Sound source direction-of-arrival estimation method for microphone array based on ultra-weak fiber Bragg grating distributed acoustic sensor.

A sound source direction-of-arrival (DOA) estimation method for microphone array based on ultra-weak fiber Bragg grating (UW-FBG) distributed acoustic sensor is proposed. The principle of acoustic signal demodulation is introduced, the sound pressure sensitivity and frequency response range of a single UW-FBG microphone are analyzed, and a series linear array with three UW-FBG microphones is designed. Combined with convolutional recurrent neural networks, the DOA estimation method is developed. Log-Mel spectral features and SCOT/PHAT joint weighting generalized cross correlation features are used for DOA estimation. The corresponding system is established and experimentally verified. Results show that the measured sound pressure sensitivity of the UW-FBG microphone is in the range of 0.1032-3.306 rad/Pa within the frequency range of 1000-3000 Hz, and the peak sound pressure sensitivity is about 3.306 rad/Pa. The estimated mean error of 2D DOA estimation is about 2.85°, and the error of 3D DOA estimation is about 5.465°. This method has good application prospects in distributed sound source localization.

Assessing thyroid cancer risk using polygenic risk scores.

Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points (P ≤ 1.0 × 10-9). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4-8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC.

Comparison of the effects of contrast-enhanced ultrasound and conventional ultrasound-guided radiofrequency ablation on benign thyroid nodules.

Objective: To compare the effect of contrast-enhanced ultrasound (CEUS) and conventional ultrasound-guided radiofrequency ablation (RFA) on benign thyroid nodules (BTNs). Methods: In this retrospective observational study, the data of 72 patients with BTNs who received RFA treatment in The Fourth Affiliated Hospital of Zhejiang University School of Medicine from January 2020 to December 2021 were retrospectively reviewed and selected. The records showed that 34 patients received RFA under the guidance of conventional ultrasound (conventional ultrasound group) and 38 patients received RFA under the guidance of CEUS (CEUS group). The effect of treatment, complications and recurrence of the two groups were compared and analyzed. Results: There was a smaller volume of thyroid nodules in the two groups immediately post-operation. The incidence of complications was lower in the CEUS group (5.26%) compared to the conventional ultrasound group (23.53%) (P<0.05). The recurrence rate at 6-months (0.00% vs 11.76%) and 12- months (2.63% vs 20.59%) post-operation was lower in the CEUS group compared to the conventional ultrasound group (P<0.05). Conclusions: Compared with conventional ultrasound, CEUS-guided RFA is effective in treating BTNs, with smaller postoperative nodule volume, reduced occurrence of surgical complications, and reduced recurrence rate of thyroid nodules.

Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium.

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome-wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population-based case-control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray-500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid-stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations.

Variants in LRRC34 reveal distinct mechanisms for predisposition to papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) demonstrates high heritability and a low somatic mutation burden relative to other cancers. Therefore, the genetic risk predisposing to PTC is likely due to a combination of low penetrance variants. A recent genome-wide association study revealed the association of PTC with a missense variant, rs6793295, at 3q26 in a gene called Leucine Repeat Rich Containing 34 (LRRC34). METHODS: We report the mechanisms of PTC risk at 3q26 using a combination of overexpression, mass spectroscopy, knockdown, transcriptome profiling, migration assays and genetic analysis. RESULTS: We observed differential binding of wild-type and missense LRRC34 to RANBP1. Overexpression of missense LRRC34 reduced RanGTP levels and increased apoptosis. We also identified a second linkage disequilibrium (LD) block upstream of LRRC34 containing regulatory variants with allele-specific expression. Transcriptome profiling of LRRC34 knockdown cells showed changes in genes involved with cellular movement. LRRC34 knockdown reduced the migration of thyroid cancer cell lines. Lastly, we assessed the relative contribution of PTC risk from each locus using haplotype analysis. CONCLUSIONS: Our study demonstrates two separate mechanisms, one in G protein signalling and the other in transcriptional control, dictating PTC risk at 3q26 using both biochemical and genetic techniques.

