Benchmarking deep learning methods for predicting CRISPR/Cas9 sgRNA on- and off-target activities.

In silico design of single guide RNA (sgRNA) plays a critical role in clustered regularly interspaced, short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system. Continuous efforts are aimed at improving sgRNA design with efficient on-target activity and reduced off-target mutations. In the last 5 years, an increasing number of deep learning-based methods have achieved breakthrough performance in predicting sgRNA on- and off-target activities. Nevertheless, it is worthwhile to systematically evaluate these methods for their predictive abilities. In this review, we conducted a systematic survey on the progress in prediction of on- and off-target editing. We investigated the performances of 10 mainstream deep learning-based on-target predictors using nine public datasets with different sample sizes. We found that in most scenarios, these methods showed superior predictive power on large- and medium-scale datasets than on small-scale datasets. In addition, we performed unbiased experiments to provide in-depth comparison of eight representative approaches for off-target prediction on 12 publicly available datasets with various imbalanced ratios of positive/negative samples. Most methods showed excellent performance on balanced datasets but have much room for improvement on moderate- and severe-imbalanced datasets. This study provides comprehensive perspectives on CRISPR/Cas9 sgRNA on- and off-target activity prediction and improvement for method development.

Novel Bulk Quantum Hall Effect in Nanostructured TaP Macroscopic Crystals.

Bulk quantum Hall effect (QHE), the natural extension of the two-dimensional (2D) QHE, is one of the representative phenomena of coherent electron transport. However, bulk QHE has rarely been reported in real materials with macroscopic sizes. Here, we report a novel bulk QHE in macroscopic millimeter-sized and nanostructured TaP crystals consisting of nanometer-scale lamellae. Specifically, the simultaneous quantum plateaus were observed in both transverse resistivity ρxy and vertical resistivity ρzz. The bulk QHE is attributable to synergetic action between Landau cyclotron movement under magnetic field B and periodically modulated potential due to the nanometer-scaled lamellae. This mechanism would form the fixed number of edge states along B-perpendicular and B-parallel directions respectively, equivalent to stacked 2D-QHE layers, leading to quantized ρxy and ρzz. Our work verifies that microstructure engineering could result in the coherent transport of electrons and generate new quantum phenomena in bulk materials.

Bidirectional causality between the levels of blood lipids and endometriosis: a two-sample mendelian randomization study.

BACKGROUND: Observational studies have found a correlation between the levels of blood lipids and the development and progression of endometriosis (EM). However, the causality and direction of this correlation is unclear. This study aimed to examine the bidirectional connection between lipid profiles and the risk of EM using publicly available genome-wide association study (GWAS) summary statistics. METHODS: Eligible exposure variables such as levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were selected using a two-sample Mendelian randomization (MR) analysis method following a series of quality control procedures. Data on EM were obtained from the publicly available Finnish database of European patients. Inverse variance weighted (IVW), MR Egger, weighted median, and weighted mode methods were used to analyze the causal relationship between lipid exposure and EM, exclude confounders, perform sensitivity analyses, and assess the stability of the results. Reverse MR analyses were performed with EM as exposure and lipid results as study outcomes. RESULTS: IVW analysis results identified HDL as a protective factor for EM, while TG was shown to be a risk factor for EM. Subgroup analyses based on the site of the EM lesion identified HDL as a protective factor for EM of the uterus, while TG was identified a risk factor for the EM of the fallopian tube, ovary, and pelvic peritoneum. Reverse analysis did not reveal any effect of EM on the levels of lipids. CONCLUSION: Blood lipids, such as HDL and TG, may play an important role in the development and progression of EM. However, EM does not lead to dyslipidemia.

Ultrasound manifestations and clinical analysis of 50 cases of heterotopic pregnancy.

