Increased expression of TIGIT and KLRG1 correlates with impaired CD56bright NK cell immunity in HPV16-related cervical intraepithelial neoplasia.

BACKGROUND: The onset and progression of cervical intraepithelial neoplasia (CIN) are closely associated with the persistent infection of high-risk HPV (especially type16), which is mainly caused by immune escape. Natural killer (NK) cells play an important role against virally infected cells and tumor cells through a fine balance of signals from multiple surface receptors. Overexpression of non-MHC-I specific inhibitory receptors TIGIT, KLRG1, Siglec-7, LAIR-1, and CD300a on NK cells correlates with cellular exhaustion and immune evasion, but these receptors have not been investigated in CIN. The aim of the present study was to examine the potential role of NK cell non-MHC-I specific inhibitory receptors expression in immune escape from HPV16(+)CIN patients. METHODS: The subset distribution, IFN-γ and TNF-α expression levels and immunophenotype of TIGIT, KLRG1, Siglec-7, LAIR-1, and CD300a of NK cells were investigated in peripheral blood mononuclear cell samples by flow cytometry from 82 women who were HPV16(+) with CIN grades 0, I, II-III or HPV(-) CIN 0. Immunohistochemistry was applied to detect the expression of ligands for NK receptors in the cervical tissues. HPV types were identified by PCR assays. RESULTS: The HPV16(+) subjects with high-grade lesions had an increased number of circulating peripheral blood CD56bright NK cells with reduced functionality and IFN-γ secretion. The expression levels of the inhibitory molecules TIGIT and KLRG1 on CD56bright NK cells increased in parallel with increasing CIN grade. In addition, TIGIT and KLRG1 related ligands, Poliovirus receptor (PVR), N-Cadherin and E-Cadherin expression level was also elevated with increasing CIN grade. CONCLUSIONS: Our results suggest that up-regulation of the inhibitory TIGIT, KLRG1 and their ligands may negatively regulate cervical CD56bright NK-mediated immunity to HPV16 and contribute to the progression of CIN. These results may facilitate the development of early-warning immune predictors and therapeutic strategies for HPV16(+) CIN based on the TIGIT and KLRG1 inhibitory pathways of NK cells.

Quantum Coherence Witness with Untrusted Measurement Devices.

Coherence is a fundamental resource in quantum information processing, which can be certified by a coherence witness. Due to the imperfection of measurement devices, a conventional coherence witness may lead to fallacious results. We show that the conventional witness could mistake an incoherent state as a state with coherence due to the inaccurate settings of measurement bases. In order to make the witness result reliable, we propose a measurement-device-independent coherence witness scheme without any assumptions on the measurement settings. We introduce the decoy-state method to significantly increase the capability of recognizing states with coherence. Furthermore, we experimentally demonstrate the scheme in a time-bin encoding optical system.

Lack of bidirectional association between C-reactive protein and depressive symptoms in middle-aged and older adults: Results from a nationally representative prospective cohort study.

Depression is associated with low quality of life and increased health burdens for middle-aged and older adults in resource-limited settings. Although inflammation plays an etiological role in the development and progression of depression, the directionality of the inflammation-depression relationship is unclear, especially in non-Western populations. To examine this relationship among community-dwelling Chinese middle-aged and older adults, we obtained data from the 2011, 2013, and 2015 China Health and Retirement Longitudinal Study (CHARLS). The participants were aged 45 years or above at baseline in 2011 and completed the follow-up survey in 2013 and 2015. Depressive symptoms were measured using the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10), and the C-reactive protein (CRP) level was used to measure individual inflammation levels. Cross-lagged regression analyses examined the inflammation-depression relationship. Cross-group analyses were performed to test for model invariance across the sexes. Pearson's correlations revealed no concurrent correlations between depression and CRP for both 2011 and 2015 (ps > 0.05, ranging 0.07-0.36) studies. Cross-lagged regression path analyses revealed that the paths from baseline CRP to depression in 2013 (ßstd = -0.01, p = 0.80), from baseline CRP to depression in 2015 (ßstd = 0.02, p = 0.47), from baseline depression to CRP in 2015 (ßstd = -0.02, p = 0.40), and from depression at 2013 to CRP in 2015 (ßstd = 0.03, p = 0.31) were not statistically significant. Additionally, the autoregressive model did not vary across the sexes (△χ 2 = 78.75, df = 54, p = 0.02, △ comparative fit index (CFI) <0.01). We failed to find a bidirectional association between the CRP levels and depressive symptoms in our sample.