Deformation detection of a double-clamped beam according to ultra-weak fiber Bragg grating.

Metal beam strain detection may offer valuable insight into health monitoring for large-scale steel structures. This research presents, to the best of our knowledge, the first implementation of ultra-weak fiber Bragg gratings for the deformation detection of a double-clamped beam because of their higher multiplexing and denser detection points compared to fiber Bragg gratings. The measured values are entirely consistent with those determined by strain gauges applied for reference and demonstrate that the strain of each sensing point increases linearly with the load at the middle of the beam. The errors of different loads at different load points between inversion maximum deflection and measured displacement are less than 9.59%.

Pilot study of a customized nanotextile wet garment treatment on moderate and severe atopic dermatitis: A randomized clinical trial.

BACKGROUND: Atopic dermatitis (AD) is a common dermatosis. The cornerstone of eczema management is to repair and maintain skin barrier and hydration, as well as to reduce inflammation. Wet wrap therapy (WWT) is a widely used adjunct to achieve this. The conventional material used for WWT is viscose, which presents drawbacks including discomfort, high cost, and poor durability. Here, we explore the possibility of using customized nanotextile (nanopolyester) for WWT, hoping to prove that this material is non-inferior to viscose in clinical effectiveness and patient acceptance. METHODS: Patients aged 0-18 years with moderate to severe eczema were randomized to receive either viscose (Tubifast™) or nanotextile for WWT. Patients were instructed to apply WWT daily overnight for 2 weeks. Patients' disease severity score (IGA, SCORAD) and quality of life (QoL) score (IDQOL/CDLQI) were measured on day 0, 7, and 14 of treatment. Patient survey was conducted to collect patients' feedback about garment use. RESULTS: Fifty-three children aged 7 months to 17 years were recruited (27 in Tubifast™ and 26 in nanotextile group). Patients in both groups showed significant improvement in disease severity and QoL from baseline (P < .001), and such improvement was similar in both groups. However, nanotextile garment was significantly more comfortable (2.73/10 vs 5.12/10, P = .001), easier to wear (2.78/10 vs 5.24/10, P = .003), and cooler (2.43/10 vs 3.96/10, P = .033) from patients' feedback. CONCLUSION: This study demonstrates that nanomaterial is as effective as conventional viscose in WWT, while superior in patient acceptability. Nanotextile for WWT has good potential in eczema management, especially in patients with suboptimal response to topicals alone.

MYH9 binds to lncRNA gene PTCSC2 and regulates FOXE1 in the 9q22 thyroid cancer risk locus.

A locus on chromosome 9q22 harbors a SNP (rs965513) firmly associated with risk of papillary thyroid carcinoma (PTC). The locus also comprises the forkhead box E1 (FOXE1) gene, which is implicated in thyroid development, and a long noncoding RNA (lncRNA) gene, papillary thyroid cancer susceptibility candidate 2 (PTCSC2). How these might interact is not known. Here we report that PTCSC2 binds myosin-9 (MYH9). In a bidirectional promoter shared by FOXE1 and PTCSC2, MYH9 inhibits the promoter activity in both directions. This inhibition can be reversed by PTCSC2, which acts as a suppressor. RNA knockdown of FOXE1 in primary thyroid cells profoundly interferes with the p53 pathway. We propose that the interaction between the lncRNA, its binding protein MYH9, and the coding gene FOXE1 underlies the predisposition to PTC triggered by rs965513.

Fine mapping of 14q13 reveals novel variants associated with different histological subtypes of papillary thyroid carcinoma.

