many questions regarding the mechanisms by which the relative magnitudes of these opposing forces are remained unanswered. Regulatory T cells (Tregs), which comprise diverse subtypes with suppressive function, have long been attracted extensive attention owing to their capability to limit the development and progression of allergic diseases. In this review we seek to update the recent advances that support an essential role for Tregs in the induction of allergen tolerance and attenuation of asthma progression once allergic airway inflammation established. We also discuss the current concepts about Treg induction and Treg-expressed mediators relevant to controlling asthma, and the therapies designed based on these novel insights against asthma in clinical settings.

Aloperine is an anti-inflammatory compound isolated from the Chinese herb Sophora alopecuroides L. Previously, our group has reported that the generation of induced Treg was promoted by aloperine treatment in a mouse colitis model. However, the effect of aloperine on effector T cell subsets remains unclear. We therefore carefully examined the effect of aloperine on the differentiation of major subsets of T helper cells. Based on our results, psoriasis, a Th17 dominant skin disease, is selected to explore the potential therapeutic effect of aloperine in vivo. Herein, we demonstrated that topical application of aloperine suppressed epidermal proliferation, erythema, and infiltration of inflammatory cells in skin lesions. Mechanistic studies revealed that aloperine suppressed the differentiation of Th17 cells directly through inhibiting the phosphorylation of STAT3 or indirectly through impairing the secretion of Th17-promoting cytokines by dendritic cells. Moreover, aloperine enhanced the conversion of Th17 into Treg via altering the pSTAT3/pSTAT5 ratio. Collectively, our study supported that aloperine possesses the capacity to affect Th17 differentiation and modulates Th17/Treg balance, thereby alleviating imiquimod (IMQ)-induced psoriasis in mice.

Type 1 diabetes (T1D) stems from pancreatic β cell destruction by islet reactive immune cells. Similar as other autoimmune disorders, there is no curative remedy for T1D thus far. Chronic insulitis is the hallmark of T1D, which creates a local inflammatory microenvironment that impairs β cell function and ultimately leads to β cell death. Immune regulation shows promise in T1D treatment by providing a time window for β cell recovery. However, due to the complex nature of T1D pathogenesis, the therapeutic effect of immune regulation is often short-lasting and unsatisfying in monotherapies. Lymphotoxins (LTs) were first identified in 1960s as the lymphocyte-producing cytokine that can kill other cell types. As a biological cousin of tumor necrosis factor alpha (TNFα), LTs play unique roles in T1D development. Herein in this review, we summarized the advancements of LTs in T1D pathogenesis. We particularly highlighted their effect on the formation of peri-islet tertiary lymphoid organs (TLOs), and discussed their synergistic effect with other cytokines on β cell toxicity and autoimmune progression. Given the complex and dynamic crosstalk between immune cells and β cells in T1D setting, blockade of lymphotoxin signaling applied to the existing therapies could be an efficient approach to delay or even reverse the established T1D.

Not required for Clinical Vignette.

Macrophages are widely distributed in various tissues and organs. They not only participate in the regulation of innate and adaptive immune response, but also play an important role in tissue homeostasis. Dysregulation of macrophage function is closely related to the initiation, development and prognosis of multiple diseases, including infection and tumorigenesis. Forkhead box transcription factor O1 (FoxO1) is an important member among the forkhead box transcription factor family. Through directly binding to the promoter regions of downstream target genes, FoxO1 is implicated in cell proliferation, apoptosis, metabolic activities and other biological processes. In this review, we summarized the regulatory role of FoxO1 in macrophage phagocytosis, migration, differentiation and inflammatory activation. We also emphasized that macrophage reciprocally modulated FoxO1 activity via a post-translational modification (PTM) dominant manner.

Argininosuccinate synthase 1 (ASS1) serves as a critical enzyme in arginine biosynthesis; however, its role in interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF), remains largely unknown. This study aims at characterization and targeting of ASS1 deficiency in pulmonary fibrosis. We find that ASS1 was significantly decreased and inversely correlated with fibrotic status. Transcriptional downregulation of ASS1 was noted in fibroblastic foci of primary lung fibroblasts isolated from IPF patients. Genetic manipulations of ASS1 studies confirm that ASS1 expression inhibited fibroblast cell proliferation, migration, and invasion. We further show that the hepatocyte growth factor receptor (Met) receptor was activated and acted upstream of the Src-STAT3 axis signaling in ASS1-knockdown fibroblasts. Interestingly, both arginine-free conditions and arginine deiminase treatment were demonstrated to kill fibrotic fibroblasts, attenuated bleomycin-induced pulmonary fibrosis in mice, as well as synergistically increased nintedanib efficacy. Our data suggest ASS1 deficiency as a druggable target and also provide a unique therapeutic strategy against pulmonary fibrosis.