Electrostatic Adsorption of Dense AuNPs onto Silica Core as High-Performance SERS Tag for Sensitive Immunochromatographic Detection of Streptococcus pneumoniae.

Streptococcus pneumoniae (S. pneumoniae) is a prominent pathogen of bacterial pneumonia and its rapid and sensitive detection in complex biological samples remains a challenge. Here, we developed a simple but effective immunochromatographic assay (ICA) based on silica-Au core-satellite (SiO2@20Au) SERS tags to sensitively and quantitatively detect S. pneumoniae. The high-performance SiO2@20Au tags with superior stability and SERS activity were prepared by one-step electrostatic adsorption of dense 20 nm AuNPs onto 180 nm SiO2 core and introduced into the ICA method to ensure the high sensitivity and accuracy of the assay. The detection limit of the proposed SERS-ICA reached 46 cells/mL for S. pneumoniae and was 100-fold more sensitive than the traditional AuNPs-based colorimetric ICA method. Further, considering its good stability, specificity, reproducibility, and easy operation, the SiO2@20Au-SERS-ICA developed here has great potential to meet the demands of on-site and accurate detection of respiratory pathogens.

The ß-catenin/CBP signaling axis participates in sepsis-induced inflammatory lung injury.

Sepsis-induced inflammatory lung injury is a key factor causing failure of the lungs and other organs, as well as death, during sepsis. In the present study, a caecal ligation and puncture (CLP)-induced sepsis model was established to investigate the effect of ß-catenin on sepsis-induced inflammatory lung injury and the corresponding underlying mechanisms. C57BL/6 mice were randomly divided into five groups, namely, the sham, CLP, ß-catenin knockout (KO) + CLP, XAV-939 + CLP, and ICG-001 + CLP groups; the XAV-939 + CLP and ICG-001 + CLP groups were separately subjected to intraperitoneal injections of the ß-catenin inhibitors XAV-939 and ICG-001 for 1 week preoperatively and 2 days postoperatively, respectively. Forty-eight hours after CLP, we measured ß-catenin expression in lung tissues and evaluated mouse mortality, histopathological characteristics of hematoxylin and eosin (H&E)-stained lung tissues, serum cytokine (tumor necrosis factor [TNF]-α, interleukin [IL]-10, and IL-1ß) levels, lung myeloperoxidase (MPO) activity, and the number of apoptotic cells in the lung tissues. Our results indicated that both the inhibition of ß-catenin expression and blockage of ß-catenin/CREB-binding protein (CBP) interactions by ICG-001 effectively decreased mouse mortality, alleviated pathological lung injury, and reduced the serum TNF-α, IL-10, and IL-1ß levels, in addition to reducing the lung MPO activity and the number of apoptotic cells in lung tissues of the sepsis model mice. Therefore, it can be deduced that the ß-catenin/CBP signaling axis participates in regulating sepsis-induced inflammatory lung injury.

Effect of immunotherapy on the immune microenvironment in advanced recurrent cervical cancer.

