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Abstract The loss of dopaminergic neurons in the substantia nigra is a hallmark of pathology in Parkinson’s disease (PD). Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) is the critical enzyme responsible for the degradation of asymmetric dimethylarginine (ADMA) which inhibits nitric oxide (NO) synthase and has been implicated in neurodegeneration. Mitochondrial dysfunction, particularly in the mitochondria-associated endoplasmic reticulum membrane (MAM), plays a critical role in this process, although the specific molecular target has not yet been determined. This study aims to examine the involvement of DDAH-1 in the nigrostriatal dopaminergic pathway and PD pathogenesis. The distribution of DDAH-1 in the brain and its colocalization with dopaminergic neurons were observed. The loss of dopaminergic neurons and aggravated locomotor disability after rotenone (ROT) injection were showed in the DDAH-1 knockout rat. l-arginine (ARG) and NO donors were employed to elucidate the role of NO respectively. In vitro, we investigated the effects of DDAH-1 knockdown or overexpression on cell viability and mitochondrial functions, as well as modulation of ADMA/NO levels using ADMA or ARG. MAM formation was assessed by the Mitofusin2 oligomerization and the mitochondrial ubiquitin ligase (MITOL) phosphorylation. We found that DDAH-1 downregulation resulted in enhanced cell death and mitochondrial dysfunctions, accompanied by elevated ADMA and reduced NO levels. However, the recovered NO level after the ARG supplement failed to exhibit a protective effect on mitochondrial functions and partially restored cell viability. DDAH-1 overexpression prevented ROT toxicity, while ADMA treatment attenuated these protective effects. The declines of MAM formation in ROT-treated cells were exacerbated by DDAH-1 downregulation via reduced MITOL phosphorylation, which was reversed by DDAH-1 overexpression. Together, the abundant expression of DDAH-1 in nigral dopaminergic neurons may exert neuroprotective effects by maintaining MAM formation and mitochondrial function probably via ADMA, indicating the therapeutic potential of targeting DDAH-1 for PD.

Energy metabolism disorder, mainly exhibiting the inhibition of fatty acid degradation and lipid accumulation, is highly related with aging acceleration. However, the intervention measures are deficient. Here, we reported Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs), especially EPA, exerted beneficial effects on maintaining energy metabolism and lipid homeostasis to slow organ aging. As the endogenous agonist of peroxisome proliferator–activated receptor α (PPARα), Omega-3 PUFAs significantly boosted fatty acid β-oxidation and ATP production in multiple aged organs. Consequently, Omega-3 PUFAs effectively inhibited age-related pathological changes, preserved organ function, and retarded aging process. The beneficial effects of Omega-3 PUFAs were also testified in mfat-1 transgenic mice, which spontaneously generate abundant endogenous Omega-3 PUFAs. In conclusion, our study innovatively demonstrated Omega-3 PUFAs administration in diet slow aging through promoting energy metabolism. The supplement of Omega-3 PUFAs or fat-1 transgene provides a promising therapeutic approach to promote healthy aging in the elderly.

Acute kidney injury (AKI) is in high prevalence worldwide but with no therapeutic strategies. Programmed cell death in tubular epithelial cells has been reported to accelerate a variety of AKI, but the major pathways and underlying mechanisms are not defined. Herein, we identified that pyroptosis was responsible for AKI progression and related to ATP depletion in renal tubular cells. We found that FAM3A, a mitochondrial protein that assists ATP synthesis, was decreased and negatively correlated with tubular cell injury and pyroptosis in both mice and patients with AKI. Knockout of FAM3A worsened kidney function decline, increased macrophage and neutrophil cell infiltration, and facilitated tubular cell pyroptosis in ischemia/reperfusion injury model. Conversely, FAM3A overexpression alleviated tubular cell pyroptosis, and inhibited kidney injury in ischemic AKI. Mechanistically, FAM3A promoted PI3K/AKT/NRF2 signaling, thus blocking mitochondrial reactive oxygen species (mt-ROS) accumulation. NLRP3 inflammasome sensed the overload of mt-ROS and then activated Caspase-1, which cleaved GSDMD, pro-IL-1β, and pro-IL-18 into their mature forms to mediate pyroptosis. Of interest, NRF2 activator alleviated the pro-pyroptotic effects of FAM3A depletion, whereas the deletion of NRF2 blocked the anti-pyroptotic function of FAM3A. Thus, our study provides new mechanisms for AKI progression and demonstrates that FAM3A is a potential therapeutic target for treating AKI.

ABSTRACT: Objectives: Consuming contaminated food and water is a leading cause of food poisoning, with Salmonella being one of the primary culprits. The aim of this study is to elucidate the genomic characteristics of a blaCTX-M-27-carrying S. enterica strain recovered from a patient with diarrhoea in China. Methods: Antimicrobial susceptibility of S. enterica strain 123 was determined by microdilution broth assay. Whole-genome sequencing was performed using both long-read MinION and short-read Illumina platforms to fully characterize the genetic structure of the blaCTX-M-27-carrying plasmid of the S. enterica 123. In silico multilocus sequence typing (MLST), antimicrobial resistance genes and genomic epidemiological analysis of 69 Salmonella strains carrying the blaCTX-M-27 gene stored in NCBI GenBank were further analysed by BacWGSTdb 2.0 server. Results: The isolate was resistant to ampicillin, ampicillin/sulbactam, ceftazidime, ceftriaxone, cefepime, aztreonam, azithromycin, but still susceptible to ciprofloxacin, levofloxacin, imipenem, amikacin, trimethoprim-sulfamethoxazole and gentamicin. The complete genome sequence of Salmonella 123 is made up of one chromosome and three plasmids, which could be assigned as sequence type (ST)34. The blaCTX-M-27 gene was found in the 65 644 bp IncFII-type plasmid with IS26 and IS5 exist upstream of blaCTX-M-27 gene, and IS26 and IS1B are located downstream as a truncated fragment. The closest relative of Salmonella 123 was Salmonella strain La89, another ST34 strain recovered in 2011, which differed by only 52 SNPs. Conclusion: This study reports the complete genome of a blaCTX-M-27-carrying S. enterica that can be used for gaining insights into the antimicrobial resistance mechanisms and dissemination patterns of the emerging pandemic lineage ST34.

Abstract The mechanisms by which animals respond to rapid changes in temperature are largely unknown. Here, we found that polymodal ASH sensory neurons mediate rapid cooling-evoked avoidance behavior within the physiological temperature range in C. elegans. ASH employs multiple parallel circuits that consist of stimulatory circuits (AIZ, RIA, AVA) and disinhibitory circuits (AIB, RIM) to respond to rapid cooling. In the stimulatory circuit, AIZ, which is activated by ASH, releases glutamate to act on both GLR-3 and GLR-6 receptors in RIA neurons to promote reversal, and ASH also directly or indirectly stimulates AVA to promote reversal. In the disinhibitory circuit, AIB is stimulated by ASH through the GLR-1 receptor, releasing glutamate to act on AVR-14 to suppress RIM activity. RIM, an inter/motor neuron, inhibits rapid cooling-evoked reversal, and the loop activities thus equally stimulate reversal. Our findings elucidate the molecular and circuit mechanisms underlying the acute temperature stimuli-evoked avoidance behavior.