We study helicity polarization through the (3+1) dimensional relativistic viscous hydrodynamic models at $\sqrt{s_{NN}}=200$GeV Au+Au collisions. Similar to the local spin polarization, we consider the helicity polarization beyond global equilibrium and investigate the contributions induced by thermal vorticity, shear viscous tensor, and the fluid acceleration. We find that the local helicity polarization induced by thermal vorticity dominates over other contributions. It also implies that in the low-energy collisions, the the fluid vorticity as part of thermal vorticity may play the crucial role to the total helicity polarization. Such a finding could be useful for probing the local strength of vorticity in rotational quark gluon plasmas by measuring helicity polarization. Our simulation confirms the strict space reversal symmetry, whereas we also compare our numerical results with approximated relations derived from ideal Bjorken flow. Our studies also provide a baseline for the future investigation on local parity violation through the correlations of helicity polarization., 27 pages, 9 figures

Imbalanced nutrient intake causes abnormal energy metabolism, which results in obesity. There is feasible evidence that selenium-rich (Se-rich) foods may alleviate obesity and enhance general public health, but the underlying mechanisms remain elusive. Herein we examined the effect of Se supplementation on white adipose tissue beiging process. The mice were fed with a normal diet or a Se-deficient high-fat diet group (DHFD) until there were significant differences in body weight, intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT). Then, the diet of DHFD group was changed to a high-fat diet (HFD) containing specified amounts of selenomethionine (SeMet) (0, 150, 300, and 600 μg/kg) and continued to feed for 14 weeks. Notably, 150 μg/kg SeMet supplement was highly protected from DHFD-induced obesity, insulin resistance, and lipid deposits in liver and kidney, and featured by the enhanced beiging process in white adipose tissue and increased energy expenditure. Moreover, upon cold challenge, 150 μg/kg SeMet supplement enhanced cold tolerance in mice for inducing adipose beiging to promote energy expenditure, evidenced by the increased expression of uncoupling protein-1 (UCP1) in adipocytes. Similarly, SeMet (10 μM) promoted the differentiation of beige adipocytes from the stromal vascular fraction. Collectively, our data support that optimal supplementation of SeMet could enhance the beiging process to attenuate HFD-induced obesity, thus providing new insights into the relationship between dietary SeMet and type 2 diabetes.

Acute myeloid leukemia (AML) is a deadly cancer characterized by an expanded self-renewal capacity that is associated with the accumulation of immature myeloid cells. Emerging evidence shows that methyl-CpG-binding domain protein 2 (MBD2), a DNA methylation reader, often participates in the transcriptional silencing of hypermethylated genes in cancer cells. Nevertheless, the role of MBD2 in AML remains unclear. Herein, by using an MLL-AF9 murine model and a human AML cell line, we observed that loss of MBD2 could delay the initiation and progression of leukemia. MBD2 depletion significantly reduced the leukemia burden by decreasing the proportion of leukemic stem cells (LSCs) and inhibiting leukemia cell proliferation in serial transplantation experiments, thereby allowing leukemic blasts to transition to a more mature state reflecting normal myelopoiesis. Both gene expression analyses and bioinformatic studies revealed that MBD2 negatively modulated genes related to myeloid differentiation, and was necessary to sustain the MLL-AF9 oncogene-induced gene program. We further demonstrated that MBD2 could promote LSC cell cycle progression through epigenetic regulation of CDKN1C transcription probably by binding to its promoter region. Taken together, our data suggest that MBD2 promotes AML development and could be a therapeutic target for myeloid malignancies.

AIM: To observe the postoperative visual quality and patient satisfaction of AT LISA Toric 909MP(909M)astigmatic corrected multifocal IOL and AT TORBI 709M(709M)astigmatic corrected single-focus IOL after phacoemulsification.METHODS: Patients with age-related cataract and corneal astigmatism(>1.0D)were enrolled and accepted phacoemulsification combined with implantation of intraocular lens(IOL)in our hospital during December 2017 and December 2018. Forty cases(56 eyes)were divided into two groups according to which IOL they chose, multiple focal astigmatism(909M)group included 23 cases(35 eyes), single focal astigmatism(709M)group included 17 cases(21 eyes). Three months postoperatively, the visual acuity, defocus curve, residual astigmatism degree, rotational stability of the IOL, postoperative visual quality analysis and patient satisfaction were evaluated.RESULTS: At 3mo postoperatively, uncorrected distance visual acuity(UDVA)and corrected distance acuity in the two groups were significantly improved(PCONCLUSION: Both of the 909M and 709M had good correction effect for cataract combined with astigmatism. It provided better rotational stability. In addition, 909M provided excellent distance, near visual outcomes, and acceptable intermediate vision. At the same time, it improved the spectacle independency and satisfaction of cataract patients combined with astigmatism.

