Genetic polymorphisms in plasminogen activator inhibitor-1 predict susceptibility to steroid-induced osteonecrosis of the femoral head in Chinese population

BACKGROUND: Steroid usage has been considered as a leading cause of non-traumatic osteonecrosis of the femoral head (ONFH), which is involved in hypo-fibrinolysis and blood supply interruption. Genetic polymorphisms in plasminogen activator inhibitor-1 (PAI-1) have been demonstrated to be associated with ONFH risk in several populations. However, this relationship has not been established in Chinese population. The aim of this study was to investigate the association of PAI-1 gene polymorphisms with steroid-induced ONFH in a large cohort of Chinese population. METHODS: A case–control study was conducted, which included 94 and 106 unrelated patients after steroid administration recruited from 14 provinces in China, respectively. Two SNPs (rs11178 and rs2227631) within PAI-1 were genotyped using Sequenom MassARRAY system. RESULTS: rs2227631 SNP was significantly associated with steroid-induced ONFH group in codominant (P = 0.04) and recessive (P = 0.02) models. However, there were no differences found in genotype frequencies of rs11178 SNP between controls and patients with steroid-induced ONFH (all P > 0.05). CONCLUSIONS: Our data offer the convincing evidence for the first time that rs2227631 SNP of PAI-1 may be associated with the risk of steroid-induced ONFH, suggesting that the genetic variations of this gene may play an important role in the disease development. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1569909986109783

Enhancing Cross-task Black-Box Transferability of Adversarial Examples with Dispersion Reduction

Neural networks are known to be vulnerable to carefully crafted adversarial examples, and these malicious samples often transfer, i.e., they remain adversarial even against other models. Although great efforts have been delved into the transferability across models, surprisingly, less attention has been paid to the cross-task transferability, which represents the real-world cybercriminal's situation, where an ensemble of different defense/detection mechanisms need to be evaded all at once. In this paper, we investigate the transferability of adversarial examples across a wide range of real-world computer vision tasks, including image classification, object detection, semantic segmentation, explicit content detection, and text detection. Our proposed attack minimizes the ``dispersion'' of the internal feature map, which overcomes existing attacks' limitation of requiring task-specific loss functions and/or probing a target model. We conduct evaluation on open source detection and segmentation models as well as four different computer vision tasks provided by Google Cloud Vision (GCV) APIs, to show how our approach outperforms existing attacks by degrading performance of multiple CV tasks by a large margin with only modest perturbations linf=16.Comment: arXiv admin note: substantial text overlap with arXiv:1905.0333

Increased Formation of Follicular Antrum in Aquaporin-8-Deficient Mice Is Due to Defective Proliferation and Migration, and Not Steroidogenesis of Granulosa Cells

Aquaporin-8 (AQP8) is a water channel protein expressed exclusively in granulosa cells (GCs) in mouse ovary. Our previous studies of AQP8-deficient (AQP8-/-) mice demonstrated that AQP8 participates in folliculogenesis, including in the formation of follicles, ovulation, and atresia. However, its physiological function in formation of the antral follicle is still largely unknown. In the present study, we observed significantly increased numbers of antral follicles in AQP8-/- ovaries as well as significantly increased follicular antrum formation in in vitro 3D culture of AQP8-/- follicles. Functional detection of AQP8-/- GCs indicated that cell proliferation is impaired with FSH treatment, and wound healing and Transwell migration are also impaired with or without FSH treatment, compared with that in WT. However, the biosynthesis of estradiol and progesterone as well as the mRNA levels of key steroidogenic enzyme genes (CYP19A1 and StAR) in AQP8-/- GCs did not change, even with addition of FSH and/or testosterone. In order to estimate the influence of the impaired proliferation and migration on the density of GC mass, preantral follicles were injected with FITC-dextran, which distributes only in the intercellular space, and analyzed by confocal microscopy. The micrographs showed significantly higher transmission of fluorescence in AQP8-/- follicles, suggesting increased intercellular space of GCs. Based on this evidence, we concluded that AQP8 deficiency leads to increased formation of follicular antra in vivo and in vitro, and the mechanism may be associated with increased intercellular space of GCs, which may be caused by defective proliferation and migration of GCs. This study may offer new insight into the molecular mechanisms of the formation of follicular antrum

Ecological engineering projects increased vegetation cover, production, and biomass in semiarid and subhumid Northern China