OBJECTIVE: To investigate the value of ultrasonography in the diagnosis of heterotopic pregnancy and the follow-up. METHODS: A retrospective analysis of 50 cases of clinically diagnosed heterotopic pregnancy in our hospital was performed, the clinical characteristics and ultrasonographic manifestations of the patients were summarized, the reasons for initial ultrasound missed diagnosis and misdiagnosis were analyzed, and the pregnancy outcomes were followed up. RESULTS: Among the 50 cases, the initial ultrasound diagnoses of intrauterine pregnancy were all gestational sac type, 32 cases of ectopic pregnancy were located in the fallopian tube, and 10 cases were located in the uterine horn, 1 case at cervix, and 1 case at caesarean section scar. Forty-one cases were consistent with surgery and/or pathology, representing initial ultrasound diagnosis coincidence rate of about 82%. Six cases were missed in the initial ultrasound examination (12%), and three cases were misdiagnosed (6%). The maximum diameter of the intrauterine gestational sac was 9-48 mm, the average was about 24.90 ± 9.56 mm, the maximum diameter of the ectopic pregnancy gestational sac or mass was 11-63 mm, and the average was about 31.45 ± 13.82 mm (p < 0.05). Intrauterine pregnancy outcomes were followed up, 45 patients with complete data and 5 patients were lost to follow-up. The follow-up rate was about 90%. CONCLUSION: Combining the patient's medical history and clinical characteristics can reduce missed diagnosis and misdiagnosis of heterotopic pregnancy. Ultrasonography has important value in the assessment of intrauterine pregnancy growth and development, and the integrity of maternal uterus.

The application value of prenatal ultrasound in conjoined twins.

OBJECTIVE: To evaluate the application and effectiveness of prenatal ultrasound in diagnosing and managing conjoined twins. METHODS: A retrospective analysis was conducted on 20 cases of conjoined twins diagnosed at our hospital between January 2016 and December 2022. The types of conjoined twins, ultrasonographic characteristics, and associated anomalies were assessed. RESULTS: The gestational age at diagnosis ranged from 10 to 35 weeks, with an average of 14.21 ± 5.69 weeks. Thirteen cases were detected in the first trimester, five in the early second trimester, one at 23 + 2 weeks, and one at 35 weeks. Thoracopagus was the most common type (11 cases, 55%), followed by omphalopagus (4 cases, 20%), cephalopagus (4 cases, 20%), and parapagus dicephalus (1 case, 5%). In the first trimester, the most common abnormalities observed included increased nuchal translucency (NT), cystic hygroma, hydrops fetalis, and generalized edema. Major birth defects identified in conjoined twins were omphalocele (3 cases), congenital heart malformations (3 cases), neural tube defects (2 cases), urachal cyst (1 case), and umbilical cyst (1 case). Pregnancy was terminated in 18 cases, one case resulted in spontaneous abortion during the second trimester, and one case was delivered by cesarean section at 37 weeks, with successful separation and recovery. CONCLUSION: Prenatal ultrasound is the primary diagnostic tool for conjoined twins. It effectively assesses the extent of twin fusion, provides critical information for clinical decision-making, and aids in the management of obstetric care.

Integrated Flexible Microscale Mechanical Sensors Based on Cascaded Free Spectral Range-Free Cavities.

Photonic mechanical sensors offer several advantages over their electronic counterparts, including immunity to electromagnetic interference, increased sensitivity, and measurement accuracy. Exploring flexible mechanical sensors on deformable substrates provides new opportunities for strain-optical coupling operations. Nevertheless, existing flexible photonics strategies often require cumbersome signal collection and analysis with bulky setups, limiting their portability and affordability. To address these challenges, we propose a waveguide-integrated flexible mechanical sensor based on cascaded photonic crystal microcavities with inherent deformation and biaxial tensile state analysis. Leveraging the advanced multiplexing capability of the sensor, for the first time, we successfully demonstrate 2D shape reconstruction and quasi-distributed strain sensing with 110 µm spatial resolution. Our microscale mechanical sensor also exhibits exceptional sensitivity with a detected force level as low as 13.6 µN in real-time measurements. This sensing platform has potential applications in various fields, including biomedical sensing, surgical catheters, aircraft and spacecraft engineering, and robotic photonic skin development.