The first two genome wide association studies (GWAS) of papillary thyroid carcinoma (PTC) detected five variants associated with PTC. Two of them (rs944289 and rs116909374) are located at 14q13 making that locus an important target of research into the genetic predisposition to PTC. We aimed at uncovering other variants at 14q13 associated with PTC independently from the GWAS variants. We performed next generation sequencing of the 14q13 region and analyzed the allele frequencies of single nucleotide polymorphisms (SNPs) in n = 90 PTC cases vs. n = 379 EUR controls from the 1,000 Genome Project. The variants associated with PTC were validated in an Ohio cohort of n = 1,216 PTC cases and n = 1,416 controls. Next, we analyzed the association between SNPs and expression of nearby genes and clinical parameters. We showed that rs368187 was associated with PTC (OR = 1.31, p = 2.20 × 10-6 ). Rs1632250, Rs1863347 and rs1755787 showed association with classical PTC (cPTC) (n = 891; OR = 1.24, 2.22 × 10-3 , OR = 1.31, p = 2.15 × 10-4 and OR = 1.24, p = 2.06 × 10-3 , respectively) while variant rs28397092 showed association with follicular variant (n = 243; OR = 1.51, p = 1.36 × 10-3 ). Rs1863347 was associated with suppression of PTCSC3 in unaffected thyroid tissue (p = 0.026). Rs1632250, rs1863347 and rs1755787 showed association with multifocality (OR = 1.85, p = 0.001, OR = 1.98, p = 0.001 and OR = 1.76, p = 0.003 respectively) and N stage (OR = 1.79, p = 0.014, OR = 1.73, p = 0.023 and OR = 1.81, p = 0.013, respectively) in microPTC (n = 328) while rs368187 was associated with M stage (OR = 0.56, p = 0.034) in cPTC. Our results disclose multiple variants associated with PTC and clinical features in the 14q13 superlocus. We suggest that translational genotype/phenotype studies should take into account not only somatic mutations but also germline variants.

The role of SMAD3 in the genetic predisposition to papillary thyroid carcinoma.

PURPOSE: To identify and characterize the functional variants, regulatory gene networks, and potential binding targets of SMAD3 in the 15q22 thyroid cancer risk locus. METHODS: We performed linkage disequilibrium (LD) and haplotype analyses to fine map the 15q22 locus. Luciferase reporter assays were applied to evaluate the regulatory effects of the candidate variants. Knockdown by small interfering RNA, microarray analysis, chromatin immunoprecipitation (ChIP) and quantitative real-time polymerase chain reaction assays were performed to reveal the regulatory gene network and identify its binding targets. RESULTS: We report a 25.6-kb haplotype within SMAD3 containing numerous single-nucleotide polymorphisms (SNPs) in high LD. SNPs rs17293632 and rs4562997 were identified as functional variants of SMAD3 by luciferase assays within the LD region. These variants regulate SMAD3 transcription in an allele-specific manner through enhancer elements in introns of SMAD3. Knockdown of SMAD3 in thyroid cancer cell lines revealed its regulatory gene network including two upregulated genes, SPRY4 and SPRY4-IT1. Sequence analysis and ChIP assays validated the actual binding of SMAD3 protein to multiple SMAD binding element sites in the region upstream of SPRY4. CONCLUSION: Our data provide a functional annotation of the 15q22 thyroid cancer risk locus.

Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer.

The [A] allele of SNP rs965513 in 9q22 has been consistently shown to be highly associated with increased papillary thyroid cancer (PTC) risk with an odds ratio of ∼1.8 as determined by genome-wide association studies, yet the molecular mechanisms remain poorly understood. Previously, we noted that the expression of two genes in the region, forkhead box E1 (FOXE1) and PTC susceptibility candidate 2 (PTCSC2), is regulated by rs965513 in unaffected thyroid tissue, but the underlying mechanisms were not elucidated. Here, we fine-mapped the 9q22 region in PTC and controls and detected an ∼33-kb linkage disequilibrium block (containing the lead SNP rs965513) that significantly associates with PTC risk. Chromatin characteristics and regulatory element signatures in this block disclosed at least three regulatory elements functioning as enhancers. These enhancers harbor at least four SNPs (rs7864322, rs12352658, rs7847449, and rs10759944) that serve as functional variants. The variant genotypes are associated with differential enhancer activities and/or transcription factor binding activities. Using the chromosome conformation capture methodology, long-range looping interactions of these elements with the promoter region shared by FOXE1 and PTCSC2 in a human papillary thyroid carcinoma cell line (KTC-1) and unaffected thyroid tissue were found. Our results suggest that multiple variants coinherited with the lead SNP and located in long-range enhancers are involved in the transcriptional regulation of FOXE1 and PTCSC2 expression. These results explain the mechanism by which the risk allele of rs965513 predisposes to thyroid cancer.