This study evaluated the basic immune status of cervical cancer and the influences of immunotherapy on the immune microenvironment, and analyzed the correlation between changes in the immune microenvironment and prognosis. We retrospectively analyzed the treatment status of 8 patients with advanced recurrent cervical cancer treated with PD-1 inhibitors and detected the tumor-infiltrating immune markers (CD3, CD4, CD8, CD20, CD56, CD68, PD-1, and PD-L1) by immunohistochemistry. All patients showed good tolerance during the treatment. Complete response (CR), partial response (PR) and stable disease (SD) was observed in 3, 2, and 3 patients, respectively. Immunohistochemical analysis showed immunotherapy resulted in increased infiltration of T lymphocytes, natural killer cells, and B cells, especially among those who responded well. The expression of B cells in 4 of the 5 patients with clinical benefit was relatively high, and the expression of PD-L1 in these 5 patients showed a combined positive score > 3. PD-L1 expression increased significantly after treatment with PD-1 inhibitors. Second-generation sequencing showed that the tumor mutation burden of two patients with adenocarcinoma was high, and after immunotherapy, one case recurred after cure and the other remained stable. PR was also observed in squamous cell carcinoma patients with dMMR (p.R2165H/c.6494G > A) and PIK3CA (p.E545K(E9)) mutations. The expression of B cells and PD-L1 has certain predictive effect for the efficacy of immunotherapy in cervical cancer under the condition of high or low T cell infiltration, and can inform treatment decision-making for patients with advanced cervical cancer.

Sex- and size-dependent accumulation of Dechlorane Plus flame retardant in a wild frog-eating snake Amphiesma stolata.

Despite several studies having addressed the bioaccumulation of Dechlorane Plus (DP) flame retardant in wildlife, there is still a dearth of information for reptiles in general and for snakes in particular. Here, we report the residue levels and trophic transfer of syn-, anti-, and anti-Cl11-DP in a frog-eating snake-namely, the striped keelback snake Amphiesma stolata-from a DP hotspot in South China. The concentrations of syn-, anti-, and anti-Cl11-DP in A. stolata ranged from 1.06-21.2, 2.13-21.5, and 0.16-10.6 ng/g lipid weight, respectively, with significantly higher levels in males compared with females. Statistical analysis showed that the concentrations of these chemicals were negatively correlated with body sizes (length and mass) of the snake. The fractional abundance of anti-DP (fanti) did not significantly differ either between the sexes or between A. stolata and its diet (i.e., frogs). However, fanti showed positive correlations with the snake's body size and negative correlations with ∑DP concentrations (summed concentrations of syn- and anti-DP), indicating that body size and DP residue levels are important factors influencing DP isomeric profiles in these snakes. Biomagnification factors estimated based on the relationship between A. stolata and frogs were 0.49 ± 0.01 (mean ± SE), 0.44 ± 0.09, and 1.79 ± 0.54 for syn-, anti-, and anti-Cl11-DP, respectively, suggesting trophic dilution of syn- and anti-DP and a mild biomagnification of anti-Cl11-DP from frogs to snakes.

Bioaccumulation and maternal transfer of two understudied DDT metabolites in wild fish species.

While the secondary metabolites of DDT such as 2,2-bis(chlorophenyl)-1-chloroethylene (DDMU) and 2,2-bis(chlorophenyl)methane (DDM) have been detected in the environment for several decades, knowledge is extremely limited on their bioaccumulation characteristics. Here, we reported the bioaccumulation and maternal transfer of p,p'-DDMU and p,p'-DDM in two wild fishes, i.e., the northern snakehead (Channa argus) and crucian carp (Carassius auratus), from a DDT contaminated site in South China. The hepatic concentrations of p,p'-DDMU and p,p'-DDM in the fish were up to 549 and 893 ng/g lipid weight, contributing 5.3% and 3.2% in average to ΣDDXs (the sum concentrations of DDT and its 6 metabolites), respectively. The residues of p,p'-DDMU and p,p'-DDM in the fish exhibited interspecific and intraspecific variations, resulting from the differences in lipid content, sex, and body sizes (length and mass) between or within species. Both p,p'-DDMU and p,p'-DDM were consistently detected in the fish eggs, demonstrating their maternal transfer in female fish. The mean eggs to liver lipid-normalized concentration (E/L) ratios of p,p'-DDMU and p,p'-DDM were 0.98 and 1.77 in the northern snakehead, 0.35 and 0.01 in crucian carp, respectively; which were comparable to or even exceeded those of DDT and its major metabolites calculated in the same individual. Statistical analyses of the data showed that the E/L ratios were positively correlated with body sizes of the fish, but negatively correlated with the hepatic concentrations of p,p'-DDMU and p,p'-DDM in females; suggesting the influences of fish sizes and the mother body residues on their maternal transfer efficiencies.