Seeing is believing. The direct observation of GFP-Atg8 vacuolar delivery under confocal microscopy is one of the most useful end-point measurements for monitoring yeast macroautophagy/autophagy. However, manually labelling individual cells from large-scale sets of images is time-consuming and labor-intensive, which has greatly hampered its extensive use in functional screens. Herein, we conducted a time-course analysis of nitrogen starvation-induced autophagy in wild-type and knockout mutants of 35 AuTophaGy-related (ATG) genes in Saccharomyces cerevisiae and obtained 1,944 confocal images containing > 200,000 cells. We manually labelled 8,078 autophagic and 18,493 non-autophagic cells as a benchmark dataset and developed a new deep learning tool for autophagy (DeepPhagy), which exhibited superior accuracy in recognizing autophagic cells compared to other existing methods, with an area under the curve (AUC) value of 0.9710 from 10-fold cross-validations. We further used DeepPhagy to automatically analyze all the images and quantitatively classified the autophagic phenotypes of the 35 atg knockout mutants into 3 classes. The high consistency in our computational and biochemical results indicated the reliability of DeepPhagy for measuring autophagic activity. Moreover, we used DeepPhagy to analyze 3 additional types of autophagic phenotypes, including the targeting of Atg1-GFP to the vacuole, the vacuolar delivery of GFP-Atg19, and the disintegration of autophagic bodies indicated by GFP-Atg8, all with satisfying accuracies. Taken together, our study not only enables the GFP-Atg8 fluorescence assay to become a quantitative measurement for analyzing autophagic phenotypes in S. cerevisiae but also demonstrates that deep learning-based methods could potentially be applied to different types of autophagy. Abbreviations: Ac: accuracy; ALP: alkaline phosphatase; ALR: autophagic lysosomal reformation; ATG: AuTophaGy-related; AUC: area under the curve; CNN: convolutional neural network; Cvt: cytoplasm-to-vacuole targeting; DeepPhagy: deep learning for autophagy; fc_2: second fully connected; GFP: green fluorescent protein; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3 beta; HAT: histone acetyltransferase; HemI: Heat map Illustrator; JRE: Java Runtime Environment; KO: knockout; LRN: local response normalization; MCC: Mathew Correlation Coefficient; OS: operating system; PAS: phagophore assembly site; PC: principal component; PCA: principal component analysis; PPI: protein-protein interaction; Pr: precision; QPSO: Quantum-behaved Particle Swarm Optimization; ReLU: rectified linear unit; RF: random forest; ROC: receiver operating characteristic; ROI: region of interest; SD: systematic derivation; SGD: stochastic gradient descent; Sn: sensitivity; Sp: specificity; SRG: seeded region growing; t-SNE: t-distributed stochastic neighbor embedding; 2D: 2-dimensional; WT: wild-type.

In this paper, a composite technique of ultrasonic incremental forming and laser shock peeing is proposed. The former process is mainly used for the manufacturing of complex-shaped sheet and strengthening coating that is prepared for subsequent laser treatment. The latter is applied for secondary surface reinforcement with ultra-high energy. This work focused on the novel ultrasonic incremental forming method and its effects on surface mechanical properties and micro-structure of a 7075 aluminum alloy. First, a kind of 2-dimension ellipse ultrasonic vibration incremental forming process and the unique double-mechanism method of sectionalized cooperative control of plastic deformation and mechanical performance were designed. Second, the single-point incremental forming, the longitudinal ultrasonic vibration incremental forming, and the 2 dimension ellipse ultrasonic vibration incremental forming were performed for the manufacture of conical components of 7075 aluminum alloy. Third, the Vickers micro-hardness testing results and images of the fracture morphology of the machined part for the novel technique confirm that softening mechanisms become dominant inside the metal sheet. Furthermore, a strengthening coating with excellent mechanical properties and a residual compressive stress field were created on its surface simultaneously. In a word, the research shows potential values of the proposed technique for the manufacture of aircraft panels of complex shape and excellent surface properties.