The Comparison of Spectral Classification Based on DBN, BP Neural Network and SVM.

The stellar classification was an important research field for understanding the formation and evolution of stars and galaxies. With large sky surveys and its massive data, the speed and accuracy of the celestial automatic classification was very important. The depth confidence neural network (DBN), support vector machines (SVM) and BP neural networks used in the star classification were compared in this paper. And the applicability of star classification with these three methods was analyzed. First, K, F stars are classified according to the depth of confidence neural network and BP neural network and support vector machine.Then the K1, K3, K5 sub-type and F2, F5, F9 sub-type were separately identified. Finally, the data which did not belong to the k sub-type were excluded by a secondary classification model based on SVM support vector machine . The results shows that: the depth of belief networks is better for K, F-type star classification, but it is poor for K, F sub-type classification results; The recognition rate of SVM is high for the K, F-type stars and the classification effects of this method is better for K, F-type stars than the corresponding sub-type stars by comparison; The recognition rate of BP neural network is ordinary general for K, F-type stars and their sub-types. The experiment showed that the accuracy of excluding non-k-sub-type data can be up to 100% which indicates that the unknown spectral data can be screened and classified with SVM.

The polymorphism rs944289 predisposes to papillary thyroid carcinoma through a large intergenic noncoding RNA gene of tumor suppressor type.

A genome-wide association study of papillary thyroid carcinoma (PTC) pinpointed two independent SNPs (rs944289 and rs965513) located in regions containing no annotated genes (14q13.3 and 9q22.33, respectively). Here, we describe a unique, long, intergenic, noncoding RNA gene (lincRNA) named Papillary Thyroid Carcinoma Susceptibility Candidate 3 (PTCSC3) located 3.2 kb downstream of rs944289 at 14q.13.3 and the expression of which is strictly thyroid specific. By quantitative PCR, PTCSC3 expression was strongly down-regulated (P = 2.84 × 10(-14)) in thyroid tumor tissue of 46 PTC patients and the risk allele (T) was associated with the strongest suppression (genotype [TT] (n = 21) vs. [CT] (n = 19), P = 0.004). In adjacent unaffected thyroid tissue, the genotype [TT] was associated with up-regulation of PTCSC3 ([TT] (n = 21) vs. [CT] (n = 19), P = 0.034). The SNP rs944289 was located in a binding site for the CCAAT/enhancer binding proteins (C/EBP) α and ß. The risk allele destroyed the binding site in silico. Both C/EBPα and C/EBPß activated the PTCSC3 promoter in reporter assays (P = 0.0009 and P = 0.0014, respectively) and the risk allele reduced the activation compared with the nonrisk allele (C) (P = 0.026 and P = 0.048, respectively). Restoration of PTCSC3 expression in PTC cell line cells (TPC-1 and BCPAP) inhibited cell growth (P = 0.002 and P = 0.019, respectively) and affected the expression of genes involved in DNA replication, recombination and repair, cellular movement, tumor morphology, and cell death. Our data suggest that SNP rs944289 predisposes to PTC through a previously uncharacterized, long intergenic noncoding RNA gene (PTCSC3) that has the characteristics of a tumor suppressor.

Presumed Pathogenic Germ Line and Somatic Variants in African American Thyroid Cancer.