UPLC-Q-TOF/MS-based plasma metabolome to identify biomarkers and time of injury in traumatic brain injured rats.

BACKGROUND: To identify the potent metabolic biomarkers and time of injury of traumatic brain injured (TBI). METHODS: A total of 70 Sprague-Dawley rats were used to establish the TBI model in this study. The serum was collected at 3 h, 6 h, 12 h, 24 h, 3 days and 7 days after surgery. Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was performed to analyze metabolic changes in the serum of the TBI rats from different groups. The differences between the metabolic profiles of the rats in seven groups were analyzed using partial least squares discriminant analysis. RESULTS: Metabolic profiling revealed significant differences between the sham-operated and other groups. A total of 49 potential TBI metabolite biomarkers were identified between the sham-operated group and the model groups at different time points. Among them, six metabolites (methionine sulfone, kynurenine, 3-hydroxyanthranilic acid, 3-Indolepropionic acid, citric acid and glycocholic acid) were identified as biomarkers of TBI to estimate the injury time. CONCLUSION: Using metabolomic analysis, we identified new TBI serum biomarkers for accurate detection and determination of the timing of TBI injury.

Sensitive and Easy-Read CRISPR Strip for COVID-19 Rapid Point-of-Care Testing.

Rapid and clinically sensitive detection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) play an important role in the contact tracing and containment of the COVID-19 pandemic. A recently developed field-deployable clustered regularly interspaced short palindromic repeats (CRISPR) detection assay with lateral flow strips shows promise for point-of-care detection of SARS-CoV-2. However, the limit of detection of paper strip-based assays (10-100 copies/µL) is much lower than that of fluorescence-based detection methods. In this study, we developed an easy-readout and sensitive enhanced (ERASE) strip to visualize the results of CRISPR detection and improve the sensitivity to 1 copy/µL with an unambiguous easy-read result. Using 649 clinical samples from blind specimens collected from patients in China, we validated our ERASE assay for SARS-CoV-2 RNA detection with 90.67% positive predictive agreement and 99.21% negative predictive agreement. In conclusion, our study provided a customized CRISPR strip for use in a simple, rapid, ultrasensitive, and highly specific assay for SARS-CoV-2 detection. (Clinical Trial Registration number: 2020-008-01; [2020]IEC(ZD01); PJ-NBEY-2020-009-01; 2020#34).

Halogenated flame retardants in wild, prey-sized mud carp from an e-waste recycling site in South China, 2006-2016: Residue dynamics and ecological risk assessment.

The crude e-waste recycling has been regulated in China since the late 2000s; however, information on the recent levels and the ecological risks of e-waste derived contaminants such as halogenated flame retardants (HFRs) in the e-waste sites are limited. We therefore examined the concentrations of several HFRs in wild, prey-sized mud carps collected from a typical e-waste site in 2006, 2011 and 2016, to understand the exposure dynamics and ecological risk of these chemicals. Several ecological and biological parameters including δ15N, δ13C, body size and lipid content of the fish were also examined, to ensure an overall uniformity of the sample set among the sampling years. Among the HFRs measured, polybrominated diphenyl ethers (PBDEs) were detected at the highest concentrations (contributing >90% to ∑HFRs), followed by Dechlorane Plus (DPs), polybrominated biphenyls (PBBs), and alternative brominated flame retardants (ABFRs). The fish concentrations of ∑PBDEs, ∑PBBs and ∑DPs significantly dropped by 65%, 57% and 53% from 2006 to 2011, and 12%, 74% and 51% from 2011 to 2016, respectively; likely reflecting the positive impact of the environmental regulations on crude e-waste recycling. The ∑ABFRs concentrations were also decreased by 80% from 2006 to 2011, but increased by 127% from 2011 to 2016; suggesting possible fresh input of these novel HFRs in recent years. In addition to the changes in the HFR concentrations, contaminant profiles in the fish were also changed, possibly due to environmental degradation of the HFRs. Despite our conservative method of risk assessment, we found that PBDEs posed an important risk both for the mud carp and for piscivorous wildlife that inhabit the e-waste site.

