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This paper investigates a two-dimensional Riemann–Liouville distributed-order space fractional diffusion equation (RLDO-SFDE). However, many challenges exist in deriving analytical solutions for fractional dynamic systems. Efficient and reliable methods need to be explored for solving the RLDO-SFDE numerically. We develop an alternating direction implicit scheme and prove that the numerical method is unconditionally stable and convergent with an accuracy of O(σ2+ρ2+τ+hx+hy). After employing an extrapolated technique, the convergence order is improved to second order in time and space. Furthermore, a fast algorithm is constructed to reduce computational costs. Two numerical examples are presented to verify the effectiveness of the numerical methods. This study may provide more possibilities for simulating diffusion complexities by fractional calculus.

Continuous ergonomic risk assessment of the human body is critical to avoid various musculoskeletal disorders (MSDs) for people involved in physical jobs. This paper presents a digital upper limb assessment (DULA) system that automatically performs rapid upper limb assessment (RULA) in real-time for the timely intervention and prevention of MSDs. While existing approaches require human resources for computing the RULA score, which is highly subjective and untimely, the proposed DULA achieves automatic and objective assessment of musculoskeletal risks using a wireless sensor band embedded with multi-modal sensors. The system continuously tracks and records upper limb movements and muscle activation levels and automatically generates musculoskeletal risk levels. Moreover, it stores the data in a cloud database for in-depth analysis by a healthcare expert. Limb movements and muscle fatigue levels can also be visually seen using any tablet/computer in real-time. In the paper, algorithms of robust limb motion detection are developed, and an explanation of the system is provided along with the presentation of preliminary results, which validate the effectiveness of the new technology.

Background Patients with severe bone fractures and complex bone deformities are treated by orthopedic surgeons with external fixation for several months. During this long treatment period, there is a high risk of inflammation and infection at the superficial skin area (pin site). This can develop into a devastating, sometimes fatal, and always costly condition of deep bone infection. Objective For pin site infection surveillance, thermography technology could be the solution to build an objective and continuous home-based remote monitoring tool to avoid frequent nursing care and hospital visits. However, future studies of infection monitoring require a preliminary step to automate the process of locating and detecting the pin sites in thermal images reliably for temperature measurement, and this step is the aim of this study. Methods This study presents an automatic approach for identifying and annotating pin sites on visible images using bounding boxes and transferring them to the corresponding thermal images for temperature measurement. The pin site is detected by applying deep learning-based object detection architecture YOLOv5 with a novel loss evaluation and regression method, control distance intersection over union. Furthermore, we address detecting pin sites in a practical environment (home setting) accurately through transfer learning. Results and conclusion The proposed model offers the pin site detection in 1.8 ms with a high precision of 0.98 and enables temperature information extraction. Our work for automatic pin site annotation on thermography paves the way for future research on infection assessment on thermography.

Abstract DDRGK domain-containing protein 1 (DDRGK1) is an important component of the newly discovered ufmylation system and its absence has been reported to induce extensive endoplasmic reticulum (ER) stress. Recently, emerging evidence indicates that the ufmylation system is correlated with autophagy, although the exact mechanism remains largely unknown. To explore the regulation mechanism of DDRGK1 on autophagy, in this study, we established an immortalized mouse embryonic fibroblast (MEF) cell lines harvested from the DDRGK1F/F:ROSA26-CreERT2 mice, in which DDRGK1 depletion can be induced by 4-hydroxytamoxifen (4-OHT) treatment. Here, we show that DDRGK1 deficiency in MEFs has a dual effect on autophagy, which leads to a significant accumulation of autophagosomes. On one hand, it promotes autophagy induction by impairing mTOR signaling; on the other hand, it blocks autophagy degradation by inhibiting autophagosome–lysosome fusion. This dual effect of DDRGK1 depletion on autophagy ultimately aggravates apoptosis in MEFs. Further studies reveal that DDRGK1 loss is correlated with suppressed lysosomal function, including impaired Cathepsin D (CTSD) expression, aberrant lysosomal pH, and v-ATPase accumulation, which might be a potential trigger for impairment in autophagy process. Hence, this study confirms a crucial role of DDRGK1 as an autophagy regulator by controlling lysosomal function. It may provide a theoretical basis for the treatment strategies of various physiological diseases caused by DDRGK1 deficiency.

Abstract Background Triple negative breast cancer (TNBC) is one of the most biologically aggressive breast cancers and lacks effective treatment options, resulting in a poor prognosis. Therefore, studies aiming to explore new therapeutic strategies for advanced TNBC are urgently needed. According to recent studies, microRNA-124 (miR124) not only inhibits tumour growth but also increases the sensitivity of TNBC to paclitaxel (PTX), suggesting that a platform combining PTX and miR124 may be an advanced solution for TNBC. Results Herein, we constructed a stepped cleavable calcium phosphate composite lipid nanosystem (CaP/LNS) to codeliver PTX and miR124 (PTX/miR124-NP). PTX/miR124-NP exhibited superior tumor microenvironment responsive ability, in which the surface PEG layer was shed in the mildly acidic environment of tumor tissues and exposed oligomeric hyaluronic acid (o-HA) facilitated the cellular uptake of CaP/LNS by targeting the CD44 receptor on the surface of tumor cells. Inside tumour cells, o-HA detached from CaP/LNS due to the reduction of disulfide bonds by glutathione (GSH) and inhibited tumour metastasis. Then, PTX and miR124 were sequentially released from CaP/LNS and exerted synergistic antitumour effects by reversing the Epithelial-Mesenchymal Transition (EMT) process in MDA-MB-231 cells. Moreover, PTX/miR124-NP showed significant antitumour efficiency and excellent safety in mice bearing MDA-MB-231 tumours. Conclusion Based on these results, the codelivery of PTX and miR124 by the CaP/LNS nanosystem might be a promising therapeutic strategy for TNBC.

This paper proposes a robust digital signal recovery (DSR) technique to tackle the high signal-to-noise ratio (SNR) variation and transmitter memory effects for broadband power efficient down-link in next-generation low Earth orbit (LEO) satellite constellations. The robustness against low SNR is achieved by concurrently integrating magnitude normalization and noise feature filtering using a filtering block built with one batch normalization (BN) layer and two bidirectional long short-term memory (BiLSTM) layers. Moreover, unlike existing deep neural network-based DSR techniques (DNN-DSR), which failed to effectively take into account the memory effects of radio-frequency power amplifiers (RF-PAs) in the model design, the proposed BiLSTM-DSR technique can extracts the sequential characteristics of the adjacent in-phase (I) and quadrature (Q) samples, and hence can obtain superior memory effects compensation compared with the DNN-DSR technique. Experimental validation results of the proposed BiLSTM-DSR with a 100 MHz bandwidth OFDM signal demonstrate an excellent performance of 11.83 dB and 9.4% improvement for adjacent channel power ratio (ACPR) and error vector magnitude (EVM), respectively. BiLSTM-DSR also outperforms the existing DNN-DSR technique in terms of the ACPR and EVM by 2.4 dB and 0.9%, which provides a promising solution for developing deep learning-assisted receivers for high-throughput LEO satellite networks.

Calcific aortic valve disease (CAVD) is a common heart valve disease in aging populations, and aberrant osteogenic differentiation of valvular interstitial cells (VICs) plays a critical role in the pathogenesis of ectopic ossification of the aortic valve. miR-214 has been validated to be involved in the osteogenesis process. Here, we aim to investigate the role and mechanism of miR-214 in CAVD progression. miR-214 expression was significantly downregulated in CAVD aortic valve leaflets, accompanied by upregulation of osteogenic markers. Overexpression of miR-214 suppressed osteogenic differentiation of VICs, while silencing the expression of miR-214 promoted this function. miR-214 directly targeted ATF4 and Sp7 to modulate osteoblastic differentiation of VICs, which was proved by dual luciferase reporter assay and rescue experiment. miR-214 knockout rats exhibited higher mean transvalvular velocity and gradient. The expression of osteogenic markers in aortic valve leaflets of miR-214 knockout rats was upregulated compared to that of the wild-type group. Taken together, our study showed that miR-214 inhibited aortic valve calcification via regulating osteogenic differentiation of VICs by directly targeting ATF4 and Sp7, indicating that miR-214 may act as a profound candidate of targeting therapy for CAVD.