Background: African American (AA) thyroid cancer patients have worse prognoses than European Americans (EA), which has been attributed to both health care disparities and possible genetic differences. We investigated the impact of both germ line and somatic variants on clinical outcome in a cohort of AA nonmedullary thyroid cancer (NMTC) patients who had received therapeutic intervention from cancer centers. Methods: Whole-exome sequencing was performed on DNA from available blood/normal tissues (N = 37) and paired tumor samples (N = 32) collected from 37 and 29 AA NMTC patients, respectively. Variants with Combined Annotation Depletion Dependent (CADD) score of ≥20 and VarSome Clinical classification of likely pathogenic or pathogenic were classified as presumed pathogenic germ line or somatic variants (PPGVs/PPSVs). PPGVs/PPSVs in cancer-related genes and PPGVs in cardiovascular risk genes were further investigated, and PPGVs/PPSVs associated with African (AFR) ancestry were identified. Results: Among 17 PPGVs identified in 16 cancer predisposition or known cancer-related genes, only WRN was previously known to associate with NMTC predisposition. Among PPSVs, BRAFV600E was most the prevalent and detected in 12 of the 29 (41%) tumors. Examining PPGVs/PPSVs among three patients who died from NMTC, one patient who died from papillary thyroid carcinoma/anaplastic thyroid carcinoma (PTC/ATC) led us to speculate that the PPGV ERCC4R799W may have increased the risk of PPSV TP53R273H acquisition. Among PPGVs identified in 18 cardiovascular risk genes, PPGVs in SC5NA, GYG1, CBS, CFTR, and SI are known to have causal and pathogenic implications in cardiovascular disease. Conclusion: In this cohort, most AA-NMTC patients exhibit favorable outcomes after therapeutic intervention given at cancer centers, suggesting that health care disparity is the major contributor for worse prognoses among AA-NMTC patients. Nevertheless, the clinical impact of PPGVs that might facilitate the acquisition of TP53 tumor mutations, and/or PPGVs that predispose individuals to adverse cardiovascular events, which could be exacerbated by therapy-induced cardiotoxicity, needs to be further explored. Integrated analysis of PPGV/PPSV profiles among NMTC patients with different stages of disease may help to identify NMTC patients who require close monitoring or proactive intervention.

A Booster for Radiofrequency Ablation: Advanced Adjuvant Therapy via In Situ Nanovaccine Synergized with Anti-programmed Death Ligand 1 Immunotherapy for Systemically Constraining Hepatocellular Carcinoma.

Radiofrequency ablation (RFA) is one of the most common minimally invasive techniques for treating hepatocellular carcinoma (HCC), which could destroy tumors through hyperthermia and generate massive tumor-associated antigens (TAAs). However, residual malignant tissues or small satellite lesions are hard to eliminate, generally resulting in metastases and recurrence. Herein, an advanced in situ nanovaccine formed by layered double hydroxides carrying cGAMP (STING agonist) (LDHs-cGAMP) and adsorbed TAAs was designed to potentiate the RFA-induced antitumor immune response. As-prepared LDHs-cGAMP could effectively enter cancerous or immune cells, inducing a stronger type I interferon (IFN-I) response. After further adsorption of TAAs, nanovaccine generated sustained immune stimulation and efficiently promoted activation of dendritic cells (DCs). Notably, infiltrations of cytotoxic lymphocytes (CTLs) and activated DCs in tumor and lymph nodes were significantly enhanced after nanovaccine treatment, which distinctly inhibited primary, distant, and metastasis of liver cancer. Furthermore, such a nanovaccine strategy greatly changed the tumor immune microenvironment and promoted the response efficiency of anti-programmed death ligand 1 (αPD-L1) immunotherapy, significantly arresting the poorly immunogenic hepa1-6 liver cancer progression. These findings demonstrate the potential of nanovaccine as a booster for RFA in liver cancer therapy and provide a promising in situ cancer vaccination strategy.

The diagnostic value of novel ultrasound attenuation analysis in detecting liver steatosis identified by the controlled attenuation parameter: a diagnostic accuracy study.