Crispr-SGRU: Prediction of CRISPR/Cas9 Off-Target Activities with Mismatches and Indels Using Stacked BiGRU.

CRISPR/Cas9 is a popular genome editing technology, yet its clinical application is hindered by off-target effects. Many deep learning-based methods are available for off-target prediction. However, few can predict off-target activities with insertions or deletions (indels) between single guide RNA and DNA sequence pairs. Additionally, the analysis of off-target data is challenged due to a data imbalance issue. Moreover, the prediction accuracy and interpretability remain to be improved. Here, we introduce a deep learning-based framework, named Crispr-SGRU, to predict off-target activities with mismatches and indels. This model is based on Inception and stacked BiGRU. It adopts a dice loss function to solve the inherent imbalance issue. Experimental results show our model outperforms existing methods for off-target prediction in terms of accuracy and robustness. Finally, we study the interpretability of this model through Deep SHAP and teacher-student-based knowledge distillation, and find it can provide meaningful explanations for sequence patterns regarding off-target activity.

Household Environments and Cognitive Decline Among Middle-Aged and Older Adults in China: Exploring Gender, Age, and Residential Variations.

This study examined the relationship between household environments and trajectories of cognitive function among middle-aged and older adults in China and its urban/rural, gender, and age variations. We estimated multi-level linear growth curve models using a representative sample of 16,111 respondents aged 45 years and over from the China Health and Retirement Longitudinal Study (2011-2018). Older people who lived with a spouse, but not with children, and those with higher living expenditures, better housing quality, and indoor clean fuels for cooking had a slower cognitive decline. Living arrangement more strongly predicted men's cognitive decline, while living expenditure, solid fuel use, and housing quality significantly predicted only women's cognitive decline. Only for older adults and rural residents, those living alone had significantly faster cognitive decline than those living with a spouse only. These findings underscore the importance of improving the living conditions of older adults to help alleviate their cognitive decline.

High Q-factor, ultrasensitivity slot microring resonator sensor based on chalcogenide glasses: erratum.

We correct the error in [Opt. Express30, 3866 (2022)10.1364/OE.450092], Fig. 6(c). The unit of the vertical axis in the figure should be arbitrary units, not dB. All the conclusions are unchanged after the correction.

Embedded racetrack microring resonator sensor based on GeSbSe glasses: erratum.

We correct the error in [Opt. Express31, 1103(2023)10.1364/OE.478613] Fig. 5(c). The unit of the vertical axis in the figure should be arbitrary units, not dB. All the conclusions are not changed after the correction.

Embedded racetrack microring resonator sensor based on GeSbSe glasses.

In this article, a compact racetrack double microring resonator (MRR) sensor based on Ge28Sb12Se60 (GeSbSe) is investigated. The sensor device consists of a racetrack microring, an embedded small microring, and a strip waveguide. Electron beam lithography (EBL) and dry etching are used to fabricate the device. The compact racetrack double MRR device are obtained with Q-factor equal to 7.17 × 104 and FSR of 24 nm by measuring the transmission spectrum. By measuring different concentrations of glucose solutions, a sensitivity of 297 nm/RIU by linear fitting and an intrinsic limit of detection (iLOD) of 7.40 × 10-5 are obtained. It paves the way for the application of chalcogenide glasses in the field of biosensing.

Creation and preservation of superoscillation in a dielectric optical waveguide.

Superoscillation refers to a phenomenon where a band-limited wave locally oscillates faster than its highest Fourier component. Current research on optical superoscillations predominantly lies on the basis of free-space waves. As the optical waveguides play a key role in energy and information transportation, guided waves with precisely controlled deep-subwavelength features offers unprecedented flexibility for applications. In this Letter, we numerically show that, by superimposing eigenmodes of a multimode SiO2 waveguide and forcing the resultant field to pass through a set of predetermined points, superoscillatory fields in various shapes can be formed in preset cross-sectional planes. Furthermore, by padding prescribed intensities in multiple cross sections, we successfully create a persistent superoscillatory saddle.

Food Insecurity and Stress Among Rural Residents in South Carolina: The Moderating Influences of Household Characteristics, Neighborhood Social Environment and Food Environment.