Abstract Background Cobalamin C deficiency (cblC) caused by the MMACHC mutations is the most common type of the disorders of intracellular cobalamin metabolism. While the c.609G > A mutation is most frequent in Chinese cblC patients, its correlation with phenotype has not been delineated. Here we aim to investigate the factors affecting variable phenotypes and outcomes associated with the MMACHC c.609G > A homologous mutation in 149 Chinese cases to have implications for treatment and prevention. Methods We assessed 149 cblC patients caused by MMACHC c.609G > A homozygous mutation. The clinical manifestations, complications, treatment, and outcomes were evaluated; 120 patients were followed-up till December 2019. Results Two patients (1.3%) were prenatally diagnosed, treated after birth and consequently showed normal development. In 15 patients (10.1%) detected by newborn screening, 10 were treated at the age of 2 weeks and showed normal development, while the other 5 were treated after onset and showed neurologic disorders. All 132 clinically diagnosed patients (88.6%) developed symptoms at age from few minutes after birth to 72 months. Among them, 101 (76.5%) had early-onset (before the age of 12 months) and 31 (23.5%) had late-onset (after the age of 12 months). Totally 5 patients died and 24 were lost to follow-up. Of the 132 clinical diagnosed patients, 92 (69.7%) presented with developmental delay, 65 (49.2%) had seizures, 37 (28.0%) had anemia, 24 (18.2%) had feeding difficulty, 23 (17.4%) had ocular problems, and 22 (16.7%) had hydrocephalus. Compared with the non-developmental delay group, the onset age, the age at treatment initiation and the time from onset to treatment initiation were later in the developmental delay group. Seizure group showed significantly higher urinary methylmalonic acid concentration. During long-term follow-up, plasma total homocysteine (tHcy) levels were significantly higher in patients in the uncontrolled group than those in the seizure-free group. Conclusions Most cblC patients caused by MMACHC c.609G > A homozygous mutation showed early-onset. The clinically diagnosed patients usually showed the presence of irreversible brain disorders. Patients treated from the pre-symptomatic stage showed favorable outcomes. Therefore, newborn screening, prenatal diagnosis and early treatment are crucial and the c.609G > A mutant allele should be listed in the pre-pregnancy carrier screening panel in China.

Abstract Background Since the inception of newborn screening programs in China in the 1990s, pregnancy among patients with inherited, metabolic disorders has become more common. This study explores the management and outcomes of planned, full-term pregnancies in patients with phenylketonuria (PKU). Method Married patients with PKU from 2012 to 2017 were enrolled to receive prenatal counseling and regular health assessments. Study-related assessments included the timing of Phe-restricted diets, maternal weight gain, gestational age, pregnancy complications, and blood Phe concentrations (both pre-conception and during pregnancy), obstetrical data, and offspring outcomes(e.g. anthropomorphic measurements and developmental quotients [DQs]). Results A total of six offspring were successfully delivered. The mean ± SD (range) age of the mother at delivery was 26.3 ± 4.7 (range: 21.1–32.5) years. The mean duration of Phe control before pregnancy was 5.5 ± 1.3(range: 3.1–6.5) months. During pregnancy, the proportion of blood Phe concentrations within the clinically-recommended target range (120–360 μmol/L) ranged from 63.2–83.5%. Low birth weight (

The new generation of 5G mobile communication systems is using millimeter wave (mmWave) active phased arrays (APA) which have up to hundreds of individual analog transmitter and receiver chains and antennas. For these highly integrated systems linearization of each analog path is very challenging. Therefore a single input single output (SISO) system in combination with over the air (OTA) measurement is considered as an efficient approach for linearization. However, the knowledge about the dependency of the total SISO nonlinearity on the contributions from different blocks in the antenna array, as well as the linearization trade-offs is still missing. In this paper, an overview of the possible linearization trade-offs in an OTA setup with a mmWave APA is provided. The linearization technique is applied to a $4\times 4$ active phased array containing up-conversion of a sub 6 GHz LTE10 signal to an RF frequency of 28 GHz. Through measurements, the effects on adjacent channel power ratio (ACPR) and error vector magnitude (EVM) have been investigated for the following scenarios: i. impact from the up-converter, ii. impact of the steering angle due to antenna crosstalk and iii. a linearity comparison between a linearized and a backed-off system.

This paper proposes a novel deep neural network (DNN)-based receiver for next-generation low Earth orbit (LEO) satellite communications. The DNN receiver can concurrently compensate for multiple imperfections of the satellite communication system to improve the quality of satellite-to-ground transmission. A special focus has been placed on handling the nonlinear distortion in the transmitted signal caused by space-borne high-efficiency radio frequency power amplifiers (RF-PAs), which is crucial in high-throughput satellite communications, but has been overlooked by existing relevant research. In this receiver, a DNN is designed and trained to learn the channel effects, nonlinearities of the RF-PAs, and digital modulation schemes in the received signal for demodulation and nonlinearity/channel effect compensation at the same time. The proposed receiver has been evaluated using five popular filtered orthogonal frequency division modulations with the nonlinear distortions experimentally extracted from a real gallium nitride (GaN) RF-PA and the additive white Gaussian noise channel generated by simulations. The validation results demonstrate that the DNN receiver can accommodate different modulation schemes and two typical groups of RF-PA classes with a satisfactory bit error rate performance. It has the potential to boost the performance of existing on-orbit LEO satellite communication systems with minimal system modifications and serves as a promising solution for future satellite communication services.

Objectives: The main markers of cerebral small vessel disease (cSVD) on MRI may be entered into a scoring system, with the total score representing the overall burden of cSVD. An association between total cSVD score and cognitive dysfunction has been reported in several cohorts. The present study aimed to investigate this association in outpatients with amnestic disorders.Materials and Methods: Outpatients with amnestic complaints in a memory clinic (n = 289) were recruited retrospectively. All the patients had undergone clinical and cognitive evaluation at first presentation. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) scale. The total cSVD score was based on the following markers on MRI: lacune; white matter hyperintensities, microbleed, and enlarged perivascular spaces. The association between total cSVD score and MoCA score was tested via Spearman's analysis and a linear regression model.Results: Among the 289 patients, rates for 0–4 cSVD markers respectively ranged from 30.4 to 2.8%. A multiple linear regression model revealed an inverse correlation between the total cSVD score and MoCA score. The association remained significant after adjusting for gender, age, education, levels of medial temporal lobe atrophy, and classical vascular risk factors [β = −0.729, 95% CI (−1.244, −0.213); P = 0.006]. When individual markers were individually analyzed after adjusting for the same factors, only microbleed associated with MoCA score [β = −3.007, 95% CI (−4.533, −1.480), P < 0.001].Conclusions: A significant association was demonstrated between total cSVD score and cognitive performance in the outpatients with amnestic disorders.

Objective: To investigate the factors associated with recurrence/progression after endoscopic endonasal resection of suprasellar craniopharyngiomas. Special attention was paid to assess the impact of pituitary stalk preservation on tumor recurrence/progression and endocrinological outcomes.Methods: We retrospectively recruited 73 patients with suprasellar craniopharyngiomas undergone endoscopic endonasal approach (EEA) surgery from September 2014 to May 2019 and assessed their clinical characteristics, surgical outcomes, and recurrence/progression. Stalk preservation or sacrifice was determined by reviewing operative records, videos, and post-operative magnetic resonance imaging.Results: Gross total resection (GTR) was achieved in 51 cases (69.9%). Tumor recurrence was seen in 5 cases (9.8%) and progression was seen in 8 cases (36.4%), respectively. GTR (OR = 0.248 CI 0.081–0.759; p = 0.015) was the only independent factor influencing recurrence/progression. Kaplan-Meier survival analysis showed that the mean recurrence/progression-free survival were 53 (95% CI 48–59) and 39 (95% CI 28–50) months, respectively, in patients with and without GTR (p = 0.011). Pituitary stalk preservation was more common in cases with peripheral type tumors (83% vs. 30%, p < 0.01). Preserving the pituitary stalk does not appear to decrease the percentage of GTR (75.5% vs. 55.0%, p = 0.089), or increase the rate of tumor recurrence (12.5% vs. 0%, p = 0.508) or progression (46.2% vs. 22.2%, p = 0.486). However, surgically induced hypothyroidism (60.5% vs. 100%, p = 0.041) and diabetes insipidus (35.1% vs. 81.8%, p = 0.017) were significantly lower in patients with stalk preservation. For patients who had hypopituitarism before EEA, there was no difference between those with and without stalk preservation regarding post-operative hypopituitarism (p > 0.05).Conclusion: GTR is the only independent predictor of recurrence/progression after EEA surgery for suprasellar craniopharyngiomas. Preserving the pituitary stalk does not appear to increase the risk of non-GTR and tumor recurrence/progression and might help reduce the risk of surgically induced hypothyroidism and diabetes insipidus. We recommend preserving the pituitary stalk in peripheral type suprasellar craniopharyngiomas with normal pituitary function, especially in cases without hypothyroidism or diabetes insipidus. On the other hand, stalk sacrifice could be considered in central type tumors with severe pre-operative endocrinopathy.