Background: Ultrasound attenuation analysis (USAT) is a type of novel ultrasound attenuation imaging that can be used to detect hepatic steatosis based on the attenuation coefficient. We sought to evaluate the diagnostic accuracy for assessing the severity of liver steatosis by USAT using the controlled attenuation parameter (CAP) as a reference in patients with non-alcoholic fatty liver diseases (NAFLD) and chronic hepatitis B (CHB) infections. Methods: In total, 326 consecutive subjects with or without chronic liver diseases were enrolled in this study who underwent CAP examination and USAT to evaluate hepatic steatosis from October 2022 to November 2022 at The Fourth Affiliated Hospital of Zhejiang University School of Medicine. Hepatic steatosis stage (S) was determined by CAP according to the following cut-off values recommended by the manufacturer: S ≥ S1 (≥11%, mild): 238 dB/m; S ≥ S2 (≥34%, moderate): 259 dB/m; and S ≥ S3 (≥67%, severe): 292 dB/m, and thus the optimal cut-off values for the USAT were acquired. The area under the receiver operating characteristic curves (AUROCs) for the categories of steatosis were used to measure the diagnostic accuracy of USAT. Results: A total of 296 patients were recruited, including 101 (34.1%) patients with NAFLD, 172 (58.1%) with CHB and the remainder were healthy control subjects (7.8%). We used the CAP as the reference standard and found that the USAT increased gradually as the stage of steatosis increased (P<0.001). A strong positive correlation was found between USAT and CAP (r=0.787, P<0.001). In the whole population, the AUROCs of the USAT for S ≥ S1, S ≥ S2 and S ≥ 3 were 0.89, 0.90, and 0.90, respectively, and the cut-off values according to the Youden index for S ≥ S1, S ≥ S2, and S ≥ 3 were 0.62, 0.66, and 0.72 dB/cm/MHz, respectively. Our study showed that the USAT had a good ability to detect hepatic steatosis in NAFLD and CHB patients. Conclusions: USAT had a strong association with CAP and a good diagnostic capability in the detection of hepatic steatosis, which appears to be a promising tool for the non-invasive detection and quantification of hepatic steatosis.

Combined analysis of single-cell and bulk RNA sequencing reveals the expression patterns of circadian rhythm disruption in the immune microenvironment of Alzheimer's disease.

Background: Circadian rhythm disruption (CRD) represents a critical contributor to the pathogenesis of Alzheimer's disease (AD). Nonetheless, how CRD functions within the AD immune microenvironment remains to be illustrated. Methods: Circadian rhythm score (CRscore) was utilized to quantify the microenvironment status of circadian disruption in a single-cell RNA sequencing dataset derived from AD. Bulk transcriptome datasets from public repository were employed to validate the effectiveness and robustness of CRscore. A machine learning-based integrative model was applied for constructing a characteristic CRD signature, and RT-PCR analysis was employed to validate their expression levels. Results: We depicted the heterogeneity in B cells, CD4+ T cells, and CD8+ T cells based on the CRscore. Furthermore, we discovered that CRD might be strongly linked to the immunological and biological features of AD, as well as the pseudotime trajectories of major immune cell subtypes. Additionally, cell-cell interactions revealed that CRD was critical in the alternation of ligand-receptor pairs. Bulk sequencing analysis indicated that the CRscore was found to be a reliable predictive biomarker in AD patients. The characteristic CRD signature, which included 9 circadian-related genes (CRGs), was an independent risk factor that accurately predicted the onset of AD. Meanwhile, abnormal expression of several characteristic CRGs, including GLRX, MEF2C, PSMA5, NR4A1, SEC61G, RGS1, and CEBPB, was detected in neurons treated with Aß1-42 oligomer. Conclusion: Our study revealed CRD-based cell subtypes in the AD microenvironment at single-cell level and proposed a robust and promising CRD signature for AD diagnosis. A deeper knowledge of these mechanisms may provide novel possibilities for incorporating "circadian rhythm-based anti-dementia therapies" into the treatment protocols of individualized medicine.