Transcatheter device closure of postmyocardial infarction ventricular septal defect.

BACKGROUND: Transcatheter device closure of postmyocardial infarction ventricular septal defect (PMIVSD) is less invasive than surgical repair. However, its feasibility, timing, outcome, and prognostic factors remain unclear. METHODS: This was a multicenter, retrospective cohort study. Between February 2012 and July 2015, a total of 10 (8 male and 2 female) patients with PMIVSD undergoing attempted device closure were enrolled retrospectively. The procedures were performed under general anesthesia with fluoroscopic and transesophageal echocardiographic guidance. RESULTS: The patients enrolled in the study were in the age range 50-85 years (median age of 76.5 years). The interval from infarction to device closure ranged from 6-147 days, with the median of 12 days. A total of 13 devices were implanted in 10 patients. There were five Amplatzer muscular ventricular septal defect occluders, four Amplatzer septal occluders, three Amplatzer PMIVSD occluders and one Amplatzer vascular plug II. Complications included transient ventricular tachycardia in three patients, device embolization in one patient, and tracheal bleeding in one patient. No procedure-related death, stroke, or cardiac tamponade was noted. During follow-up, two patients died of heart failure and two patients died of sepsis. Overall, subjects with age ≥ 80 years, systolic blood pressure ≤ 90 mmHg, and procedure time ≥180 minutes were significant predictor factors for mortality. All patients with the interval of infarction to device closure >12 days survived. CONCLUSION: Our findings indicate that transcatheter device closure of PMIVSD is technically feasible, safe, and effective to reduce the shunt. The crucial prognostic factors were ascertained to be age ≥ 80 years, systolic blood pressure ≤ 90 mmHg, and procedure time ≥180 minutes.

Note: Fully integrated 3.2 Gbps quantum random number generator with real-time extraction.

We present a real-time and fully integrated quantum random number generator (QRNG) by measuring laser phase fluctuations. The QRNG scheme based on laser phase fluctuations is featured for its capability of generating ultra-high-speed random numbers. However, the speed bottleneck of a practical QRNG lies on the limited speed of randomness extraction. To close the gap between the fast randomness generation and the slow post-processing, we propose a pipeline extraction algorithm based on Toeplitz matrix hashing and implement it in a high-speed field-programmable gate array. Further, all the QRNG components are integrated into a module, including a compact and actively stabilized interferometer, high-speed data acquisition, and real-time data post-processing and transmission. The final generation rate of the QRNG module with real-time extraction can reach 3.2 Gbps.

The generation of 68 Gbps quantum random number by measuring laser phase fluctuations.

The speed of a quantum random number generator is essential for practical applications, such as high-speed quantum key distribution systems. Here, we push the speed of a quantum random number generator to 68 Gbps by operating a laser around its threshold level. To achieve the rate, not only high-speed photodetector and high sampling rate are needed but also a very stable interferometer is required. A practical interferometer with active feedback instead of common temperature control is developed to meet the requirement of stability. Phase fluctuations of the laser are measured by the interferometer with a photodetector and then digitalized to raw random numbers with a rate of 80 Gbps. The min-entropy of the raw data is evaluated by modeling the system and is used to quantify the quantum randomness of the raw data. The bias of the raw data caused by other signals, such as classical and detection noises, can be removed by Toeplitz-matrix hashing randomness extraction. The final random numbers can pass through the standard randomness tests. Our demonstration shows that high-speed quantum random number generators are ready for practical usage.