Objectives: The aim of this study was to determine the molecular etiology and clinical manifestations of a pair of Chinese twins affected with epidermolysis bullosa simplex. Pediatricians should pay attention to the early genetic diagnosis of this disease.Methods: Histopathological examination of HE-stained skin, electron microscopy of biopsied normal skin, and whole-exome sequencing was performed to assess pathogenicity and conservation of detected mutations. Two years later, the cutaneous and extracutaneous manifestations of the twins were comprehensively evaluated.Results:A de novo pathogenic variant c.2T>C (p.M1T) in KLHL24 (NM_017,644) was identified in both twins. The characteristics of extensive skin defects on the extremities at birth and the tendency to lesson with increasing age were confirmed. No positive sensitive markers, such as B-type natriuretic peptide, cardiac troponin I, for cardiac dysfunction were detected.Conclusions: The de novo pathogenic variants c.2T>C (p.M1T) in KLHL24 (NM_017,644) contributes to the development of epidermolysis bullosa. Genetic diagnosis at birth or early infancy can better predict the disease prognosis and guide the treatment.

Background: Cerebral small vessel disease (cSVD) and neurodegeneration are the two main causes of dementia and are considered distinct pathological processes, while studies have shown overlaps and interactions between the two pathological pathways. Medial temporal atrophy (MTA) is considered a classic marker of neurodegeneration. We aimed to investigate the relationship of total cSVD burden and MTA on MRI using a total cSVD score and to explore the impact of the two MRI features on cognition.Methods: Patients in a memory clinic were enrolled, who underwent brain MRI scan and cognitive evaluation within 7 days after the first visit. MTA and total cSVD score were rated using validated visual scales. Cognitive function was assessed by using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scales. Spearman's correlation and regression models were used to test (i) the association between MTA and total cSVD score as well as each cSVD marker and (ii) the correlation of the MRI features and cognitive status.Results: A total of 312 patients were finally enrolled, with a median age of 75.0 (66.0–80.0) years and 40.7% (127/312) males. All of them finished MRI and MMSE, and 293 subjects finished MoCA. Of note, 71.8% (224/312) of the patients had at least one of the cSVD markers, and 48.7% (152/312) of them had moderate–severe MTA. The total cSVD score was independently associated with MTA levels, after adjusting for age, gender, years of education, and other vascular risk factors (OR 1.191, 95% CI 1.071–1.324, P = 0.001). In regard to individual markers, a significant association existed only between white matter hyperintensities and MTA after adjusting for the factors mentioned above (OR 1.338, 95% CI 1.050–1.704, P = 0.018). Both MTA and total cSVD score were independent risk factors for MMSE ≤ 26 (MTA: OR 1.877, 95% CI 1.407–2.503, P < 0.001; total cSVD score: OR 1.474, 95% CI 1.132–1.921, P = 0.004), and MoCA < 26 (MTA: OR 1.629, 95% CI 1.112–2.388, P = 0.012; total cSVD score: OR 1.520, 95% CI 1.068–2.162, P = 0.020). Among all the cSVD markers, microbleed was found significantly associated with MMSE ≤ 26, while no marker was demonstrated a relationship with MoCA < 26.Conclusion: Cerebral small vessel disease was related to MTA in patients of a memory clinic, and both the MRI features had a significant association with cognitive impairment.

Under stress conditions, luteinizing hormone (LH)-mediated ovulation is inhibited, resulting in insufficient oocyte production and excretion during follicular development. When the body is stressed, a large amount of corticosterone (CORT) is generated, which will lead to a disorder of the body’s endocrine system and damage to the body. Our previous work showed that CORT can block follicular development in mice. Since LH acts through binding with the luteinizing hormone receptor (Lhcgr), the present study aimed to investigate whether and how corticosterone (CORT) influences Lhcgr expression in mouse ovarian granulosa cells (GCs). For this purpose, three-week-old ICR female mice were injected intraperitoneally with pregnant mare serum gonadotropin (PMSG). In addition, the treatment group was injected with CORT (1 mg/mouse) at intervals of 8 h and the control group was injected with the same volume of methyl sulfoxide (DMSO). GCs were collected at 24 h, 48 h, and 55 h after PMSG injection. For in vitro experiments, the mouse GCs obtained from healthy follicles were treated with CORT alone, or together with inhibitors against the glucocorticoid receptor (Nr3c1). The results showed that the CORT caused a downregulation of Lhcgr expression in GCs, which was accompanied by impaired cell viability. Moreover, the effect of the CORT was mediated by binding to its receptor (Nr3c1) in GCs. Further investigation revealed that Nr3c1 might regulate the transcription of Lhcgr through inhibiting the expression of Lhcgr transcription factors, including AP1 and Creb. Taken together, our findings suggested a possible mechanism of CORT-induced anovulation involving the inhibition of Lhcgr expression in GCs by the CORT–Nr3c1–AP1/Creb axis.

A novel joint satellite-transmitter and ground-receiver (JSG) digital pre-distortion (DPD) (JSG-DPD) technique is proposed to improve the linearity and power efficiency of the space-borne active phased arrays (APAs) in low Earth orbit (LEO) satellite communications. Different from the conventional DPD technique that requires a complex RF feedback loop, the DPD coefficients based on a generalized memory polynomial (GMP) model are extracted at the ground-receiver and then transmitted to the digital baseband front-end of the LEO satellite-transmitter via a satellite–ground bi-directional transmission link. The issue of the additive white Gaussian noise (AWGN) of the satellite–ground channel affecting the extraction of DPD coefficients is tackled using a superimposing training sequences (STS) method. The proposed technique has been experimentally verified using a 28 GHz phased array. The performance improvements in terms of error vector amplitude (EVM) and adjacent channel power ratio (ACPR) are 7.5% and 3.6 dB, respectively. Requiring limited space-borne resources, this technique offers a promising solution to achieve APA DPD for LEO satellite communications.

Follicular atresia is primarily caused by breakdown to granulosa cells (GCs) due to oxidative stress (OS). MicroRNAs (miRNAs) elicit a defense response against environmental stresses, such as OS, by acting as gene-expression regulators. However, the association between miRNA expression and OS in porcine GCs (PGCs) is unclear. Here, we examined the impact of H2O2-mediated OS in PGCs through miRNA-Seq. We identified 22 (14 upregulated and 8 downregulated) and 33 (19 upregulated and 14 downregulated) differentially expressed miRNAs (DEmiRNAs) at 100 μM and 300 μM H2O2, respectively, compared with the control group. Among the DEmiRNAs, mi-192 was most induced by H2O2-mediated OS, and the downregulation of miR-192 alleviated PGC oxidative injury. The dual-luciferase reporter assay results revealed that miR-192 directly targeted Acvr2a. The Acvr2a level was found to be remarkably decreased after OS. Furthermore, grape seed procyanidin B2 (GSPB2) treatment significantly reduced the H2O2-induced upregulation of miR-192, and decreased PGC apoptosis and oxidative damage. Meanwhile, GSPB2 prevented an H2O2-induced increase in caspase-3 activity, which was enhanced by the application of the miR-192 inhibitor. These results indicate that GSPB2 protects against PGC oxidative injury via the downregulation of miR-192, the upregulation of Acvr2a expression, and the suppression of the caspase-3 apoptotic signaling pathway.

Lake Dianchi is one of the most eutrophic lakes in China. The decline in water quality and the occurrence of massive algal blooms pose a significant threat to the health and environmental safety of the water ecosystem, making Lake Dianchi a key concern for algal bloom management in China. Obtaining the spatiotemporal dynamics of algal blooms for the longest time possible is crucial to algal bloom management and future prediction. However, it is difficult to acquire a long-term record of algal blooms from a single sensor in order to cover a more extended period of eutrophication in the lake due to the limitation of the spatial and temporal resolution of the sensors. In this study, Landsat and Moderate-Resolution Imaging Spectroradiometer (MODIS) images were combined with the Floating Algae Index (FAI) to reconstruct a unified time series of bloom areas to analyze the algal bloom dynamics in Lake Dianchi in recent decades. Regarding the interannual variation, the bloom area showed an increasing trend from 1987 to 2021, with larger bloom areas in 1991–1992, 2000–2003, 2012–2013, and 2020–2021. In terms of seasonal characteristics, the bloom area was significantly more prominent in the rainy season compared with the dry season during the year. The spatial distribution of the bloom frequency showed a pattern of higher frequencies in the north and lower frequencies in the south. From 2000 to 2021, the initial bloom time and bloom duration showed a trend of delaying and then advancing and decreasing and then increasing, respectively. We analyzed the importance of long-term records of algal blooms and found that the percentage of rainy season images is an essential factor in reconstructing time series based on different sensors. In addition, the relationship between environmental factors and algal blooms was analyzed. The results show that wind speed and air temperature were the main meteorological factors controlling the interannual variation in algal blooms in Lake Dianchi. Water quality factors such as nutrients have less of an influence on the variation in algal blooms because the algal growth demand has been met. Environmental management measures taken by local governments have led to improvements in the lake’s trophic state, and continued strengthening of environmental pollution control is expected to curb the algal blooms in Lake Dianchi. This study provides a long-term record of algal blooms in Lake Dianchi, which provides essential reference information for a comprehensive understanding of the development process of algal blooms in Lake Dianchi and its sustainable development.

BackgroundN6-methyladenosine (m6A) RNA modification is vital for cancers because methylation can alter gene expression and even affect some functional modification. Our study aimed to analyze m6A RNA methylation regulators and m6A-related genes to understand the prognosis of early lung adenocarcinoma.MethodsThe relevant datasets were utilized to analyze 21 m6A RNA methylation regulators and 5,486 m6A-related genes in m6Avar. Univariate Cox regression analysis, random survival forest analysis, Kaplan–Meier analysis, Chi-square analysis, and multivariate cox analysis were carried out on the datasets, and a risk prognostic model based on three feature genes was constructed.ResultsRespectively, we treated GSE31210 (n = 226) as the training set, GSE50081 (n = 128) and TCGA data (n = 400) as the test set. By performing univariable cox regression analysis and random survival forest algorithm in the training group, 218 genes were significant and three prognosis-related genes (ZCRB1, ADH1C, and YTHDC2) were screened out, which could divide LUAD patients into low and high-risk group (P < 0.0001). The predictive efficacy of the model was confirmed in the test group GSE50081 (P = 0.0018) and the TCGA datasets (P = 0.014). Multivariable cox manifested that the three-gene signature was an independent risk factor in LUAD. Furthermore, genes in the signature were also externally validated using the online database. Moreover, YTHDC2 was the important gene in the risk score model and played a vital role in readers of m6A methylation.ConclusionThe findings of this study suggested that associated with m6A RNA methylation regulators and m6A-related genes, the three-gene signature was a reliable prognostic indicator for LUAD patients, indicating a clinical application prospect to serve as a potential therapeutic target.

ObjectiveTo determine the risk factors for erectile dysfunction (ED) in male patients with acromegaly and to prospectively investigate the short-term changes of erectile function after surgery or medical treatment.MethodsSixty-three male patients were subjected to nocturnal penile tumescence and rigidity (NPTR) test for the evaluation of erectile function. The measurement of serum nitric oxide (NO) was also performed. Twenty-seven patients were re-evaluated by NPTR after surgery or long-term somatostatin analogues (SSA) treatment.ResultsTwenty-two patients (34.9%) had ED. Patients with ED showed higher random GH (17.89 [10.97-44.19] μg/L vs 11.63 [4.31-28.80] μg/L, p = 0.020) and GH nadir (GHn) (10.80 [6.69-38.30] μg/L vs 8.76 [3.62-18.19] μg/L, p = 0.044) during oral glucose tolerance test (OGTT). The NO levels of ED patients were lower than non-ED patients (9.15 [5.58-22.48] μmol/L vs 16.50 [12.33-31.78] μmol/L, p = 0.012). After treatment, patients who present improvement in erectile function showed lower post-GHn (0.07 [0.03-0.12] ng/ml vs 1.32 [0.09-3.60] ng/ml, p = 0.048) and post-IGF-1 index (1.03 ± 0.38 vs 1.66 ± 0.95, p = 0.049). The multivariate analysis indicated post-GHn was still associated with the improvement of erectile function after correction of other covariates (OR: 0.059, 95% CI: 0.003-1.043, p = 0.053).ConclusionsExcessive GH is related to ED in male patients with acromegaly. GH normalization after treatment is beneficial for short-term erectile function recovery.

In an era of information explosion, improving information literacy for academical innovation is essential for postgraduate students. However, the majority of these students lack information literacy knowledge, and even a few lack access to related courses. To improve the ratio and level of the information literacy of postgraduate students, we design a novel framework for general information literacy. It consists of four parts, namely, teaching process, methods, abilities, and applications. The methods part of the framework includes questionnaire, intensive teaching, embedded pedagogy, and free sharing. They provide support for the teaching process and abilities improvement. Notably, postgraduate students' abilities are expected to be enhanced, namely, learning (using search engines to enhance search quotient), academic research (conducting literature search, analysis, and assessment), and innovation (evaluating innovation and managing information). These abilities are applicable to academic research, internship, and academic competitions, among others. Moreover, we design a questionnaire to evaluate the effectiveness of the proposed framework. The statistical results demonstrate that the information literacy of postgraduate students maintained an upward trend, and the course was evaluated with a high level of satisfaction.

Abstract Background Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with a 5-year survival rate of less than 8%. The complicated tumor microenvironment, particularly TGF-β, provides possible convenience for the progression of PC cells. TGF-β regulates critical cellular processes, including autophagy. However, the mechanism and effects of TGF-β-mediated autophagy are still poorly understood. Methods Bioinformatics analysis, western blot, transmission electron microscopy and confocal microscopy were used to identify that TFEB is the key factors in TGF-β-induced autophagy. The biological effects of TFEB-driven autophagy were investigated in vitro using transwell and wound healing assays and in vivo using liver metastasis and LSL-KrasG12D/Pdx1-Cre mice models. Luciferase assays and motif analysis were used to assess regulation of RAB5A gene promoter activity by TGF-β-induced TFEB. TFEB levels were measured by real-time PCR, western blot and immunohistochemical staining in clinical pancreatic ductal adenocarcinoma tissues. Results We demonstrated that TGF-β induces TFEB expression via the canonical smad pathway in Smad4-positive PC cells and facilitates TFEB-mediated autophagic activation. TFEB-driven autophagy caused by TGF-β regulates RAB5A-dependent endocytosis of Itgα5 and promotes progression of PC cells. We further showed that enhanced TFEB expression and its direct target RAB5A both predict poor prognosis in PC patients. Conclusions Our findings reveal TFEB-driven autophagy is required for TGF-β induced migration and metastasis of PC cells by promoting endocytosis of Itgα5β1 and focal adhesion disassembly through the TGF-β-TFEB-RAB5A axis. Our results highlight the potential utility of suppressing TFEB-driven autophagy to block PC metastasis.

Current understanding is that receptor interacting serine/threonine protein kinase 1 (RIPK1) can lead to two distinct forms of cell death: RIPK3‐mediated necroptosis or caspase 8 (Casp8)‐mediated apoptosis. Here, we report that RIPK1 signaling is indispensable for protection from hepatocellular injury in a steatotic liver undergoing ischemia reperfusion injury (IRI) but not in the lean liver. In lean liver IRI, RIPK1‐mediated cell death is operational, leading to protection in RIP1 kinase‐dead knock‐in (RIPK1K45A) mice and necrostatin‐1s (Nec1s)‐treated lean wild‐type (WT) mice. However, when fed a high‐fat diet (HFD), RIPK1K45A‐treated and Nec1s‐treated WT mice undergoing IRI demonstrate exacerbated hepatocellular injury along with decreased RIPK1 ubiquitylation. Furthermore, we demonstrate that HFD‐fed RIPK3–/–/Casp8–/– mice show protection from IRI, but HFD‐fed RIPK3–/–/Casp8–/+ mice do not. We also show that blockade of RIPK1 leads to increased Casp8 activity and decreases mitochondrial viability. Conclusion: Although more studies are required, we provide important proof of concept for RIPK1 inhibition leading to distinctive outcomes in lean and steatotic liver undergoing IRI. Considering the rising incidence of nonalcoholic fatty liver disease (NAFLD) in the general population, it will be imperative to address this critical difference when treating patients with RIPK1 inhibitors. This study also presents a new target for drug therapy to prevent hepatocellular injury in NAFLD.

Climate change and human activities have been heavily affecting oceanic and inland waters, and it is critical to have a comprehensive understanding of the aquatic optical properties of lakes. Since many key watercolor parameters of Qinghai Lake are not yet available, this paper aims to study the spatial and temporal variations of the water clarity (i.e., Secchi-disk depth, ZSD) and suspended particulate matter concentration (CSPM) in Qinghai Lake from 2001 to 2020 using MODIS images. First, the four atmospheric correction models, including the NIR–SWIR, MUMM, POLYMER, and C2RCC were tested. The NIR–SWIR with decent accuracy in all bands was chosen for the experiment. Then, four existing models for ZSD and six models for CSPM were evaluated. Two semi-analytical models proposed by Lee (2015) and Jiang (2021) were selected for ZSD (R2 = 0.74) and CSPM (R2 = 0.73), respectively. Finally, the distribution and variation of the ZSD and CSPM were derived over the past 20 years. Overall, the water of Qinghai Lake is quite clear: the monthly mean ZSD is 5.34 ± 1.33 m, and CSPM is 2.05 ± 1.22 mg/L. Further analytical results reveal that the ZSD and CSPM are highly correlated, and the relationship can be formulated with ZSD=8.072e−0.212CSPM (R2 = 0.65). Moreover, turbid water mainly exists along the edge of Qinghai Lake, especially on the northwestern and northeastern shores. The variation in the lakeshore exhibits some irregularity, while the main area of the lake experiences mild water quality deterioration. Statistically, 81.67% of the total area is dominated by constantly increased CSPM, and the area with decreased CSPM occupies 4.56%. There has been distinct seasonal water quality deterioration in the non-frozen period (from May to October). The water quality broadly deteriorated from 2001 to 2008. The year 2008 witnessed a sudden distinct improvement, and after that, the water quality experienced an extremely inconspicuous degradation. This study can fill the gap regarding the long-time monitoring of water clarity and total suspended matter in Qinghai Lake and is expected to provide a scientific reference for the protection and management of the lake.

BackgroundAcute myeloid leukemia (AML) is a heterogeneous disease of the hematopoietic system, for which identification of novel molecular markers is potentially important for clinical prognosis and is an urgent need for treatment optimization.MethodsWe selected C-type lectin domain family 11, member A (CLEC11A) for study via several public databases, comparing expression among a variety of tumors and normal samples as well as different organs and tissues. To investigated the relationship between CLEC11A expression and clinical characteristics, we derived an AML cohort from The Cancer Genome Atlas (TCGA); we also investigated the Bloodspot and HemaExplorer databases. The Kaplan-Meier method and log-rank test were used to evaluate the associations between CLEC11A mRNA expression, as well as DNA methylation, and overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS). DNA methylation levels of CLEC11A from our own 28 de novo AML patients were assessed and related to chemotherapeutic outcomes. Bioinformatics analysis of CLEC11A was carried out using public databases.ResultsMultiple public databases revealed that CLEC11A expression was higher in leukemia. The TCGA data revealed that high CLEC11A expression was linked with favorable prognosis (OS p-value = 2e-04; EFS p-value = 6e-04), which was validated in GSE6891 (OS p-value = 0; EFS p-value = 0; RFS p-value = 2e-03). Methylation of CLEC11A was negatively associated with CLEC11A expression, and high CLEC11A methylation level group was linked to poorer prognosis (OS p-value = 1e-02; EFS p-value = 2e-02). Meanwhile, CLEC11A hypermethylation was associated with poor induction remission rate and dismal survival. Bioinformatic analysis also showed that CLEC11A was an up-regulated gene in leukemogenesis.ConclusionCLEC11A may be used as a prognostic biomarker, and could do benefit for AML patients by providing precise treatment indications, and its unique gene pattern should aid in further understanding the heterogeneous AML mechanisms.

PurposeTo investigate the different clinical characteristics of silent corticotroph adenomas (SCAs) with positive and negative adrenocorticotropic hormone (ACTH) immunostaining, and to explore the value of pituitary-restricted transcription factor (Tpit) immunostaining for diagnosing SCAs.MethodsThe clinical materials of patients with SCAs who had a typical pathological feature with positive Tpit immunostaining and positive/negative ACTH immunostaining, and without clinical features and biochemical evidence for Cushing’s Syndrome in our center from April 2018 to March 2019 were analyzed retrospectively. The differences in clinical characteristics and surgical results between ACTH-positive and -negative SCAs were explored.ResultsA total of one hundred and five patients (94.3% female) with SCAs were included. There were 66 SCAs with ACTH-negative (66/105, 62.9%), and 39 SCAs with ACTH-positive (39/105, 37.1%). Cases with ACTH-negative SCAs were more likely to have lower ACTH levels (27.5 ± 24.0 vs. 54.4 ± 58.6, P = 0.011), more multiple microcysts (81.8% vs. 61.5%, P = 0.022) and lower levels of Ki-67 expression (low expression rate 90.9% vs. 74.4%, P = 0.023). No statistical significant differences were observed between patients with ACTH-positive and -negative SCAs regarding gender (97.0% vs. 89.7%, P = 0.192), age (50.3 ± 10.3 vs. 49.0 ± 11.2, P = 0.543), surgical history (16.7% vs. 23.1%, P = 0.419), suprasellar extension (66.7% vs. 74.4%, P = 0.408), sphenoid sinus extension (51.5% vs. 56.4%, P = 0.627), cavernous sinus invasion (75.8% vs. 66.7%, P = 0.314), large cyst on Magnetic Resonance Imaging (MRI) (47.0% vs. 61.5%, P = 0.149), or gross total resection rate (42.4% vs. 51.3%, P = 0.379).ConclusionsACTH-negative SCAs were observed to be more clinically silent and more likely to demonstrate multiple microcysts on MRI. The prevalence of SCAs, especially ACTH-negative SCAs, proved to be substantially underestimated and thus they should be given enough attention in consideration of the high aggressiveness of this subtype of refractory pituitary adenoma (PA).

Water transparency, usually denoted by Secchi disk depth (SSD), represents the first-order description of water quality and has important implications for the diversity and productivity of aquatic life. In China, lakes supply freshwater and ecosystem services to nearly a billion people. Therefore, real time monitoring of lake transparency is of great significance. Moreover, understanding how and why transparency varies in space and time in response to different driving forces is needed to understand, manage, and predict lake water quality. Based on the time-saving and low-cost Google Earth Engine cloud platform, this study developed a new algorithm for quickly mapping SDDs in Chinese lakes. SDDs were retrieved for 412 Chinese lakes (> 20 km2) for the period 2000–2018. Results demonstrated that lake water depth spatially differentiated transparency. Deep lakes usually had high transparency and water depth explained 88.81 % of the spatial variations. With increasing catchment vegetation coverage and lake water depth, 70.15 % of lakes witnessed increasing transparency during 2000–2018. Of these 42.72 % were significant (p < 0.05). Transparency of deep lakes was generally determined by phytoplankton density not sediment resuspension. Minimum transparency occurred in summer. Future increases in lake water levels in response to factors such as climate change may contribute to further improvements in transparency. Management should focus on controlling eutrophication and increasing vegetation cover in catchments.

BackgroundMatrix metallopeptidase 14 (MMP14) is an important gene in the regulation of T-cell function. However, the correlation between MMP14 expression, prognosis, and immune cell infiltration in diffuse large B-cell lymphoma (DLBCL) remains unclear.MethodsWe investigated the influence of MMP14 on clinical prognosis using data obtained from three Gene Expression Omnibus (GEO) database sets (GSE98588, GSE10846, and GSE4475). The expression of MMP14 was analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA). The correlation between MMP14 and immune cell infiltration was investigated using the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Tumor Immune Estimation Resource (TIMER) tools. In addition, the correlation between MMP14 expression and immune gene markers was analyzed by TIMER and GEPIA.ResultsMMP14 expression positively correlated with favorable progression-free survival (PFS; GSE98588, P = 0.02) and overall survival (OS; GSE98588, P = 0.003; GSE10846, P = 5.517e-05; and GSE4475, P = 9.85e-04). Moreover, MMP14 expression was higher in DLBCL tumors than in normal tissues. Regarding clinical characteristics, high MMP14 expression was found to be correlated with race. MMP14 expression was also correlated with immune cell infiltration and had a remarkable correlation with various immune marker sets. It was found that M0 macrophages were the immune cells most related to survival, decreasing with the increase in Ann Arbor clinical stage. The results especially showed that MMP14 was a prognostic biomarker and related to the macrophages M0.ConclusionThe results suggest that MMP14 is a novel prognostic molecular marker for DLBCL and is related to the immune cell infiltration, especially related to the macrophages M0. Our study provides insights for understanding the potential roles of MMP14 in tumor immunology and its suitability as a prognosis biomarker in DLBCL.

Evidence from clinical and epidemiological studies indicates that asthma is associated with allergic diseases including hay fever, allergic rhinitis, and eczema. Genetic analysis demonstrated that asthma had a positive genetic correlation with allergic diseases. A Mendelian randomization (MR) analysis using the rs16969968 single-nucleotide variant as the instrumental variable indicated that smoking was associated with increased risk of asthma. However, in a different MR analysis, smoking was significantly associated with reduced hay fever and reduced allergic sensitization risk. These findings revealed inconsistencies in the association of smoking with asthma and allergic diseases. Hence, we conducted an updated MR analysis to investigate the causal association between lifetime smoking and asthma risk by using 124 genetic variants as the instrumental variables. No significant pleiotropy was detected using the MR–Egger intercept test. We found that increased lifetime smoking was significantly associated with decreased asthma risk by using the inverse variance weighted (IVW) method (OR = 0.97, 95% CI 0.956–0.986, and P = 1.77E-04), the weighted median regression method (OR = 0.976, 95% CI 0.96–0.994, and P = 8.00E-03), and the MR–Egger method (OR = 0.919, 95% CI 0.847–0.998, and P = 4.5E-02). Importantly, MR pleiotropy residual sum and outlier (MR-PRESSO) MR analysis also indicated a significant association between increased lifetime smoking and decreased asthma risk with OR = 0.971, 95% CI 0.956–0.986, and P = 2.69E-04. After the outlier was removed, MR-PRESSO outlier test further supported the significant association with OR = 0.971, 95% CI 0.959–0.984, P = 1.57E-05.

Algal blooms and the resulting deterioration of water quality have threatened the environmental health of inland lakes. This study investigated the spatiotemporal dynamics of gypsum blooms in the Salton Sea, the largest inland water body in California. An innovative gypsum bloom index (GI) was proposed to detect gypsum blooms based on Moderate Resolution Imaging Spectroradiometer (MODIS)/Terra data for three bands (469, 555, and 859 nm) during 2000–2018. Discoloration (from green to reddish brown) was observed in the gypsum bloom-infested waters mapped using the hue, saturation, and value (HSV) color model. We found that: (1) the GI is able to effectively map gypsum blooms in the Salton Sea with a relatively high accuracy (85 %); (2) the largest gypsum bloom area was observed in summer (August and September), with notable gypsum blooms lasting more than 40 days in 2003, 2005, 2006, 2016, and 2018; (3) the gypsum bloom-infested waters shifted from the center to the southeastern shore of the lake during 2003–2018, and the frequency of gypsum blooms significantly increased since 2008. Meanwhile, the temporal and spatial differences between the northwestern and southeastern lake increased over the observation period; and (4) discoloration occurred in the gypsum bloom-infested waters and lasted for 14 days on average, longer periods of discoloration (more than 20 days) occurred d in 2002, 2016, and 2018. The reconstruction of gypsum bloom dynamics in the Salton Sea provides valuable information for the practical management and restoration of the Salton Sea.

Oxidative stress has been described as a prime driver of granulosa cell (GCs) death during follicular atresia. Increasing evidence suggests potential roles of melatonin in protecting GCs from oxidative injury, though the underlying mechanisms remain largely undetermined. Here we first proposed that the inhibition of autophagy through some novel regulators contributes to melatonin-mediated GCs survival under conditions of oxidative stress. Oxidant-induced loss of GCs viability was significantly reduced after melatonin administration, which was correlated with attenuated autophagic signals upon oxidative stimulation both in vivo and in vitro. Compared with melatonin treatment, suppression of autophagy displayed similar preventive effect on GCs death during oxidative stress, but melatonin provided no additional protection in GCs pretreated with autophagy inhibitors. Notably, we found that melatonin-directed regulation of autophagic death was independent of its antioxidation/radical scavenging ability. Further investigations identified FOXO1 as a critical downstream effector of melatonin in promoting GCs survival from oxidative stress-induced autophagy. Specifically, suppression of FOXO1 via the melatonin-phosphatidylinositol 3-kinase (PI3K)-AKT axis not only improved GCs resistance to oxidative stress, but also abolished the autophagic response, from genes expression to the formation of autophagic vacuoles. Moreover, the activation of SIRT1 signaling was required for melatonin-mediated deacetylation of FOXO1 and its interaction with ATG proteins, as well as the inhibition of autophagic death in GCs suffering oxidative stress. These findings reveal a brand new mechanism of melatonin in defense against oxidative damage to GCs by repressing FOXO1, which may be a potential therapeutic target for anovulatory disorders. Keywords: Melatonin, Autophagic death, FOXO1, Granulosa cells, Oxidative damage, Antioxidation-independent

Abstract Cushing’s disease results from corticotroph adenomas of the pituitary that hypersecrete adrenocorticotropin (ACTH), leading to excess glucocorticoid and hypercortisolism. Mutations of the deubiquitinase gene USP8 occur in 35–62% of corticotroph adenomas. However, the major driver mutations in USP8 wild-type tumors remain elusive. Here, we report recurrent mutations in the deubiquitinase gene USP48 (predominantly encoding p.M415I or p.M415V; 21/91 subjects) and BRAF (encoding p.V600E; 15/91 subjects) in corticotroph adenomas with wild-type USP8. Similar to USP8 mutants, both USP48 and BRAF mutants enhance the promoter activity and transcription of the gene encoding proopiomelanocortin (POMC), which is the precursor of ACTH, providing a potential mechanism for ACTH overproduction in corticotroph adenomas. Moreover, primary corticotroph tumor cells harboring BRAF V600E are sensitive to the BRAF inhibitor vemurafenib. Our study thus contributes to the understanding of the molecular mechanism of the pathogenesis of corticotroph adenoma and informs therapeutic targets for this disease.

As an invasive plant species, kudzu has been spreading rapidly in the Southeastern United States in recent years. Accurate mapping of kudzu is critical for effective invasion control and management. However, the remote detection of kudzu distribution using multispectral images is challenging because of the mixed reflectance and potential misclassification with other vegetation. We propose a three-step classification process to map kudzu in Knox County, Tennessee, using multispectral Sentinel-2 images and the integration of spectral unmixing analysis and phenological characteristics. This classification includes an initial linear unmixing process to produce an overestimated kudzu map, a phenological-based masking to reduce misclassification, and a nonlinear unmixing process to refine the classification. The initial linear unmixing provides high producer’s accuracy (PA) but low user’s accuracy (UA) due to misclassification with grasslands. The phenological-based masking increases the accuracy of the kudzu classification and reduces the domain for further processing. The nonlinear unmixing further refines the kudzu classification via the selection of an appropriate nonlinear model. The final kudzu classification for Knox County reaches relatively high accuracy, with UA, PA, Jaccard, and Kappa index values of 0.858, 0.907, 0.789, and 0.725, respectively. Our proposed method has potential for continuous monitoring of kudzu in large areas.