Diagnostic accuracy of contrast-enhanced ultrasound synchronized with shear wave elastography in the differential diagnosis of benign and malignant breast lesions: a diagnostic test.

Background: Breast cancer (BC) is one of the most common malignancies affecting women. Timely and accurate diagnosis is crucial for treatment and prognosis. Some studies have found that elastography combined with microperfusion characteristics, which are mostly described by contrast-enhanced ultrasound (CEUS), could help in the diagnosis of breast lesions. This study aimed to assess the diagnostic performance of CEUS synchronized with shear wave elastography (SWE) in discriminating between benign and malignant breast lesions by using real-time contrast elastography images to analyze shell elasticity and contrast intensity. Methods: A total of 26 pathologically confirmed breast lesions in 26 patients were retrospectively reviewed. Each patient underwent conventional B-mode ultrasound, CEUS, and then SWE data was obtained from a frame of image that was almost identical to the B-mode and CEUS images when acquiring time to peak (TTP). Breast lesions were evaluated based on the Breast Imaging Reporting and Data System (BI-RADS) and quantitative characteristics that describe the stiffness and intensity of contrast of the 1.0-3.0 mm shell region. Quantitative aspects of the inner lesions and shell on the elastogram included the maximum (Emax), mean (Emean), and minimum (Emin) Young's moduli. Quantitative enhanced features included maximum (Imax) and mean (Imean) intensity. We took postoperative pathological results as the gold standard. Receiver operating characteristic (ROC) curves were used to compare the diagnostic efficacy of the 2 examination modalities, either alone or in combination. Results: The age of the patients ranged from 23 to 76 years, with a 42.5-year average age. In all breast lesions, 19 were benign and 7 were malignant. SWE synchronized with CEUS can effectively improve the diagnostic performance of breast lesions, and Emean + Imean and Emax + Emean + Imean of shell at 1.0 mm both had the highest area under the curve (AUC) of 0.86 [95% confidence interval (CI): 0.67, 0.96], with the sensitivity and specificity of 71.43% and 89.47%, respectively. Conclusions: The combination of CEUS and SWE has a better diagnostic value in differentiating benign and malignant breast lesions compared to separate techniques.

CpxA/R-Controlled Nitroreductase Expression as Target for Combinatorial Therapy against Uropathogens by Promoting Reactive Oxygen Species Generation.

The antibiotic resistances emerged in uropathogens lead to accumulative treatment failure and recurrent episodes of urinary tract infection (UTI), necessitating more innovative therapeutics to curb UTI before systematic infection. In the current study, the combination of amikacin and nitrofurantoin is found to synergistically eradicate Gram-negative uropathogens in vitro and in vivo. The mechanistic analysis demonstrates that the amikacin, as an aminoglycoside, induced bacterial envelope stress by introducing mistranslated proteins, thereby constitutively activating the cpxA/R two-component system (Cpx signaling). The activation of Cpx signaling stimulates the expression of bacterial major nitroreductases (nfsA/nfsB) through soxS/marA regulons. As a result, the CpxA/R-dependent nitroreductases overexpression generates considerable quantity of lethal reactive intermediates via nitroreduction and promotes the prodrug activation of nitrofurantoin. As such, these actions together disrupt the bacterial cellular redox balance with excessively-produced reactive oxygen species (ROS) as "Domino effect", accelerating the clearance of uropathogens. Although aminoglycosides are used as proof-of-principle to elucidate the mechanism, the synergy between nitrofurantoin is generally applicable to other Cpx stimuli. To summarize, this study highlights the potential of aminoglycoside-nitrofurantoin combination to replenish the arsenal against recurrent Gram-negative uropathogens and shed light on the Cpx signaling-controlled nitroreductase as a potential target to manipulate the antibiotic susceptibility.