Multiple ecological engineering projects have been implemented in semiarid and subhumid Northern China since 1978 with the purpose to combat desertification, control dust storms, and improve vegetation cover. Although a plethora of local studies exist, the effectiveness of these projects has not been studied in a systematic and comprehensive way. Here, we used multiple satellite-based time-series data as well as breakpoint analysis to assess shifts in leaf area index (a proxy for green vegetation cover), gross primary production, and aboveground biomass in Northern China. We documented increased vegetation growth in northwest and southeastern parts of the region, despite drought anomalies as documented by the standardized precipitation-evapotranspiration index during 1982–2016. Significant breakpoints in leaf area index were observed for over 72.5% of the southeastern and northwestern regions, and 70.6% of these breakpoints were detected after 1999, which correspond well to the areas with the highest ecological engineering efforts. Areas with negative trends were mainly located in the Inner Mongolian Plateau, Hulun Biur, Horqin Sand Land, and urban areas. The Loess Plateau had the largest increase in vegetation growth, followed by the north parts of Northern China where biomass increased more in the provinces of Shanxi, Liaoning, Shannxi, Hebei, and Beijing than Xinjiang, Inner Mongolia, Tianjin, and Qinghai. Our results show that multiple ecological engineering projects in the region have increased vegetation cover, production, and aboveground biomass that have led to improved environmental conditions in the study area

Acetylome analyses provide novel insights into the effects of chronic intermittent hypoxia on hippocampus-dependent cognitive impairment

IntroductionChronic intermittent hypoxia (CIH) can negatively affect hippocampal function through various molecular mechanisms. Protein acetylation, a frequently occurring modification, plays crucial roles in synaptic plasticity and cognitive processes. However, the global protein acetylation induced by CIH in the hippocampus and its specific effects on hippocampal function and behavior remain poorly understood.MethodsTo address this gap, we conducted a study using liquid chromatography-tandem mass spectrometry to analyze the lysine acetylome and proteome of the hippocampus in healthy adult mice exposed to intermittent hypoxia for 4 weeks (as a CIH model) compared to normoxic mice (as a control).ResultsWe identified and quantified a total of 2,184 lysine acetylation sites in 1,007 proteins. Analysis of these acetylated proteins revealed disturbances primarily in oxidative phosphorylation, the tricarboxylic acid (TCA) cycle, and glycolysis, all of which are localized exclusively to mitochondria. Additionally, we observed significant changes in the abundance of 21 proteins, some of which are known to be associated with cognitive impairments.DiscussionThis study helps to elucidate the molecular mechanisms underlying CIH-induced changes in protein acetylation in the hippocampus. By providing valuable insights into the pathophysiological processes associated with CIH and their impacts on hippocampal function, our findings contribute to a better understanding of the consequences of CIH-induced changes in protein acetylation in the hippocampus and the potential role of CIH in cognitive impairment

Clinical efficacy of Osteoking in knee osteoarthritis therapy: a prospective, multicenter, non-randomized controlled study in China

BackgroundOsteoking has been extensively used for the treatment of knee osteoarthritis (KOA). However, it is lack of high-quality evidence on the clinical efficacy of Osteoking against KOA and the comparison with that of nonsteroidal anti-inflammatory drugs (NSAIDs).AimsTo evaluate the efficacy and safety of Osteoking in treating KOA.MethodsIn the current study, a total of 501 subjects were recruited from 20 medical centers, and were divided into the Osteoking treatment group (n = 428) and the NSAIDs treatment group (n = 73). The Propensity Score Matching method was used to balance baseline data of different groups. Then, the therapeutic effects of Osteoking and NSAIDs against KOA were evaluated using VAS score, WOMAC score, EQ-5D-3L and EQ-VAS, while the safety of the two treatment were both assessed based on dry mouth, dizziness, diarrhea, etc.ResultsAfter 8 weeks of treatment, the Osteoking group was compared with the NSAIDs group, the VAS score [2.00 (1.00, 3.00) vs. 3.00 (2.00, 4.00)], WOMAC pain score [10.00 (8.00, 13.00) vs. 11.00 (8.00, 16.00) ], WOMAC physical function score [32.00 (23.00, 39.00) vs. 39.07 ± 16.45], WOMAC total score [44.00 (31.00, 55.00) vs. 53.31 ± 22.47) ], EQ-5D-3L score [0.91 (0.73, 0.91) vs. 0.73 (0.63, 0.83) ] and EQ-VAS score [80.00 (79.00, 90.00) vs. 80.00 (70.00, 84.00) ] were improved by the treatment of Osteoking for 8 weeks more effectively than that by the treatment of NSAIDs. After 8 weeks of treatment with Osteoking, the VAS scores of KOA patients with the treatment of Osteoking for 8 weeks were reduced from 6.00 (5.00, 7.00) to 2.00 (1.00, 3.00) (p < 0.05), which was better than those with the treatment of NSAIDs starting from 2 weeks during this clinical observation. Importantly, further subgroup analysis revealed that the treatment of Osteoking was more suitable for alleviating various clinical symptoms of KOA patients over 65 years old, with female, KL II-III grade and VAS 4-7 scores, while the clinical efficacy of NSAIDs was better in KOA patients under 65 years old and with VAS 8–10 scores. Of note, there were no differences in adverse events and adverse reactions between the treatment groups of the two drugs.ConclusionOsteoking may exert a satisfying efficacy in relieving joint pain and improving life quality of KOA patients without any adverse reactions, especially for patients with KL II-III grades and VAS 4–7 scores.Clinical Trial Registration:https://www.chictr.org.cn/showproj.html?proj=55387, Identifier ChiCTR200003447

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation