The remission status of AML patients after allo-HCT is associated with a distinct single-cell bone marrow T-cell signature.

ABSTRACT: Acute myeloid leukemia (AML) is a hematologic malignancy for which allogeneic hematopoietic cell transplantation (allo-HCT) often remains the only curative therapeutic approach. However, incapability of T cells to recognize and eliminate residual leukemia stem cells might lead to an insufficient graft-versus-leukemia (GVL) effect and relapse. Here, we performed single-cell RNA-sequencing (scRNA-seq) on bone marrow (BM) T lymphocytes and CD34+ cells of 6 patients with AML 100 days after allo-HCT to identify T-cell signatures associated with either imminent relapse (REL) or durable complete remission (CR). We observed a higher frequency of cytotoxic CD8+ effector and gamma delta (γδ) T cells in CR vs REL samples. Pseudotime and gene regulatory network analyses revealed that CR CD8+ T cells were more advanced in maturation and had a stronger cytotoxicity signature, whereas REL samples were characterized by inflammatory tumor necrosis factor/NF-κB signaling and an immunosuppressive milieu. We identified ADGRG1/GPR56 as a surface marker enriched in CR CD8+ T cells and confirmed in a CD33-directed chimeric antigen receptor T cell/AML coculture model that GPR56 becomes upregulated on T cells upon antigen encounter and elimination of AML cells. We show that GPR56 continuously increases at the protein level on CD8+ T cells after allo-HCT and confirm faster interferon gamma (IFN-γ) secretion upon re-exposure to matched, but not unmatched, recipient AML cells in the GPR56+ vs GPR56- CD8+ T-cell fraction. Together, our data provide a single-cell reference map of BM-derived T cells after allo-HCT and propose GPR56 expression dynamics as a surrogate for antigen encounter after allo-HCT.

Novel Acute Retinal Artery Ischemia and Reperfusion Model in Nonhuman Primates.

BACKGROUND AND PURPOSE: The retina, as an externally located neural tissue, offers unique advantages in investigating the effect of therapeutic intervention on the brain. In this study, we put forth a clinically relevant model of retinal ischemia and reperfusion in nonhuman primates. METHODS: Acute retinal artery ischemia and reperfusion was induced by injecting an autologous clot into the ophthalmic artery of adult rhesus monkeys, and recanalization was achieved by focal thrombolysis with tPA (tissue-type plasminogen activator). Digital subtraction angiography and fluorescein angiography were used to evaluate blood flow in the retina and the choroid. Electroretinogram, optical coherence tomography, and hematoxylin and eosin staining were used to evaluate the structure and function of the retina after ischemia. RESULTS: Digital subtraction angiography and fluorescein angiography images confirmed occlusion of the ophthalmic and central retinal arteries, as well as recanalization after tPA thrombolysis. Electroretinogram indicated retinal functional damage following ischemia, and thrombolysis partially rescued its impairment. Optical coherence tomography and hematoxylin and eosin staining revealed ischemia-induced changes in the retina, and tPA partially mitigated these damages. CONCLUSIONS: This novel acute retinal artery ischemia and reperfusion model in rhesus monkeys may closely simulate retinal ischemia/reperfusion in clinical practice and provide an optimal platform for screening neuroprotective strategies.

Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2.

Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4.

[Retinal vessel diameter variation analysis in diabetic patients].

OBJECTIVE: To explore the influence factors of retinal vascular changes in diabetes patients. METHODS: Case control study. One hundred and fifty-five type 2 diabetes patients were divided into NDR group (n=80) and DR group (n=70) according to the presence of diabetic retinopathy. Fundus photographs were taken after pupil dilated, the diameter of retinal arterioles and venules were measured between 1.0 PD and 1.5 PD. To analyze the relationship between retinal artery diameter, vein diameter and hypertension, diabetes duration, and DR stage. With retinal artery and vein diameter as the dependent variable, DR stage, hypertension, diabetes duration, insulin using time and age as independent variables, using step method, multiple linear regression was undergoing. RESULTS: The diameter of retinal vein in DR group and NDR group were (90.37+7.95) and (83.45±7.80) µm, the difference was statistically significant (t=5.446, P=0.000). Retinal vein diameter was positively correlated with DR stage and diabetes duration (r=0.377, 0.250; P=0.000, 0.002). DR stage (b=2.382, P=0.000) had a linear relationship with retinal vein diameter (R(2)=0.142, F=25.285). The regression equation was: retinal vein diameter =84.269+ 2.382 · DR stage. Retinal artery diameter was negatively correlated with DR stage, diabetes duration, and hypertension duration (r=-0.453, -0.343, -0.199. P=0.000, 0.000, 0.013). DR stage (b=-2.091, P=0.000) and age (b=-0.182, P=0.000) has a linear relationship with retinal artery diameter (R(2)=0.290, F=31.088). The regression equation was: retinal artery diameter =64.011-2.091·DR stage -0.182·age. CONCLUSIONS: With DR developed, retinal vein diameter increases, retinal artery diameter decreases in diabetic patients. The duration of diabetes mellitus and hypertension were not related to the diameter of retinal artery and vein.

Mitigating Accuracy-Robustness Trade-Off Via Balanced Multi-Teacher Adversarial Distillation.

Adversarial Training is a practical approach for improving the robustness of deep neural networks against adversarial attacks. Although bringing reliable robustness, the performance towards clean examples is negatively affected after Adversarial Training, which means a trade-off exists between accuracy and robustness. Recently, some studies have tried to use knowledge distillation methods in Adversarial Training, achieving competitive performance in improving the robustness but the accuracy for clean samples is still limited. In this paper, to mitigate the accuracy-robustness trade-off, we introduce the Balanced Multi-Teacher Adversarial Robustness Distillation (B-MTARD) to guide the model's Adversarial Training process by applying a strong clean teacher and a strong robust teacher to handle the clean examples and adversarial examples, respectively. During the optimization process, to ensure that different teachers show similar knowledge scales, we design the Entropy-Based Balance algorithm to adjust the teacher's temperature and keep the teachers' information entropy consistent. Besides, to ensure that the student has a relatively consistent learning speed from multiple teachers, we propose the Normalization Loss Balance algorithm to adjust the learning weights of different types of knowledge. A series of experiments conducted on three public datasets demonstrate that B-MTARD outperforms the state-of-the-art methods against various adversarial attacks.

Agricultural land management and rural financial development: coupling and coordinated relationship and temporal-spatial disparities in China.

The integrated development of agricultural land and finance not only promotes rural financial innovation and breaks the bottleneck of agricultural financing but also facilitates agricultural land transfer and scaled operations. This leads to the advancement of the effective growth of contemporary agriculture. The reform of the 'separation of three rights' in agricultural land promotes land circulation, which, in turn, offers an institutional guarantee for the tandem development of rural finance and agricultural land management. This paper measures the comprehensive development index of agricultural land management and rural finance in 30 provinces of China from 2005 to 2020. In light of this, it calculates the degree of coupling and coordination between China's agricultural land management and rural financial development. The Dagum Gini coefficient, kernel density, and the Moran index were used to analyze regional differences and patterns of agglomeration. The study found that the degree of coupling coordination between China's agricultural land management and rural finance is increasing annually. However, there remains a significant gap in achieving high-quality coupling. Notably, the growth rate of rural financial development exceeds that of agricultural land management, and hypervariable density is a major source of regional variation. There is polarization in the coupled development of farmland management and rural finance. Provinces in the eastern and central regions tend to be located in the high-high agglomeration (H-H) in terms of the level of development of agricultural land and financial integration, while the western region tends to fall in low-low aggregation (L-L).

A cross-scale framework for evaluating flexibility values of battery and fuel cell electric vehicles.