As a novel therapeutic approach, photothermal therapy (PTT) combined with chemotherapy can synergistically produce antitumor effects. Herein, dithiodipropionic acid (DTDP) was used as a donor of disulfide bonds sensitive to the tumor microenvironment for establishing chemical bonding between the photosensitizer indocyanine green amino (ICG-NH2) and acidified single-walled carbon nanotubes (CNTs). The CNT surface was then coated with conjugates (HD) formed by the targeted modifier hyaluronic acid (HA) and 1,2-tetragacylphosphatidyl ethanolamine (DMPE). After doxorubicin hydrochloride (DOX), used as the model drug, was loaded by CNT carriers, functional nano-delivery systems (HD/CNTs-SS-ICG@DOX) were developed. Nanosystems can effectively induce tumor cell (MCF-7) death in vitro by accelerating cell apoptosis, affecting cell cycle distribution and reactive oxygen species (ROS) production. The in vivo antitumor activity results in tumor-bearing model mice, further verifying that HD/CNTs-SS-ICG@DOX inhibited tumor growth most significantly by mediating a synergistic effect between chemotherapy and PTT, while various functional nanosystems have shown good biological tissue safety. In conclusion, the composite CNT delivery systems developed in this study possess the features of high biocompatibility, targeted delivery, and responsive drug release, and can achieve the efficient coordination of chemotherapy and PTT, with broad application prospects in cancer treatment.

Abstract Copulas are mathematical tools for modeling joint probability distributions. In the past 60 years they have become an essential analysis tool on classical computers in various fields. The recent finding that copulas can be expressed as maximally entangled quantum states has revealed a promising approach to practical quantum advantages: performing tasks faster, requiring less memory, or, as we show, yielding better predictions. Studying the scalability of this quantum approach as both the precision and the number of modeled variables increase is crucial for its adoption in real-world applications. In this paper, we successfully apply a Quantum Circuit Born Machine (QCBM) based approach to modeling 3- and 4-variable copulas on trapped ion quantum computers. We study the training of QCBMs with different levels of precision and circuit design on a simulator and a state-of-the-art trapped ion quantum computer. We observe decreased training efficacy due to the increased complexity in parameter optimization as the models scale up. To address this challenge, we introduce an annealing-inspired strategy that dramatically improves the training results. In our end-to-end tests, various configurations of the quantum models make a comparable or better prediction in risk aggregation tasks than the standard classical models.

Non-metallic armoured optoelectronic cable winch systems (NAOCWSs) play critical roles in facilitating signal transmission and powering subsea equipment. Due to the varying depths in these applications, deploying the entire cable length is unnecessary. However, the portion of the cable that remains coiled around the winch can generate an electromagnetic field, which may interfere with signal transmission and induce electromagnetic heating. This can lead to elevated temperatures within the system, affecting the cable’s lifespan. Consequently, this study examines the distributions of magnetic and temperature fields within the NAOCWS with different currents (10–30 A) and numbers of winding layers (1–10). Findings indicate that the magnetic flux density (MFD) changes periodically, and the period is closely related to the distance between the cables. At the centre of the cable, the flux density is minimum. Temperature distribution correlates with both current amplitude and the number of winding layers, where an increase in either parameter amplifies the temperature variance between the edge and intermediate cables within the same layer. The current does not affect the internal temperature distribution pattern. With the number of winding layers determined, the layer where the highest temperature of the system is located is well defined and does not vary with current.

Abstract Objectives Poor immune-nutritional status has been associated with an unfavorable outcome in critical illness. The Osaka prognostic score (OPS) and the Naples prognostic score (NPS), based on inflammatory and nutritional status, has been shown to predict prognosis following cancer and other diseases. The aim of this study was to investigate the relationship between the OPS and NPS and the short-term outcomes of patients with intracerebral hemorrhage (ICH). Methods We retrospectively analyzed the clinical data of patients hospitalized with spontaneous ICH (n = 340) at The Second Affiliated Hospital of Chongqing Medical University between August 2016 and August 2021. Inclusion criteria included patients aged between 18 and 70, and if a blood sample was taken for laboratory testing within 24 h of admission (serum C-reactive protein, albumin, total cholesterol, and counts for neutrophils, lymphocytes, and monocytes were collected on admission). Exclusion criteria included a non-spontaneous cause of ICH and patient death during hospitalization. Patients were divided into four groups based on OPS or five groups according to NPS. Outcomes were evaluated by the modified Rankin Scale (mRS) at six months post-ICH hospitalization. An unfavorable outcome was defined as a mRS score ≥ 3. Results A total of 289 patients met our inclusion criteria. The unfavorable outcome group had older age, a lower Glasgow Coma Scale score, a higher rate of complications and cerebral herniation, a longer hospital stay, and higher OPS and NPS when compared with the favorable outcome group. Univariate analysis showed that both OPS and NPS were strongly correlated with mRS (r = 0.196,P

Abstract Acute kidney injury (AKI) is rapidly increasing nowadays and at a high risk to progress into chronic kidney disease (CKD). Of note, men are more susceptive to AKI, suggesting gender differences in AKI patients. However, the underlying mechanisms remain largely unclear. To test it, we adopted two experimental models of AKI, including ischemia/reperfusion injury and rhabdomyolysis, which were constructed in age-matched male and female mice. We found severe damages of tubular apoptosis, mitochondrial dysfunction, and loss of renal function showing in male mice, while female mice only had very mild injury. We further tested the expression of Sirtuins, and found that female mice could preserve more Sirtuin members’ expression in case of kidney damage. Among Sirtuin family, Sirtuin 6 was maximally preserved in injured kidney in female mice, suggesting its important role involved in the gender differences of AKI pathogenesis. We then found that knockdown of androgen receptor (AR) attenuated tubular damage, mitochondrial dysfunction and retarded the loss of renal function. Overexpression of Sirtuin 6 also showed similar results. Furthermore, in cultured tubular cells, dihydrotestosterone (DHT) decreased Sirtuin 6 expression and exacerbated cell apoptosis. Ectopic expression of Sirtuin 6 sufficiently inhibited DHT-induced cell apoptosis. Mechanically, we found AR inhibited Sirtuin 6, leading to the repression of binding of Sirtuin 6 with PGC-1α. This resulted in acetylation of PGC-1α and inhibition of its activity, further triggered the loss of mitochondrial homeostasis. Our results provided new insights to the underlying mechanisms of gender differences in AKI, suggesting Sirtuin 6 maybe a new therapeutic target for preventing AKI in male patients.

Cervical cancer (CC) is one of the most prevalent malignancies among females. Cytoprotective autophagy could confer cancer cell tolerance to hypoxic stress, promoting cell survival and adaptation. Aspartyl-tRNA synthetase 1 antisense 1 (DARS-AS1) is an oncogenic long non-coding RNA (lncRNA) in various cancers, but how DARS-AS1 regulates cytoprotective autophagy in hypoxic environment in CC remains unclear. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted to explore the interaction between hypoxia-inducible factor 1 subunit alpha (HIF1α) and DARS-AS1 promoter. Methylated RNA immunoprecipitation (MeRIP) followed by quantitative real-time polymerase-chain reaction (RT-qPCR) detected methylated RNA level. The process of autophagic maturation was monitored by immunofluorescence staining. Higher DARS-AS1 expression was found in CC tissues and cytoprotective. We also uncovered that hypoxic exposure induced cytoprotective autophagy via HIF1α/DARS-AS1/DARS axis. Moreover, DARS-AS1 was validated to facilitate DARS translation via recruiting N6-adenosine-methyltransferase methyltransferase like 3 (METTL3) and methyltransferase like 14 (METTL14), which bound with DARS mRNA DARS mRNA 5’ untranslated region (5ʹUTR) and promoting its translation. The present study demonstrated that the ‘HIF1α/DARS-AS1/DARS/ATG5/ATG3’ pathway regulated the hypoxia-induced cytoprotective autophagy of CC and might be a promising target of therapeutic strategies for patients afflicted with CC.