In mammalian, the periodic growth and development of ovarian follicles constitutes the physiological basis of female estrus and ovulation. Concomitantly, follicular angiogenesis exerts a pivotal role in the growth of ovarian follicles. Melatonin (N-acetyl-5-methoxytryptamine, Mel), exists in follicle fluid, was suggested to affect the development of follicles and angiogenesis. This research was conducted to investigate the effects and mechanisms of Mel on the development of ovarian follicles and its angiogenesis. In total, 40 ICR mice at age of 3 weeks were allocated into four groups at liberty: control, Mel, FSH and FSH + Mel for a 12-day trial. Ovaries were collected at 8:00 a.m. on Day 13 for detecting the development of ovarian follicles and angiogenesis. Results indicated that Mel promoted the development of ovarian follicles of 50–250 μm (secondary follicles) and periphery angiogenesis, while FSH remarkably increased the number of antral follicles and periphery angiogenesis. Mechanically, Mel and FSH may regulate the expression of VEGF and antioxidant enzymes in different follicular stages. In conclusion, Mel primarily acted on the secondary follicles, while FSH mainly promoted the development of antral follicles. They both conduced to related periphery angiogenesis by increasing the expression of VEGF. These findings may provide new targets for the regulating of follicular development.

Various environmental stimuli, including oxidative stress, could lead to granulosa cell (GC) death through mitophagy. Recently, it was reported that melatonin (MEL) has a significant effect on GC survival during oxidative damage. Here, we found that MEL inhibited oxidative stress-induced mitophagy to promote GC survival. The loss of cell viability upon H2O2 exposure was significantly restored after MEL treatment. Concomitantly, MEL inhibited the activation of mitophagy during oxidative stress. Notably, blocking mitophagy repressed GC death caused by oxidative stress. However, MEL cannot further restore viability of cells treated with mitophagy inhibitor. Moreover, PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase, was inhibited by MEL during oxidative stress. As a result, the E3 ligase Parkin failed to translocate to mitochondria, leading to impaired mitochondria clearance. Using RNAi to knock down PINK1 expression, we further verified the role of the MEL-PINK1-Parkin (MPP) pathway in maintaining GC survival by suppressing mitophagy. Our findings not only clarify the protective mechanisms of MEL against oxidative damage in GCs, but also extend the understanding about how circadian rhythms might influence follicles development in the ovary. These findings reveal a new mechanism of melatonin in defense against oxidative damage to GCs by repressing mitophagy, which may be a potential therapeutic target for anovulatory disorders.

The new type of L-LLC resonant bidirectional DC-DC converter (L-LLC-BDC) has merits of high efficiency, high-power density and wide gain and power ranges, and it is suitable for energy interface between energy storage systems and DC micro grid. However, the resonances are sensitive to the parasitic parameters, which will deteriorate the efficiency. This paper investigates the intrinsic mechanism of parasitic parameters on the L-LLC-BDC operating principle and working characteristics based on the analysis of working modes and resonance tank. By taking the oscillation of parasitic parameters produced in the stage for the freewheeling stage into consideration, a parameter optimization method is proposed to reduce the resonant current oscillation while maintaining the characteristic of the natural soft switching. The experiment results not only validated the proposed parameter optimization design method, but also testified to the improvement of the efficiency through the minimization of the conduction and switching loss.

Macrophage accumulation within the vascular wall is a hallmark of atherosclerosis. Controlling macrophage conversion into foam cells remains a major challenge for treatment of atherosclerotic diseases. Here, we show that Wip1, a member of the PP2C family of Ser/Thr protein phosphatases, modulates macrophage migration and phagocytosis associated with atherosclerotic plaque formation. Wip1 deficiency increases migratory and phagocytic activities of the macrophage under stress conditions. Enhanced migration of Wip1-/- macrophages is mediated by Rac1-GTPase and PI3K/AKT signalling pathways. Elevated phagocytic ability of Wip1-/- macrophages is linked to CD36 plasma membrane recruitment that is regulated by AMPK activity. Our study identifies Wip1 as an intrinsic negative regulator of macrophage chemotaxis. We propose that Wip1-dependent control of macrophage function may provide avenues for preventing or eliminating plaque formation in atherosclerosis.

Abstract Dynamics and collapse of two-dimensional Airy beams are investigated numerically in nonlocal nonlinear media with split step Fourier transform method. In particular, the stability and self-healing properties of the Airy beams depend crucially on the location and topological charge of the vortex when the beams carry angular momentum. The propagation of abruptly autofocusing Airy beams is also demonstrated in local and nonlocal media. In strongly self-focusing regime, with the help of nonlocality, stationary propagation of two-dimensional Airy beams can be obtained, which always collapse in local nonlinear media.

Snow cover plays an important role in hydrological processes and seasonal water balance. Especially in the Tibetan Plateau (TP), snow cover is an important source of the Yangtze River, Yellow River and Lancang River (SRYYL), which greatly influences regional water balance. In this study, we quantified the temporal trend and spatial variation of snow cover across the TP by calibrating and developing the Advance Very High Resolution Radiometer (AVHRR) Long Term Data Record (LTDR)-derived snow cover products during 1982-2011. We also examined the relationship of snow cover with temperature and precipitation over the TP during 1982–2011. The results indicate that seasonal snow cover generally starts to accumulate from central plateau in October, while significant melting starts to occur from the southeastern plateau in May of following year. The long-term variability of snow cover is characterized by the tendency for a slight decrease in the mean snow coverage during the period of hydrological year (HY) 1982–1993 and a slight increase from HY2001 to 2011, but the total snow cover area remains relatively stable over the past 30 years. The results also show that temperature plays a critical role in controlling the snow cover days.

Abstract Background Subependymal giant cell astrocytoma (SEGA) is a clinically benign brain tumor associated with tuberous sclerosis complex (TSC). There are still controversies on early diagnosis of the tumor. Methods CT and MR imaging of 20 patients with pathologically confirmed SEGA were retrospectively reviewed. Two radiologists evaluated the location, shape, size, number, edge, cerebral edema, homogeneous or heterogeneous appearance, attenuation and signal intensity, degree of enhancement and calcification of lesions. Their prognoses were based on clinical observations. Results SEGA showed similar features in imaging: an extra-axial, well-circumscribed, periventricular mass, isodense or slightly hyperdense on CT, hypointensity on T1-weighted imaging and isointensity to hyperintensity on T2-weighted imaging. The mass enhanced markedly and heterogeneously after the administration of contrast agent. Subependymal nodules were demonstrated in 5 cases. Remarkably, 17 patients (85%) showed ventricular dilatation and 14 patients (70%) showed calcification in CT and MR imaging. Moreover, perifocal edema was not significantly near the masses. Four cases are associated with tuberous sclerosis complex (TSC). Conclusions Although there are no pathognomonic imaging findings for SEGA, the following clinical and imaging features might be helpful for the diagnosis, such as the initial age of first or second decade, typical location in the periventricular regions adjacent to the foramen of Monro, hydrocephalus accompanied with raised intracranial pressure, TSC and marked heterogeneous enhancement.

Pancreatic cancer (PC) is one of the most lethal diseases, and effective treatment of PC patients remains an enormous challenge. Rocaglamide A (Roc-A), a bioactive molecule extracted from the plant Aglaia elliptifolia, has aroused considerable attention as a therapeutic choice for numerous cancer treatments. Nevertheless, the effects and underlying mechanism of Roc-A in PC are still poorly understood. Here, we found that Roc-A inhibited growth and stimulated apoptosis by induction of mitochondria dysfunction in PC. Moreover, Roc-A accelerated autophagosome synthesis and triggered mitophagy involving the PTEN-induced putative kinase 1 (PINK1)/Parkin signal pathway. We also demonstrated that inhibition of autophagy/mitophagy can sensitize PC cells to Roc-A. Finally, Roc-A treatment results in an obvious accumulation of reactive oxygen species (ROS), and pretreatment of cells with the reactive oxygen species scavenger N-acetylcysteine reversed the apoptosis and autophagy/mitophagy induced by Roc-A. Together, our results elucidate the potential mechanisms of action of Roc-A. Our findings indicate Roc-A as a potential therapeutic agent against PC and suggest that combination inhibition of autophagy/mitophagy may be a promising therapeutic strategy in PC.