Flexibility has become increasingly important considering the intermittency of variable renewable energy in low-carbon energy systems. Electrified transportation exhibits great potential to provide flexibility. This article analyzed and compared the flexibility values of battery electric vehicles and fuel cell electric vehicles for planning and operating interdependent electricity and hydrogen supply chains while considering battery degradation costs. A cross-scale framework involving both macro-level and micro-level models was proposed to compute the profits of flexible EV refueling/charging with battery degradation considered. Here we show that the flexibility reduction after considering battery degradation is quantified by at least 4.7% of the minimum system cost and enlarged under fast charging and low-temperature scenarios. Our findings imply that energy policies and relevant management technologies are crucial to shaping the comparative flexibility advantage of the two transportation electrification pathways. The proposed cross-scale methodology has broad implications for the assessment of emerging energy technologies with complex dynamics.

Resonant Tunnelling and Intersubband Optical Properties of ZnO/ZnMgO Semiconductor Heterostructures: Impact of Doping and Layer Structure Variation.

ZnO-based heterostructures are up-and-coming candidates for terahertz (THz) optoelectronic devices, largely owing to their innate material attributes. The significant ZnO LO-phonon energy plays a pivotal role in mitigating thermally induced LO-phonon scattering, potentially significantly elevating the temperature performance of quantum cascade lasers (QCLs). In this work, we calculate the electronic structure and absorption of ZnO/ZnMgO multiple semiconductor quantum wells (MQWs) and the current density-voltage characteristics of nonpolar m-plane ZnO/ZnMgO double-barrier resonant tunnelling diodes (RTDs). Both MQWs and RTDs are considered here as two building blocks of a QCL. We show how the doping, Mg percentage and layer thickness affect the absorption of MQWs at room temperature. We confirm that in the high doping concentrations regime, a full quantum treatment that includes the depolarisation shift effect must be considered, as it shifts mid-infrared absorption peak energy for several tens of meV. Furthermore, we also focus on the performance of RTDs for various parameter changes and conclude that, to maximise the peak-to-valley ratio (PVR), the optimal doping density of the analysed ZnO/Zn88Mg12O double-barrier RTD should be approximately 1018 cm-3, whilst the optimal barrier thickness should be 1.3 nm, with a Mg mole fraction of ~9%.

In vitro heterochronic parabiosis identifies pigment epithelium-derived factor as a systemic mediator of rejuvenation by young blood.

Several decades of heterochronic parabiosis (HCPB) studies have demonstrated the restorative impact of young blood, and deleterious influence of aged blood, on physiological function and homeostasis across tissues, although few of the factors responsible for these observations have been identified. Here we develop an in vitro HCPB system to identify these circulating factors, using replicative lifespan (RLS) of primary human fibroblasts as an endpoint of cellular health. We find that RLS is inversely correlated with serum donor age and sensitive to the presence or absence of specific serum components. Through in vitro HCPB, we identify the secreted protein pigment epithelium-derived factor (PEDF) as a circulating factor that extends RLS of primary human fibroblasts and declines with age in mammals. Systemic administration of PEDF to aged mice reverses age-related functional decline and pathology across several tissues, improving cognitive function and reducing hepatic fibrosis and renal lipid accumulation. Together, our data supports PEDF as a systemic mediator of the effect of young blood on organismal health and homeostasis and establishes our in vitro HCPB system as a valuable screening platform for the identification of candidate circulating factors involved in aging and rejuvenation.

Effect of low-intensity transcranial ultrasound stimulation on theta and gamma oscillations in the mouse hippocampal CA1.

Previous studies have demonstrated that low-intensity transcranial ultrasound stimulation (TUS) can eliminate hippocampal neural activity. However, until now, it has remained unclear how ultrasound modulates theta and gamma oscillations in the hippocampus under different behavioral states. In this study, we used ultrasound to stimulate the CA1 in mice in anesthesia, awake and running states, and we simultaneously recorded the local field potential of the stimulation location. We analyzed the power spectrum, phase-amplitude coupling (PAC) of theta and gamma oscillations, and their relationship with ultrasound intensity. The results showed that (i) TUS significantly enhanced the absolute power of theta and gamma oscillations under anesthesia and in the awake state. (ii) The PAC strength between theta and gamma oscillations is significantly enhanced under the anesthesia and awake states but is weakened under the running state with TUS. (iii) Under anesthesia, the relative power of theta decreases and that of gamma increases as ultrasound intensity increases, and the result under the awake state is opposite that under the anesthesia state. (iv) The PAC index between theta and gamma increases as ultrasound intensity increases under the anesthesia and awake states. The above results demonstrate that TUS can modulate theta and gamma oscillations in the CA1 and that the modulation effect depends on behavioral states. Our study provides guidance for the application of ultrasound in modulating hippocampal function.

The regulation of Insulin/IGF-1 signaling by miR-142-3p associated with human longevity.

MicroRNAs (miRNAs) have been demonstrated to modulate life span in the invertebrates C. elegans and Drosophila by targeting conserved pathways of aging, such as insulin/IGF-1 signaling (IIS). However, a role for miRNAs in modulating human longevity has not been fully explored. Here we investigated novel roles of miRNAs as a major epigenetic component of exceptional longevity in humans. By profiling the miRNAs in B-cells from Ashkenazi Jewish centenarians and 70-year-old controls without a longevity history, we found that the majority of differentially expressed miRNAs were upregulated in centenarians and predicted to modulate the IIS pathway. Notably, decreased IIS activity was found in B cells from centenarians who harbored these upregulated miRNAs. miR-142-3p, the top upregulated miRNA, was verified to dampen the IIS pathway by targeting multiple genes including GNB2, AKT1S1, RHEB and FURIN . Overexpression of miR-142-3p improved the stress resistance under genotoxicity and induced the impairment of cell cycle progression in IMR90 cells. Furthermore, mice injected with a miR-142-3p mimic showed reduced IIS signaling and improved longevity-associated phenotypes including enhanced stress resistance, improved diet/aging-induced glucose intolerance, and longevity-associated change of metabolic profile. These data suggest that miR-142-3p is involved in human longevity through regulating IIS-mediated pro-longevity effects. This study provides strong support for the use of miR-142-3p as a novel therapeutic to promote longevity or prevent aging/aging-related diseases in human.

A Data-Driven Optimized Mechanism for Improving Online Collaborative Learning: Taking Cognitive Load into Account.

Research on online collaborative learning has explored various methods of collaborative improvement. Recently, learning analytics have been increasingly adopted for ascertaining learners' states and promoting collaborative performance. However, little effort has been made to investigate the transformation of collaborative states or to consider cognitive load as an essential factor for collaborative intervention. By bridging collaborative cognitive load theory and system dynamics modeling methods, this paper revealed the transformation of online learners' collaborative states through data analysis, and then proposed an optimized mechanism to ameliorate online collaboration. A quasi-experiment was conducted with 91 college students to examine the potential of the optimized mechanism in collaborative state transformation, awareness of collaboration, learning achievement, and cognitive load. The promising results demonstrated that students learning with the optimized mechanism performed significantly differently in collaboration and knowledge acquisition, and no additional burden in cognitive load was noted.

Dual-Graph Attention Convolution Network for 3-D Point Cloud Classification.

Three-dimensional point cloud classification is fundamental but still challenging in 3-D vision. Existing graph-based deep learning methods fail to learn both low-level extrinsic and high-level intrinsic features together. These two levels of features are critical to improving classification accuracy. To this end, we propose a dual-graph attention convolution network (DGACN). The idea of DGACN is to use two types of graph attention convolution operations with a feedback graph feature fusion mechanism. Specifically, we exploit graph geometric attention convolution to capture low-level extrinsic features in 3-D space. Furthermore, we apply graph embedding attention convolution to learn multiscale low-level extrinsic and high-level intrinsic fused graph features together. Moreover, the points belonging to different parts in real-world 3-D point cloud objects are distinguished, which results in more robust performance for 3-D point cloud classification tasks than other competitive methods, in practice. Our extensive experimental results show that the proposed network achieves state-of-the-art performance on both the synthetic ModelNet40 and real-world ScanObjectNN datasets.

Using CT-guided stereotactic prostate radiation therapy (CT-SPRT) to assess sustained murine prostate ablation.

The prostate is a hormone-responsive organ where testicular androgens drive the proliferation and survival of prostatic cells, ensuring the development and functioning of this gland throughout life. Androgen deprivation therapy leads to apoptosis of prostatic cells and organ regression, and is a cornerstone of prostate cancer and benign prostatic hypertrophy treatment. For several decades, androgen deprivation has been used as an adjuvant to external beam radiotherapy, however, emerging data suggests that the low rates of epithelial proliferation in the castrated prostate imparts radio-resistance. As proliferating cells exhibit increased sensitivity to radiation, we hypothesized that short bursts of synchronized epithelial proliferation, which can be achieved by exogeneous testosterone supplementation prior to targeted high-dose radiation, would maximize sustained prostate ablation, while minimizing damage to surrounding tissues. To test this hypothesis, we designed a novel computed-tomography (CT)-guided stereotactic prostate radiation therapy (CT-SPRT) technique to deliver a single high-dose 25 Gy fraction of X-ray radiation. Sustained prostatic cell ablation was assessed post CT-SPRT by measuring prostate weight, epithelial cell number, and relative contributions of luminal and basal epithelial populations in control and testosterone-pretreated glands. CT-SPRT was safely delivered with no observed damage to surrounding rectal and bladder tissues. Importantly, castrated mice that received a pulse of testosterone to induce synchronous cell proliferation prior to CT-SPRT exhibited significant sustained gland ablation compared to control mice. These results provide new insights in stereotactic radiotherapy sensitivity to maximize prostatic cell ablation and improve our understanding of prostate gland regeneration that can potentially lead to improved non-invasive therapies for benign prostatic hypertrophy and prostate cancer.

Author Correction: Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche.

In the version of this article originally published, the key for Fig. 4c was incorrect. The symbols for 'Sham' and 'Den' were reversed. The error has been corrected in the PDF and HTML versions of the manuscript.

Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche.

Aging of hematopoietic stem cells (HSCs) is associated with a decline in their regenerative capacity and multilineage differentiation potential, contributing to the development of blood disorders. The bone marrow microenvironment has recently been suggested to influence HSC aging, but the underlying mechanisms remain largely unknown. Here we show that HSC aging critically depends on bone marrow innervation by the sympathetic nervous system (SNS), as loss of SNS nerves or adrenoreceptor ß3 signaling in the bone marrow microenvironment of young mice led to premature HSC aging, as evidenced by appearance of HSC phenotypes reminiscent of physiological aging. Strikingly, supplementation of a sympathomimetic acting selectively on adrenoreceptor ß3 to old mice significantly rejuvenated the in vivo function of aged HSCs, suggesting that the preservation or restitution of bone marrow SNS innervation during aging may hold the potential for new HSC rejuvenation strategies.

Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia.

IMPORTANCE: Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established. OBJECTIVE: To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia. DESIGN, SETTING, AND PARTICIPANTS: We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia. MAIN OUTCOMES AND MEASURES: Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation. RESULTS: We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias. CONCLUSIONS AND RELEVANCE: This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia.

[Short-term outcomes of radical resection of rectal carcinoma: hand-assisted laparoscopy versus traditional laparoscopic approach].

OBJECTIVE: To study the feasibility of hand-assisted laparoscopic radical resection of rectal carcinoma and compare the short-term outcomes of HALS versus traditional laparoscopy approach. METHODS: Clinical data of 42 cases of rectal carcinoma between January 2010 and March 2011 were enrolled in this study. Nineteen cases underwent HALS total mesorectal excision and 23 cases underwent traditional laparoscopy approach. RESULTS: All the operations were successfully accomplished without conversions to open surgery. The mean operation time of the HALS group was shorter than that of the traditional laparoscopic group (152 min vs. 168 min, P=0.009). Incision length was significantly longer in the HALS group (5.6 cm vs. 4.5 cm, P=0.000). The median overall costs were lower in HALS group (26 000 RMB vs. 29 000 RMB, P=0.008). The number of lymph nodes in resected specimen, intra-operative blood loss, length of hospital stay, time to passage of flatus were comparable between the two groups. CONCLUSIONS: Hand-assisted laparoscopic surgery has the advantages of laparoscopic surgery including minimal invasiveness, safety, and quicker postoperative recovery.