Abstract Background Genome-wide association studies (GWAS) have identified some variants associated with subclinical atherosclerosis (SCA) in general population but lacking sufficient validation. Besides traditional risk factors, whether and how would genetic variants associate with SCA among people with HIV (PWH) remains to be elucidated. Method A large original GWAS and gene-environment interaction analysis of SCA were conducted among Chinese PWH (n = 2850) and age/sex-matched HIV-negative controls (n = 5410). Subgroup analyses by age and functional annotations of variants were also performed. Results Different from HIV-negative counterparts, host genome had a greater impact on young PWH rather than the elders: one genome-wide significant variant (rs77741796, P = 2.20 × 10−9) and eight suggestively significant variants (P

Abstract Acute kidney injury (AKI) is in high prevalence in the world. However, the therapeutic strategies for AKI are still in mystery. Studies have shown to improve autophagy and lysosomal function could inhibit AKI. But their modulators need to be explored in detail. Annexin A2 (ANXA2) is a phospholipid-binding protein involving in organelle membrane integrity function, suggesting its important role in autophagy and lysosome homeostasis. It implicates ANXA2 potentially protects against AKI. However, this has not been elucidated. Herein, we found that ANXA2 is increased in renal tubules in cisplatin-induced AKI mice. Ectopic expression of ANXA2 improved lysosomal functions and enhanced autophagic flux, further protecting against renal tubular cell apoptosis and kidney injury. Conversely, knockdown of ANXA2 inhibited lysosomal function and autophagy, which aggravated the progression of AKI. Transcriptome sequencing revealed β-catenin signaling is highly responsible for this process. In vitro, we found ANXA2 induced β-catenin activation, further triggering T-cell factor-4 (TCF4)-induced transcription factor EB (TFEB). Furthermore, TFEB promoted lysosome biogenesis to enhance autophagic flux, resulting in the alleviation of AKI. Our new findings underline ANXA2 is a new therapeutic potential for AKI through modulating autophagy and lysosomal function. The underlying mechanism is associated with its inductive effects on β-catenin/TFEB pathway.

Intranasal administration is a promising strategy to enhance the delivery of the sEVsomes-based drug delivery system to the central nervous system (CNS). This study aimed to explore central distributive characteristics of mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) and underlying pathways. Here, we observed that intranasal MSC-sEVs were rapidly distributed to various brain regions, especially in the subcortex distant from the olfactory bulb, and were absorbed by multiple cells residing in these regions. We captured earlier transportation of intranasal MSC-sEVs into the perivascular space and found an increase in cerebrospinal fluid influx after intranasal administration, particularly in subcortical structures of anterior brain regions where intranasal sEVs were distributed more significantly. These results suggest that the perivascular pathway may underlie the rapid and widespread central delivery kinetics of intranasal MSC-sEVs and support the potential of the intranasal route to deliver MSC-sEVs to the brain for CNS therapy.

Objective: Females are more vulnerable to renal impairment (RI) in people living with HIV (PLWH), but few studies have examined sex disparity in the association of HIV serostatus with RI. Methods: In total, 2,101 PLWH on antiretroviral treatment (ART) and 4,202 HIV-negative people were selected and frequency matched in 1:2 ratio by sex and age categories. RI was defined as estimated glomerular filtration rate (eGFR)

Abstract Objectives This study aims to investigate the association between CD4+ T cell count and combined antiretroviral therapy (cART) with the prevalence of anal human papillomavirus (HPV) infection among HIV-positive male cohort in China. Methods A survey was conducted in men from a HIV cohort in Taizhou, China between 2016 and 2019. A face-to-face questionnaire interview was administered, and an anal-canal swab was collected for HPV genotyping. Results A total of 766 HIV-positive men were recruited. The HPV prevalence was lower among those with increased CD4+ T cell count than those with decreased or unchanged (46.5 vs. 56.6%, p = 0.033) from baseline. In multivariable models, having the current CD4+ T cell count of 350–499 cells/µL (aOR 0.28, 95% CI 0.13–0.64), and of ≥ 500 cells/µL (aOR 0.26, 95% CI 0.11–0.60) were associated with lower prevalence of any type HPV infection compared with those with

Chiral BIC can reach ultrahigh quality factors (Q-factor) based on its asymmetry, with broken mirror symmetries and in-plane inversion. Only by in-plane structural perturbation can chiral quasi-BIC (q-BIC) appear, so it is much more realizable and reasonable for the manufacturers in practical productions and fabrications considering the technology and means that are available. In this paper, we design a new dielectric metasurface employing H-shaped silica meta-atoms in the lattice, which is symmetrical in structure, obtaining chiral BIC with ultrahigh Q-factor (exceeding 105). In this process, we change the length of the limbs of the structure to observe the specific BICs. Previous scholars have focused on near-infrared-wavelength bands, while we concentrate on the terahertz wavelength band (0.8–1 THz). We found that there is more than one BIC, thus realizing multiple BICs in the same structure; all of them exhibit excellent circular dichroism (CD) (the maximum value of CD is up to 0.8127) for reflectance and transmittance, which provides significant and unique guidance for the design of multi-sensors. Meanwhile, we performed temperature sensing with chiral BIC; the sensitivity for temperature sensing can reach 13.5 nm/°C, which exhibits high accuracy in measuring temperature. As a consequence, the result proposed in this study will make some contributions to advanced optical imaging, chiral sensors with high frequency and spectral resolution, optical monitoring of environmental water quality, multiple sensors, temperature sensing, biosensing, substance inspection and ambient monitoring and other relevant optical applications.

Bound state in the continuum (BIC), as a novel eigenmode with infinitely high-quality factor, has received great attention in modern optical science. Mode coupling in dielectric metasurfaces opens possibilities in searching for robust BICs. Here, we discover multiple BICs in periodic dielectric resonators composed of a silicon rectangular bar and a silicon ring in one lattice. For the symmetry-protected BIC at-Γ point, a sharp electromagnetically induced transparency window can be formed by either tilting incident angle to induce the ‘bright-bright’ mode coupling, or by displacing the ring to generate the ‘bright-dark’ mode coupling. Besides, the coupling between two resonators leads to a new energy band in the dielectric metasurface. As a result, two off-Γ BICs are formed owing to avoided crossings with two energy bands, and another one belongs to the single-resonance parametric BIC. Thus, our coupled resonators possess superior abilities to judiciously engineer BICs via versatile physical mechanisms. Taking advantage exclusively of coupled resonators in dielectric metasurfaces provides fresh insights into the creation of both symmetry-protected and accidental BICs, which enables profound advancements in designing novel photonic devices.

ObjectiveThe diagnosis of prostate cancer has been a challenging task. Compared with traditional diagnosis methods, the radiofrequency (RF) signal is not only non-invasive but also rich in microscopic lesion information. This paper proposes a novel and accurate method for detecting prostate cancer based on the ultrasound RF signal.MethodOur approach is based on low-dimensional features in the frequency domain and high-throughput features in the spatial domain. The whole process could be divided into two parts: first, we calculate three feature maps from the ultrasound original RF signal, and 1,050 radiomics features are extracted from the three feature maps; second, we extracted 37 spectral features from the normalized frequency spectrum after Fourier transform.ResultsWe use LASSO regression as the method for feature selection; moreover, we use support vector machine (SVM) for classification 10-fold cross-validation for examining the classification performance of the SVM. An AUC (area under the receiver operating characteristic curve) of 0.84 was obtained on 71 subjects.ConclusionsOur method is feasible to detect prostate cancer based on the ultrasound RF signal with superior classification performance.

Introduction Payments for Ecosystem Services (PES) programs have been implemented globally to protect ecosystems while securing the well-being of affected people. Reasonable payment standards are key to successful PES programs. Although some approaches are available for determining payment standards, few studies have applied them for grassland conservation with location indicators and socioeconomic contexts properly considered.Methods Using China’s first pilot Grassland Ecological Compensation Policy (GECP) as an example, we analyzed the effects of payment levels, other natural and socioeconomic factors on herders’ willingness to participate in the GECP in Damao County in Inner Mongolia where grassland degradation is happening at an alarming rate due to overgrazing and cropland expansion.Outcomes Our results show that households with lower herding income, older age, higher education, larger grassland areas, and worse social relationships are more inclined to participate in the GECP. Conservation payment level, as well as natural and socioeconomic contextual factors, significantly affect the response of herdsmen, and a reasonable grassland payment standard with a 95% policy compliance rate should be 8.8 yuan mu−1.Discussion and Conclusion Our findings can inform governments to develop effective PES programs to balance the need of human well-being improvement and grassland conservation in China and beyond.

Abstract Streptococcus pneumoniae (S. pneumoniae) is a leading agent worldwide, which could cause community-acquired pneumonia, bacteraemia, and meningitis. However, the pathogeneses remain unclear. This study was conducted to investigate gene pneumococcal surface antigen A (psaA) expression and the adhesion differences of various S. pneumoniae strains. A total of 24 (N) S. pneumoniae strains were collected: 11 from blood (bd-SP), 12 from sputum (sd-SP) and one was ATCC49619. One millilitre of A549 pneumocytes (3.3×108/L) and 100 µl of each S. pneumoniae strain at 1.0 McFarland were mixed and incubated under 37 °C and 5% CO2 for three hours. The cells were centrifuged and extracted for psaA mRNA analysis. The former experiment was redone. After culture, the adherent cells were collected and cultured on blood agar plates. The ?CT values of psaA were 18.9, 29.9 (±2.5), 29.6 (±2.0) and 16.0, 17.0(±3.3), 18.6(±3.8) for ATCC49619, bd-SP and sd-SP before and after stimulation respectively, with the colony units of 23, 68.4 (±6.7) and 59.1 (±7.7), which showed equal adhesion between bd-SP and sd-SP. Moderate psaA expression and adhesion of S. pneumoniae might facilitate its pathogenesis, excess of which induces faster S. pneumoniae clearance. Key Words: Streptococcus pneumoniae; Alveolar epithelial cells; Virulence; Adhesion; pneumonia. Continuous...

Renal fibrosis is a common feature of various chronic kidney diseases (CKD). However, its underlying mechanism has not been totally clarified. C-X-C motif chemokine receptor (CXCR) family plays a role in renal fibrosis, however, detailed mechanisms have not been elucidated. Here, we report that CXCR2 has a potential role in tubular cell senescence and renal fibrosis, and is associated with β-catenin-activated mitochondrial dysfunction. CXCR2 is one of most increased members among CXCR family in unilateral ureteral obstruction (UUO) mice. CXCR2 was expressed primarily in tubules and co-localized with p16INK4A, a cellular senescence marker, and β-catenin. Administration of SB225002, a selective CXCR2 antagonist, significantly inhibited the activation of β-catenin signaling, restored mitochondrial function, protected against tubular cell senescence and renal fibrosis in unilateral ureteral obstruction (UUO) mice. In unilateral ischemia-reperfusion injury (UIRI) mice, treatment with interlukin-8 (IL-8), the ligand of CXCR2, further aggravated β-catenin activation, mitochondrial dysfunction, tubular cell senescence and renal fibrosis, whereas knockdown of p16INK4A inhibited IL-8-induced these effects. In vitro, SB225002 inhibited mitochondrial dysfunction and tubular cell senescence. Furthermore, ICG-001, a β-catenin signaling blocker, significantly retarded CXCR2-induced cellular senescence and fibrotic changes. These results suggest that CXCR2 promotes tubular cell senescence and renal fibrosis through inducing β-catenin-activated mitochondrial dysfunction.

Introduction: Acute kidney injury (AKI) is at a high prevalence in hospitalized patients, especially in those receiving chemotherapy. Cisplatin is the most widely used chemotherapy drug; however, with its side effects that include nephrotoxicity, it also exhibits a risk of inducing AKI. Importantly, recent studies have shown that autophagy plays a protective role in cisplatin-induced AKI. However, therapeutic strategies and candidate drugs for inducing activation of autophagy remain limited. Methods: In the present study, we adopted a novel candidate drug from a deep sea-derived Penicillium strain, penicilliumin B, to testify its protective role in cisplatin-induced renal tubular cell injury. Results: Penicilliumin B exhibited protection against cisplatin-induced apoptosis in cultured renal tubular epithelial cells and in cisplatin-treated mice. Moreover, penicilliumin B maintained normal mitochondrial morphology and inhibited the production of mitochondrial reactive oxygen species. Further studies demonstrated that penicilliumin B enhanced autophagic flux, promoted the activation of multiple autophagy-related proteins, such as mTOR, Beclin-1, ATG5, PINK1, and LC3B, and induced the degradation of p62. Interestingly, we also found penicilliumin B triggered phosphorylation of adenosine 5‘-monophosphate-activated protein kinase (AMPK), which is an upstream inducer of nearly all autophagy pathways and also an activator of mitochondrial biogenesis. These results suggest that AMPK may represent an activated site of penicilliumin B. Consistently, compound C, an AMPK inhibitor, significantly blocked the protective effects of penicilliumin B on mitochondria and apoptotic inhibition. Conclusion: Taken together, our findings indicate that penicilliumin B represents a novel AMPK activator that may provide protection against renal tubular cell apoptosis through activation of AMPK-induced autophagy and mitochondrial biogenesis.

Based on the ideas of modulation of multiple BICs, ultrahigh Q-factor resonance has been realized by array of planar metasurfaces with H-shaped nanoholes, perforated on a Si3N4 photonic crystal slab surrounded by a silica medium. Multiple BICs of both at Γ BICs and off Γ BICs are obtained. Two BICs at the Γ point show up in the lower band of the visible light, and they can be tuned by the center position and hole size of each part of the H-shaped, the refractive index of the surrounding medium, and the lattice constant. In detail, they move apart from each other or shift together with a fixed distance, with the structure parameters changing. On the other hand, the off Γ BICs behave only in the form of monotonously shifting. The at Γ BICs transform from BICs to quasi-BICs obviously with the broken symmetry of the H-shaped nanohole; however, its influence on off Γ BICs is insignificant. BICs in both types are ultra-sensitive to the surrounding medium, and the Q-factor of the BICs reaches a value more than 106. The results here are helpful in the design of photonic filters and sensors.

In this paper, based on MSC Simufact.Forming v16.0 simulation software, the process parameters in the multi-pass spinning production of deep cylinders with a large diameter–thickness ratio are optimized, and the ten-pass spinning process of a deep cylinder with a diameter of 500 mm, thickness of 2 mm and depth of 700 mm is realized. By controlling the four process parameters of mandrel speed, feed rate, spinning wheel fillet radius and spinning wheel angle of attack, the influence of the four process parameters on the spinning force and the wall thickness deviation of the formed workpiece is studied. The results show that the radial spinning force and tangential spinning force are at their minimum when the mandrel speed, feed rate, spinning wheel fillet radius and spinning wheel angle of attack are 500 rpm, 1 mm/rev, 6 mm and 35°, respectively. At these setup conditions, the spinning efficiency is the highest and the workpiece is not prone to defects. The wall thickness deviation of the workpiece will decrease with the increase in the mandrel speed; with the increase in the feed rate, the radius of the round corner and spinning wheel angle of attack, the wall thickness deviation increases first and then decreases.

Abstract Background Tetracentron sinense is an endemic and endangered deciduous tree. It belongs to the Trochodendrales, one of four early diverging lineages of eudicots known for having vesselless secondary wood. Sequencing and resequencing of the T. sinense genome will help us understand eudicot evolution, the genetic basis of tracheary element development, and the genetic diversity of this relict species. Results Here, we report a chromosome-scale assembly of the T. sinense genome. We assemble the 1.07 Gb genome sequence into 24 chromosomes and annotate 32,690 protein-coding genes. Phylogenomic analyses verify that the Trochodendrales and core eudicots are sister lineages and showed that two whole-genome duplications occurred in the Trochodendrales approximately 82 and 59 million years ago. Synteny analyses suggest that the γ event, resulting in paleohexaploidy, may have only happened in core eudicots. Interestingly, we find that vessel elements are present in T. sinense, which has two orthologs of AtVND7, the master regulator of vessel formation. T. sinense also has several key genes regulated by or regulating TsVND7.2 and their regulatory relationship resembles that in Arabidopsis thaliana. Resequencing and population genomics reveals high levels of genetic diversity of T. sinense and identifies four refugia in China. Conclusions The T. sinense genome provides a unique reference for inferring the early evolution of eudicots and the mechanisms underlying vessel element formation. Population genomics analysis of T. sinense reveals its genetic diversity and geographic structure with implications for conservation.

Aging is an important risk factor for kidney injury. Energy homeostasis plays a key role in retarding aging, and mitochondria are responsible for energy production. In the kidney, renal tubular cells possess high abundance of mitochondria to meet the high energy consumption. AMPK is an evolutionarily conserved serine/threonine kinase which plays a central role in maintaining energy homeostasis and mitochondrial homeostasis. Besides that, AMPK also commands autophagy, a clearing and recycling process to maintain cellular homeostasis. However, the effect of AMPK activators on kidney aging has not been fully elucidated. To this end, we testified the effects of O304, a novel direct AMPK activator, in naturally aging mice model and D-Galactose (D-Gal)-treated renal tubular cell culture. We identified that O304 beneficially protects against cellular senescence and aged-related fibrosis in kidneys. Also, O304 restored energy metabolism, promoted autophagy and preserved mitochondrial homeostasis. Transcriptomic sequencing also proved that O304 induced fatty acid metabolism, mitochondrial biogenesis and ATP process, and downregulated cell aging, DNA damage response and collagen organization. All these results suggest that O304 has a strong potential to retard aged kidney injury through regulating AMPK-induced multiple pathways. Our results provide an important therapeutic approach to delay kidney aging.

Abstract Tubular injury and peripheral fibroblast activation are the hallmarks of chronic kidney disease (CKD), suggesting intimate communication between the two types of cells. However, the underlying mechanisms remain to be determined. Exosomes play a role in shuttling proteins and other materials to recipient cells. In our study, we found that exosomes were aroused by β‐catenin in renal tubular cells. Osteopontin (OPN), especially its N‐terminal fragment (N‐OPN), was encapsulated in β‐catenin‐controlled tubular cell‐derived exosome cargo, and subsequently passed to fibroblasts. Through binding with CD44, exosomal OPN promoted fibroblast proliferation and activation. Gene deletion of β‐catenin in tubular cells (Ksp‐β‐catenin−/−) or gene ablation of CD44 (CD44−/−) greatly ameliorated renal fibrosis. Notably, N‐OPN was carried by exosome and secreted into the urine of patients with CKD, and negatively correlated with kidney function. The urinary exosomes from patients with CKD greatly accelerated renal fibrosis, which was blocked by CD44 deletion. These results suggest that exosome‐mediated activation of the OPN/CD44 axis plays a key role in renal fibrosis, which is controlled by β‐catenin.

The normal operation of natural gas gathering and transportation system is strongly affected by the liquid accumulation in pipelines, a common phenomenon in gas field development. Available prediction of liquid accumulation is helpful to take timely measures to reduce the harm caused thereby, and the calculation of critical gas velocity is crucial to the prediction of liquid accumulation in pipelines. The related research on prediction of critical gas velocity in pipeline was reviewed, and the limitations of minimum pressure drop model and droplet model were pointed out, with the liquid film model being provided with better applicability. Depending on the actual situation of pipeline liquid accumulation, the keys to apply the existing research achievements of pipeline liquid accumulation to production practice are as follows: selecting the pipeline liquid accumulation criteria suitable for different situations, reasonably characterizing the circumferential distribution of liquid film in pipelines at different slope angles, taking into consideration of the gas-liquid flow characteristics of large-size wet gas pipelines under complex terrain conditions, and adopting reasonable interface friction coefficient calculation formula.

Background: Norovirus (NoV) is recognized as a leading global cause of viral acute gastroenteritis (AGE). To better understand the prevalence and genotypic patterns of NoV infection in Southeast China, we conducted a retrospective study of diarrheal syndrome surveillance of NoV and analyzed the epidemiological characteristics of AGE cases and phylogenetic evolution of NoV strains. Methods: 1464 AGE patients in two diarrhea surveillance sentinel hospitals were sampled during 2016 and 2017. NoV Positive samples were genotyped by ORF1/ORF2 overlapping regional gene sequencing. Sequences analyses of the NoV genotypes were confirmed by online NoV Genotyping Tool and the phylogenetic analysis was constructed by MEGA 7.0. Results: 139 (9.49%) of the AGE specimens were NoV positive. The GII strain was the main geno-group in NoV infected patients. At least 12 NoV genotypes and seven recombinant strains were detected. Major NoV genotypic transformations were GII.Pe/GII.4, GII.P17/GII.17 and GII.Pe/GII.17 in 2016 to GII.P16/GII.2, GII.P17/GII.17 and GII.Pe/GII.4 in 2017. Phylogenetic analysis showed that GII.P16/GII.2 recombinant strains clustered with those detected in the USA, Russia and Japan in 2016. Conclusion: We characterized the molecular epidemiology of NoV infection in AGE patients during 2016–2017. The main three NoV GII genotypes circulating in the population of Taizhou were GII.P17/GII.17, GII.Pe/GII.4 and GII.P16/GII.2.The GII.P16/GII.2 genotype has become the predominant strain since first quarter 2017. Monitoring of the NoV genotypic shift is important for the prevention and control of AGE. Keywords: Molecular epidemiology, Norovirus, Acute gastroenteritis, Genotype

Neurocognitive impairment (NCI) and gut microbiota dysbiosis are prevalent in patients with HIV infection. Docosahexanoic acid (DHA) supplementation may alleviate multiple neurocognitive diseases symptoms and plays important role in regulating gut microbiota. However, it is not known whether DHA algae oil supplements can alleviate neurocognitive impairment (NCI) and regulate gut microbiota and fecal metabolites. A randomized, double-blind, placebo-controlled trial was performed on 68 HIV-infected patients with NCI. Participants were randomized to receive a 3.15 g daily DHA algae oil supplement or placebo for 6 months. We collected blood and fecal samples from these patients before and after the trial. Mini mental state examination (MMSE) and neuropsychological tests (NP tests) were administered to assess the cognitive status of participants. The influence of DHA algae oil on the gut microbiota, fecal metabolomics, plasma proinflammatory, and oxidative stress factors was also investigated. There were no significant changes in NCI according to global diagnosis score (GDS) and MMSE score within the two groups, while patients receiving DHA had improvement in several blood lipids, pro-inflammatory and oxidative stress factors. The DHA supplement increased α-diversity indexes, increased abundances of Blautia, Bifidobacterium, Dorea, Lactobacillus, Faecalibacterium, Fusobacterium, and Agathobacter, and decreased abundances of Bacteroides and Prevotella_9. Furthermore, DHA supplement was correlated with improved fecal lipid metabolites as indicated by ceramides, bile acids, glycerophospholipids. In addition, the DHA supplement was associated with altered cholesterol metabolism and purine metabolism pathways. A daily supplement of DHA algae oil for 6 months has been shown to promote favorable transformations in gut microbiota, profiles of fecal metabolomic, and factors responsible for proinflammatory and oxidative stress, which might be beneficial for the prognosis of HIV-infected patients with NCI in the long-term.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT04242004, identifier: NCT04242004.

BackgroundMitochondrial DNA (mtDNA) profiles and contributions of mtDNA variants to CD4+T-cell recovery in Euramerican people living with HIV (PLWH) may not be transferred to East-Asian PLWH, highlighting the need to consider more regional studies. We aimed to identify mtDNA characteristics and mutations that explain the variability of short-term CD4+T-cell recovery in East-Asian PLWH.MethodEight hundred fifty-six newly reported antiretroviral therapy (ART)-naïve Chinese PLWH from the Comparative HIV and Aging Research in Taizhou (CHART) cohort (Zhejiang Province, Eastern China) were enrolled. MtDNA was extracted from peripheral whole blood of those PLWH at HIV diagnosis, amplified, and sequenced using polymerase chain reaction and gene array. Characterization metrics such as mutational diversity and momentum were developed to delineate baseline mtDNA mutational patterns in ART-naïve PLWH. The associations between mtDNA genome-wide single nucleotide variants and CD4+T-cell recovery after short-term (within ~48 weeks) ART in 724 PLWH were examined using bootstrapping median regressions.ResultsOf 856 participants, 74.18% and 25.82% were male and female, respectively. The median age was 37 years; 94.51% were of the major Han ethnicity, and 69.04% and 28.62% were of the heterosexual and homosexual transmission, respectively. We identified 2,352 types of mtDNA mutations and mtDNA regions D-loop, ND5, CYB, or RNR1 with highest mutational diversity or volume. Female PLWH rather than male PLWH at the baseline showed remarkable age-related uptrends of momentum and mutational diversity as well as correlations between CD4+T C, m.1824T>C, m.3394T>C, m.4491G>A, m.7828A>G, m.9814T>C, m.10586G>A, m.12338T>C, m.13708G>A, and m.14308T>C (at the Bonferroni-corrected significance) were negatively associated with short-term CD4+T-cell recovery whereas m.93A>G, m.15218A>G, and m.16399A>G were positively associated with short-term CD4+T-cell recovery.ConclusionOur baseline mtDNA characterization stresses the attention to East-Asian female PLWH at risk of CD4+T-cell loss-related aging and noncommunicable chronic diseases. Furthermore, mtDNA variants identified in regression analyses account for heterogeneity in short-term CD4+T-cell recovery of East-Asian PLWH. These results may help individualize the East-Asian immune recovery strategies under complicated HIV management caused by CD4+T-cell loss.

Neurological diseases remain some of the major causes of death and disability in the world. Few types of drugs and insufficient delivery across the blood–brain barrier limit the treatment of neurological disorders. The past two decades have seen the rapid development of extracellular vesicle-based therapeutics in many fields. As the physiological and pathophysiological roles of extracellular vesicles are recognized in neurological diseases, they have become promising therapeutics and targets for therapeutic interventions. Moreover, advanced nanomedicine technologies have explored the potential of extracellular vesicles as drug delivery systems in neurological diseases. In this review, we discussed the preclinical strategies for extracellular vesicle-based therapeutics in neurological disorders and the struggles involved in their clinical application.

Gut microbiota dysbiosis has been associated with many neurological diseases. However, how microbiota composition and metabolism relate to neurocognitive impairment (NCI) in HIV-infected individuals is largely unknown. In this study, a total of 102 HIV infected participants were classified into two groups—those with NCI and those without—using the global deficit score (GDS). Fecal samples were collected from the participants for 16S rRNA gene sequencing and untargeted metabolomics. The plasma level of 25 hydroxy-vitamin D (25(OH)D) was also evaluated. Although α-diversity and β-diversity were comparable, the HIV patients with NCI were significantly different from those without NCI in terms of abundance of several gut microbiota. The decreased abundance of butyrate-producing bacteria (BPB) and increased abundance of Klebsiella were related with NCI and carotid intima-media thickness (CIMT). Significant differences in fecal metabolites were also found between individuals with versus without NCI, including increased bile acids and bioactive lipids, decreased vitamin D, terpenoids, and resolvin D1 in the NCI group. Furthermore, the perturbed metabolic profile was closely related to BPB and Klebsiella. In addition, a low level of vitamin D was associated with NCI and CIMT. Both fecal and plasma vitamin D were positively correlated with BPB. Our results show that BPB and Klebsiella and the associated metabolites are associated with NCI in people with HIV. In addition, vitamin D, both in feces and blood, was associated with NCI and BPB, suggesting a protective effect of vitamin D on NCI.

Background: HIV infection and normal aging share immune and inflammatory changes that result in premature aging and non-communicable diseases (NCDs), but the exact pathophysiology is not yet uncovered. We identified the common metabolic pathways underlying various NCDs in treated HIV infection. Methods: We performed untargeted metabolomics including 87 HIV-negative (–) normal controls (NCs), 87 HIV-positive (+) NCs, and 148 HIV+ subjects with only one type of NCDs, namely, subclinical carotid atherosclerosis, neurocognitive impairment (NCI), liver fibrosis (LF) and renal impairment. All HIV+ subjects were virally suppressed. Results: HIV+ patients presented widespread alterations in cellular metabolism compared to HIV– NCs. Glycerophospholipid (GPL) metabolism was the only one disturbed pathway presented in comparisons including HIV– NCs across age groups, HIV+ NCs across age groups, HIV+ NCs vs HIV– NCs and each of HIV+ NCDs vs HIV+ NCs. D-glutamine and D-glutamate metabolism and alanine-aspartate-glutamate metabolism were presented in comparisons between HIV+ NCs vs HIV– NCs, HIV+ LF or HIV+ NCI vs HIV+ NCs. Consistently, subsequent analysis identified a metabolomic fingerprint specific for HIV+ NCDs, containing 42 metabolites whose relative abundance showed either an upward (mainly GPL-derived lipid mediators) or a downward trend (mainly plasmalogen phosphatidylcholines, plasmalogen phosphatidylethanolamines, and glutamine) from HIV– NCs to HIV+ NCs and then HIV+ NCDs, reflecting a trend of increased oxidative stress. Interpretation: GPL metabolism emerges as the common metabolic disturbance linking HIV to NCDs, followed by glutamine and glutamate metabolism. Together, our data point to the aforementioned metabolisms and related metabolites as potential key targets in studying pathophysiology of NCDs in HIV infection and developing therapeutic interventions. Funding: China National Science and Technology Major Projects on Infectious Diseases, National Natural Science Foundation of China, Yi-wu Institute of Fudan University, and Shanghai Municipal Health and Family Planning Commission.

Abstract Background The treatment for unstable intertrochanteric fractures in the elderly has always been a controversial issue. The aim in this study was to compare the curative effects of proximal femoral nail anti-rotation (PFNA) and cementless bipolar hemiarthroplasty (CPH) on femoral intertrochanteric fracture in the elderly. Methods From March 2008 to December 2012, 108 elderly patients with femoral intertrochanteric fractures were treated by PFNA or CPH. There were 63 males and 45 females, aged 75.3–99.1 years [(83.7 ± 5.6) years]. The patients’ bone mineral density was routinely measured, and the fractures were classified according to Evans-Jensen. The patients were divided into CPH group and PFNA group. The differences in operation time, intraoperative bleeding, immobilization duration, hospitalization time, Harris scores and postoperative complications including deep venous thrombosis, lung and urinary infection were analyzed. Results All patients were followed for 12.5–36.2 months [(28.0 ± 6.3) months)]. The operation time was (53.7 ± 15.2) min and (77.5 ± 16.8) min in PFNA group and CPH group, respectively (P 0.05); and the Harris scores after 1 year were (87.7 ± 7.9) points and (88.3 ± 9.2) points, respectively (P > 0.05). There was no significant difference in postoperative complications between the two groups (P > 0.05). Conclusion Both PFNA and CPH are safe and effective treatments for femoral intertrochanteric fracture in elderly patients. Nonetheless, CPH allows faster mobilization and recovery. Trial registration Registration Number: ChiCTR1900022846. Reg Date:2019-04-26 00:27:33 Retrospective registration

Bound state in the continuum (BIC) as a novel non-radiating state of light in the continuum of propagating modes has received great attention in photonics. Recently, chiral BICs have been introduced in the terahertz regime. However, strong chiroptical effects of transmitted waves remain challenging to achieve in metallic terahertz metasurfaces, especially for intrinsic chirality at normal incidences. Here, we propose a chiral quasi-BIC by simultaneously breaking the out-of-plane mirror and in-plane C2 rotation symmetries in a bilayer metallic metasurface, in which spin-selective terahertz transmittance is successfully realized. Benefiting from the symmetry-protected nature of our proposed BIC, precise tuning of structural parameters can lead to anticipated chiroptical performance. As a degree of freedom, the rotation angle of the split ring gaps can fully determine the handedness, linewidth, and working frequency with strong circular dichroism. Besides, the sensing performance shows a surrounding refractive index sensitivity of 200 GHz/RIU, which is similar to those of previous works based on terahertz metasurfaces. Taking advantage exclusively of symmetry-protected BICs to realize transmitted terahertz chiroptical response provides fresh insights into the creation of novel BICs, which enables profound advancements in the surging field of novel terahertz devices.

White matter lesions (WMLs) are a type of cerebrovascular disorder accompanied by demyelination and cognitive decline. Dl-3-n-butylphthalide (D1-NBP) is a neuroprotective drug used for the treatment of ischemic cerebrovascular diseases, although the function of DI-NBP on WML is still not clear. This study aims to investigate whether DI-NBP affects cognitive function and ameliorates demyelination in a model of WML. The bilateral carotid artery stenosis (BCAS) mouse model and in vitro brain slice cultures with low glucose and low oxygen (LGLO) treatment were adopted. The Dl-NBP was administered intragastrically for 28 days after BCAS or added at a dose of 50 μm for 48 h after LGLO. Spatial learning and memory were evaluated by an eight-arm radial maze. Demyelination was detected using a TEM. Mitochondrial dynamics were assessed by time-lapse imaging in the cultured brain slices. The function of the synapse was evaluated by the patch clamp technique. In BCAS mice, obvious demyelination and cognitive decline were observed, while both were significantly relieved by a high-dose D1-NBP treatment (100 mg/kg). Along with demyelination, mitochondrial accumulation in the axons was significantly increased in the BCAS mice model, but with the treatment of a high-dose D1-NBP, mitochondrial accumulation was mitigated, and the anterograde/retrograde transport of mitochondria was increased. Following the improved anterograde/retrograde transport of mitochondria, the synapse activity was significantly upregulated while the reactive oxygen species (ROS) generation was remarkably decreased in the cultured brain slices. In addition, we identified syntaphilin (SNPH) as the downstream target of D1-NBP. The overexpression of SNPH mediated the effects of D1-NBP in mitigating axonal mitochondrial accumulation. In conclusion, the D1-NBP treatment significantly relieved demyelination and improved spatial learning and memory in the WML model by promoting mitochondrial dynamics. These neuroprotective effects of D1-NBP were mediated by inhibiting the mitochondrial arching protein, SNPH, which provided a potential therapeutic target for WML.

Abstract Chronic kidney disease (CKD) has a high prevalence worldwide and is an intricate issue to whole medical society. Renal fibrosis is the common pathological feature for various kinds of CKD. As an anti‐aging protein, Klotho is predominantly expressed in renal tubular epithelial cells. Reports show Klotho could retard age‐related renal fibrosis. Mitochondrial dysfunction plays an important role in cellular senescence. However, the role of Klotho in mitochondrial dysfunction in CKD has not yet been determined. In this study, we treated unilateral ischemia‐reperfusion (UIRI) mice and cultured human renal tubular epithelial cells (HKC‐8) with Klotho. We assessed renal fibrosis, cellular senescence, and Wnt/β‐catenin signaling. We also focused on mitochondrial function assessment. In UIRI mice, ectopic expression of Klotho greatly retarded fibrotic lesions and the activation of Wnt/β‐catenin signaling. Interestingly, Klotho significantly preserved mitochondrial mass, inhibited mitochondrial reactive oxygen species (ROS) production and restored the expression of mitochondrial respiration chain complex subunits. Consequently, Klotho restrained cellular senescence. In HKC‐8 cells, Klotho significantly inhibited Wnt1‐ and Wnt9a‐induced mitochondrial injury, cellular senescence, and fibrotic lesions. These results suggest Klotho has a protective role in renal function through targeted protection on mitochondria. This further broads the understanding of the beneficial efficacies of Klotho in CKD.

Infectious bursal disease virus (IBDV) is one of the most important infectious diseases of poultry around the world. Gut-associated lymphoid tissues (GALT) are the first line of defense of the host against the infection. The purpose of this study was to investigate the role of innate immune antiviral signaling triggered by Toll-like receptor 3 (TLR3), as well as macrophage activation and cytokine response in the intestinal lamina propria (ILP) cells after the oral challenge of IBDV in relation to IBDV virulence and disease pathogenesis. The results showed that the expression levels of TLR3, IRF7, IFN-α/β and the corresponding downstream antiviral factors OAS, PKR and Mx were all upregulated in the SPF chicken ILP cells at 8 h post-infection (hpi) and 12 hpi. Similarly, macrophages were activated, with the initial macrophage M1 activation observed at 8 hpi, but then it rapidly shifted to a non-protective M2-type. Both Th1 (IFN-γ, TNF-α, IL-12) and Th2 (IL-4 and IL-10) types of cytokines were differentially upregulated during the early stage of infection; however, the Th1 cytokines exhibited stronger activation before 8 hpi compared to those of the Th2 cytokines. Interestingly, differential regulations of gene expression induced by different IBDV strains with different virulence were detected. The HLJ0504-like very virulent (vv) IBDV strain NN1172 induced stronger activation of TLR3-IFN-α/β pathway, macrophages and the Th1/2 cytokines’ expression, compared to those induced by the attenuated strain B87 at 8 hpi and 12 hpi in the ILP cells. In conclusion, the innate antiviral response mediated by the TLR3-IRF7 pathway, macrophage activation and cytokine expression in the GALT cells at the early stage of IBDV infection was differentially modulated, and the HLJ0504-like vvIBDV strain triggered stronger activation than the attenuated vaccine strain, and that may play an important role in the progression of disease.

Abstract Polycystic ovary syndrome (PCOS) is closely related with the onset and development of metabolic abnormalities. However, the correlation between PCOS and kidney injury has not been clarified, and the underlying mechanism remains unknown. Herein, we performed a prospective survey in 55 PCOS and 69 healthy participants. Furthermore, the correlation analyses between serum testosterone and renal functional manifestations of patients and healthy subjects, including urinary albumin to creatinine ratio (UACR), urinary κ‐light chains (KapU), urinary λ‐light chains (LamU), urinary α1‐microglobulin (α1‐MU), and urinary β2‐microglobulin (β2‐MU), were analyzed. Compared with that in normal subjects, the levels of serum testosterone and UACR were significantly higher in PCOS patients. Serum testosterone is significantly correlated with the disease severity of PCOS. Although urinary excretions of KapU, LamU, α1‐MU, and β2‐MU did not increase in PCOS patients, they had a significantly positive correlation with the extent of serum testosterone in PCOS patients. IN vitro, primary cultured human ovary granulosa cells (GCs) were isolated from the follicular fluid (FF) extracting from PCOS patients and controls. FF, especially which extracted from PCOS patients with a high expression of serum testosterone, significantly induced cell apoptosis and inflammation in human GCs. To examine the communication between PCOS and kidney injury, a human proximal tubular epithelial cell line (HKC‐8) was cultured and administered FF. Interestingly, FF from PCOS patients with a higher level of serum testosterone induced fibrotic lesions in HKC‐8 cells. These data suggest serum testosterone plays a critical role in PCOS and PCOS‐associated kidney injury. Serum testosterone may serve as a promising indicator for kidney fibrotic injury outcomes in PCOS patients.

A quantitative method for clopidogrel using online-SPE tandem LC–MS/MS was developed and fully validated according to the well-established FDA guidelines. The method achieves adequate sensitivity for pharmacokinetic studies, with lower limit of quantifications (LLOQs) as low as 10 pg/mL. Chromatographic separations were performed on reversed phase columns Kromasil Eternity-2.5-C18-UHPLC for both methods. Positive electrospray ionization in multiple reaction monitoring (MRM) mode was employed for signal detection and a deuterated analogue (clopidogrel-d4) was used as internal standard (IS). Adjustments in sample preparation, including introduction of an online-SPE system proved to be the most effective method to solve the analyte back-conversion in clinical samples. Pooled clinical samples (two levels) were prepared and successfully used as real-sample quality control (QC) in the validation of back-conversion testing under different conditions. The result showed that the real samples were stable in room temperature for 24 h. Linearity, precision, extraction recovery, matrix effect on spiked QC samples and stability tests on both spiked QCs and real sample QCs stored in different conditions met the acceptance criteria. This online-SPE method was successfully applied to a bioequivalence study of 75 mg single dose clopidogrel tablets in 48 healthy male subjects.

With the development of radio frequency identification technology, radio frequency identification system has been deployed in different applications in a large scale. It needs a densely deployed reader environment to cover the work area, especially in radio frequency identification logistics and warehousing applications. If the distribution area and the number of readers are not optimized, and some of them will be redundant, which will reduce the efficiency of the whole radio frequency identification system. Researchers have proposed many algorithms and optimization techniques to solve the problem of redundant readers. In this paper, the authors propose a novel redundant reader elimination algorithm, namely, L-NCD, in P2P-RFID reader network, combined with layered eliminate optimization and neighboring coverage density. The simulation results demonstrate that the proposed algorithm eliminates more redundant readers than the other methods such as redundant-reader elimination under the same conditions.

Bone is the third most common site of cancer metastasis. In total, 30%–40% of lung cancer cases can develop skeletal metastasis for which no effective therapy in clinic is available. RCAN1 (regulator of calcineurin 1) is an important regulator in angiogenesis which is vital to tumor growth. In this study, we investigated the changes of biological behaviors in SBC-5 and SBC-3 cells after the RCAN1 expression level was changed. Briefly, overexpression of RCAN1 significantly attenuated their malignancy, including decreased ability of proliferation, colony formation, migration, invasion, and bone adherence. Furthermore, the cell cycle progression was impeded. Although the opposite changes were observed in SBC-3 cells after the RCAN1 expression was suppressed by RNA interference, the apoptosis rate was not affected by the expression level of RCAN1 in these cells. So, our research revealed that RCAN1 was involved in the development of small cell lung cancer, and it might be a cancer-inhibiting gene for the formation of bone metastases in small cell lung cancer.

GPS have been able to offer a commercially available outdoor positioning services; however, since the quality of satellite signals declines after entering into the indoor environment, the GPS system cannot provide indoor positioning services. With the development of cloud computing and the Internet of Things technology, indoor positioning has become a hot research hotspot. Radio Frequency Identification is a wireless communication technology, and the Radio Frequency Identification reader can communicate wirelessly through electromagnetic waves with the tag. Radio Frequency Identification technology has the following advantages: no contact, recognition from the long distance, long life and fast moving objects identification, etc. Radio Frequency Identification is the key component of Internet of Things, and many fusion application systems combining Radio Frequency Identification and cloud computing are emerging. This article designs and implements the Radio Frequency Identification indoor positioning system based on Received Signal Strength Indicator, which obtains three-dimensional coordinates orientation through multiple trilateral positioning algorithm on location tag. C# and Python are used to complete positioning system, where C# dominates user interface and calculates three-dimensional coordinates. Python is responsible for three-dimensional display. The two programs communicate through a socket.

Arguably, liberal democratic societies are seeing the emergence of a ‘Fifth Estate’ that is being enabled by the Internet. This new organizational form is comparable to, but potentially more powerful than, the Fourth Estate, which developed as a significant force in an earlier period with an independent press and other mass media. While the significance of the press and the Internet to democratic governance is questioned in all societies, there is particular skepticism of their relevance outside the most liberal democratic regimes, which have a relatively free press and more pluralistic political systems, such as in North America and West Europe. Nevertheless, there have been vivid examples of where networked individuals have appeared to assert greater communicative power in the politics of governance, the media and everyday life, even in non-liberal democratic regimes, such as Hong Kong, and in some cases, China. This potential points to the need for more systematic empirical research in a wider variety of economic and political settings worldwide, particularly in states in which the Internet might offer a potential for more democratic governance and greater accountability of government controlled media. This paper examines cases in which networked individuals in China used the Internet to hold governmental and press institutions more accountable. The cases provide support for the relevance of the Fifth Estate concept in China, and also illuminates the process – showing how the Internet can be used to empower networked individuals in more autocratic regimes.

To examine homosexual and heterosexual behaviors, behavioral networks and HIV infection among men who have sex with men (MSM) in Eastern China.A cross-sectional survey was conducted among MSM in 2013 in a rural prefecture of Zhejiang province. Participants were interviewed for their sexual behaviors and sexual networks and were tested for HIV infection.A total of 620 MSM from gay bath houses and bars participated in the survey. Of them, 58.2% aged 18 to 39 years and 49.5% were currently married with a female. The age of first homosexual contact was 26.7 years on average, ranging from 12 to 66 years. 91.0% had multiple male sex partners and 86.1% also had female sex partners in lifetime. 70 (11.3%) of the participants were tested HIV-positive. A total of 620 independent egocentric sexual networks involving 620 study participants and 1,971 reported sexual partners in the past 12 months were constructed, including 70 networks for the 70 HIV-positive participants with their 221 sexual partners and 550 networks for the 550 HIV-negative participants with their 1,750 sexual partners. The median network degree was 3 (IQR 2-4) overall and was not different between HIV-positive participants (Median: 3; IQR: 2-4) and HIV-negative participants (Median: 3; IQR: 2-4) (Mann-Whitney test, Z=-0.015, P=0.998). The proportion of networks with a multiple male sexual partnership was 63.7% overall, 62.8% for HIV-positive participants and 63.8% for HIV-negative participants (χ2=0.025, P=0.875). The proportion of networks with both male and female sexual partners was 44.8% overall, 47.1% for HIV-positive participants and 44.5% for HIV-negative participants (χ2=0.169, P=0.681). Consistent condom use and knowledge of HIV infection status were rare within the network partners.The currently high HIV prevalence and complicated bisexual networks among MSM in the study area provides enhanced evidence for developing tailored prevention strategies for HIV transmission among and beyond the MSM population.