Objective: Published studies have demonstrated a closer association between vitamin D receptor (VDR) gene polymorphisms and polycystic ovary syndrome (PCOS) risk, but the results were inconsistent. We therefore performed this meta-analysis to explore the precise associations between VDR gene polymorphisms and PCOS risk.Methods: Five online electronic databases (PubMed, Embase, SCI index, CNKI and Wanfang) were searched. Odds ratios (ORs) with 95% confidence interval (CIs) were calculated to assess the association between VDR Fok I C/T (rs10735810), BsmI A/G (rs1544410), ApaI A/C (rs7975232), and TaqI T/C (rs731236) polymorphisms and PCOS risk. In addition, heterogeneity, accumulative/sensitivity analysis and publication bias were conducted to check the statistical power.Results: Overall, 10 publications (31 independent case-control studies) involving 1,531 patients and 1,174 controls were identified. We found that the C mutation of ApaI A/C was a risk factor for PCOS (C vs. A: OR = 1.20, 95%CI = 1.06–1.35, P < 0.01, I2 = 29.7%; CC vs. AA: OR = 1.49, 95%CI = 1.17–1.91, P < 0.01, I2 = 0%; CC vs. AA+AC: OR = 1.36, 95%CI = 1.09–1.69, P = 0.01, I2 = 12.8%). Moreover, the BsmI A/G polymorphism also showed a dangerous risk for PCOS in Asian population (G vs. A: OR = 1.62, 95%CI = 1.24–2.11, P < 0.01, I2 = 0%; AG vs. AA: OR = 2.08, 95%CI = 1.26–3.20, P < 0.01, I2 = 0%; GG vs. AA: OR = 2.21, 95%CI = 1.29–3.77, P < 0.01, I2 = 0%; AG+GG vs. AA: OR = 2.12, 95%CI = 1.42–3.16, P < 0.01, I2 = 0%). In addition, no significant association of Fok I C/T, and TaqI T/C polymorphisms was observed.Conclusions: In summary, our meta-analysis suggested that VDR gene polymorphisms contribute to PCOS development, especially in Asian populations.

Insufficient bone height in the posterior maxilla is a challenging problem in dental implantation. Bio-Oss, though routinely used in maxillary sinus floor elevation (MSFE), is not osteoinductive. Human amniotic mesenchymal cells (hAMSCs) isolated from placental tissues have potential for multidifferentiation and immunomodulatory properties and can be easily obtained without the need for invasive procedures and without ethical concerns. This is the first study to use hAMSCs to improve implant osseointegration and bone regeneration after MSFE. Human AMSCs were loaded into a fibrin gel and injected into rabbit MSFE models. The rabbits were assigned to four groups (n=3 per group), i.e., the control group, the hAMSC group, the Bio-Oss group, and the hAMSC/Bio-Oss group. The animals were sacrificed at postsurgery for four and twelve weeks and evaluated by histology and immunohistochemistry. Bone volume, bone volume/tissue volume, bone-to-implant contact ratio, and vessel-like structures in the hAMSC/Bio-Oss group were significantly better than those in other groups in the peri-implant and augmented areas. Immunofluorescence staining showed that alkaline phosphatase (ALP) activities of two hAMSC groups were higher than those of the other two groups. Sequential fluorescent labeling was performed in all of the 12-week groups. Observations showed that hAMSCs accelerated mineralized deposition rates on implant surfaces and in bone-augmented areas. These data demonstrated that hAMSCs could enhance implant osseointegration and bone regeneration after MSFE and might be used to optimize dental implantation in the future.

In mammalian ovaries, the avascular environment within follicular cavity is supposed to cause hypoxic status in granulosa cells (GCs), leading to apoptotic cell death accompanied by cumulative reactive oxygen species (ROS) production. Melatonin (N-acetyl-5-methoxytryptamine, MT), a broad-spectrum antioxidant that exists in porcine follicle fluid, was suggested to maintain GCs survival under stress conditions. In this study, using the established hypoxic model (1% O2) of cultured porcine GCs, we explored the effect of MT on GCs apoptosis. The results showed that MT restored cell viability and reduced the apoptosis of GCs during hypoxia exposure. In addition, GCs treated with MT exhibited decreased ROS levels and increased expression of antioxidant enzymes including heme oxygenase-1 (HO-1), glutathione S-transferase (GST), superoxide dismutase 1 (SOD1), and catalase (CAT) upon hypoxia incubation. Moreover, the hypoxia-induced expression of cleaved caspase 3, 8, and 9 was significantly inhibited after MT treatment. In contrast, blocking melatonin receptor 2 (MTNR1B) with a competitive antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT) diminished the inhibitory effects of MT on caspase 3 activation. By detecting levels of protein kinase (PKA), a downstream kinase of MTNR1B, we further confirmed the involvement of MT–MTNR1B signaling in mediating GCs protection during hypoxia stress. Together, the present data provide mechanistic evidence suggesting the role of MT in defending GCs from hypoxia-induced apoptosis.

Turbidity is an important indicator of riverine conditions, especially in a fragile environment such as the Tibetan Plateau. Remote sensing, with the advantages of large-scale observations, has been widely applied to monitor turbidity change in lakes and rivers; however, few studies have focused on turbidity change of rivers on the Tibetan Plateau. We investigated the pattern of turbidity change in the middle reaches of the Yarlung Zangbo River, southern Tibetan Plateau, based on multispectral satellite imagery and in situ measurements. We developed empirical models from in situ measured water leaving reflectance and turbidity, and applied the best performed s-curve models on satellite imagery from Sentinel-2, Landsat 8, and Landsat 5 to derive turbidity change in 2007–2017. Our results revealed an overall decreasing spatial trend from the upper to lower streams. Seasonal variations were observed with high turbidity from July to September and low turbidity from October to May. Annual turbidity showed a temporally slightly declining trend from 2007 to 2017. The pattern of turbidity change is affected by the confluence of tributaries and the changes in precipitation and vegetation along the river. These findings provide important insights into the responses of riverine turbidity to climate and environmental changes on the Tibetan Plateau.

To investigate head-brain injuries caused by windshield impact on riders using electric self-balancing scooters (ESS). Numerical vehicle ESS crash scenarios are constructed by combining the finite element (FE) vehicle model and multibody scooter/rider models. Impact kinematic postures of the head-windshield contact under various impact conditions are captured. Then, the processes during head-windshield contact are reconstructed using validated FE head/laminated windshield models to assess the severity of brain injury caused by the head-windshield contact. Governing factors, such as vehicle speed, ESS speed, and the initial orientation of ESS rider, have nontrivial influences over the severity of a rider’s brain injuries. Results also show positive correlations between vehicle speed and head-windshield impact speeds (linear and angular). Meanwhile, the time of head-windshield contact happens earlier when the vehicle speed is faster. According to the intensive study, windshield-head contact speed (linear and angular), impact location on the windshield, and head collision area are found to be direct factors on ESS riders’ brain injuries during an impact. The von Mises stress and shear stress rise when relative contact speed of head-windshield increases. Brain injury indices vary widely when the head impacting the windshield from center to the edge or impacting with different areas.

Purpose. To evaluate the change in glucose tolerance in treatment-naïve patients with acromegaly after administration of SSA and to identify predictive factors of glucose impairment during SSA therapy. Methods. Oral glucose tolerance testing (OGTT) was performed on 64 newly diagnosed and treatment-naïve patients with acromegaly both at pretreatment and 3 months after initiation of treatment with long-acting SSA. Insulin resistance (IR) was assessed by homeostatic model assessment- (HOMA-) IR and ISOGTT. Insulin secretion was assessed by HOMA-β, INS0/BG0, IGI (insulinogenic index), IGI/IR, ISSI2, and AUCINS/AUCBG. Receiver-operating characteristic (ROC) curves were generated to determine the optimal cutoffs to predict the impact of SSA on glucose metabolism. Results. Pretreatment, 19, 24, and 21 patients were categorized as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus (DM), respectively. Posttreatment, IR, represented by ISOGTT, was significantly improved in all 3 groups. Insulin secretion, represented by HOMA-β, declined in the NGT and IGT groups, but was unaltered in the DM group. The glucose tolerance status deteriorated in 18 (28.1%) patients, including 13 patients in the NGT group and 5 patients in the IGT group. Deterioration was associated with lower baseline BG120 (plasma glucose 120 min post-OGTT), less reduction of growth hormone (GH), and greater reduction of insulin secretion after SSA therapy. BG120 greater than 8.1 mmol/l provided the greatest sensitivity and specificity in predicting the stabilization and/or improvement of glucose tolerance status after SSA treatment (PPV 90.7%, NPV 66.7%, p