Food insecurity is linked with poor physical and mental health outcomes, including anxiety, depression and stress. Rural residents in particular face unique challenges obtaining healthy food; the COVID-19 pandemic exacerbated the relationship between food insecurity and mental health outcomes. This study examines the relationship between food insecurity and stress, and the moderating influence of household characteristics, neighborhood social environment and food environment on this relationship, using a sample of 630 rural South Carolina (SC) residents during COVID-19. Two measures of stress were used in this study: current levels of stress and changes in stress since COVID-19. Results showed a gradient pattern between food insecurity and stress: rural residents with high food insecurity were 6.1 times more likely and those with moderate food insecurity were 3.4 times more likely to report higher level of general stress than those with low food insecurity; rural residents with high food insecurity were 3.3 times more likely and those with moderate food insecurity were 2.0 times more likely to report greater increase in stress after COVID-19 than those with low food insecurity. Neighborhood social environment and food environment provided a buffering effect on the relationship between food insecurity and stress. A stronger social environment after COVID-19 and higher levels of easiness in food access mitigated the negative impacts of food insecurity on stress. Efforts to ameliorate food insecurity should address these broader contextual variables, involving community-level factors.

Intrathyroid thymic carcinoma: A clinicopathological analysis of 22 cases.

OBJECTIVE: Intrathyroid thymic carcinoma (ITTC) is a rare malignancy. The current understanding of ITTC is inadequate, and there is no standard treatment for ITTC. In the present study, we aimed to explore the clinicopathological characteristics of ITTC and identify potential therapeutic targets. METHODS: The clinicopathological characteristics of 22 ITTC patients at our institution were reviewed. The expression of DNA mismatch repair (MMR) proteins and PD-L1 in ITTC were assessed by immunohistochemistry (IHC). RESULTS: All patients underwent surgery. There were nine females and 13 males, with a slight male predominance. Their ages ranged from 42 to 79 years (average, 54. 1 years). The diameters of the neck masses ranged from 10 to 100 mm (average, 39 mm). Ipsilateral lymph node (LN) dissection was performed in 18 patients: 12 demonstrated LN metastasis, six showed no LN metastasis, and no lymph nodes were dissected in four. One patient had liver metastasis. CK5/6, P63, CD5, and CD117 were expressed in all cases. All cases were negative for TTF1, PAX8, thyroglobulin, and BRAF V600E. DNA MMR protein expression was retained in all tested tumors, and EBV-encoded small RNA (EBER) in situ hybridization was consistently negative. The Ki67 proliferation index ranged from 10 to 70 %. All patients were followed-up for 14-134 months, four died, six were lost to follow-up, and the remaining patients survived without disease. The PD-L1 combined positive score ranged from 10 to 80 (average: 40). CONCLUSION: Our results confirm that CD5 and CD117 co-expression support a diagnosis of ITTC. All tumors in this cohort were DNA MMR-proficient and were not associated with Epstein-Barr virus (EBV) infection. A high CPS for PD-L1 suggests that immune checkpoint inhibitor therapy may be worthy of further exploration in patients with ITTC.

Long non-coding RNA NBR2 suppresses the progression of colorectal cancer by downregulating miR-19a to regulate M2 macrophage polarization.

Colorectal cancer (CRC) is a malignant tumor of the gastrointestinal tract that significantly impacts the health of patients and lacks promising methods of diagnosis. Tumor-associated macrophages (TAMs) are involved in CRC progression, and their function is regulated by long non-coding RNAs (lncRNAs). The lncRNA NBR2 was recently reported as an oncogene, whose function in CRC remains uncertain. The present study aimed to investigate the biological function of lncRNA NBR2 in the progression of CRC and its underlying molecular mechanisms. Ten pairs of clinical CRC and para-carcinoma tissues were collected to determine the expression levels of lncRNA NBR2 and miR-19a, and the polarization state of TAMs. Quantitative reverse transcriptase-polymerase chain reaction was used to evaluate the expression of miR-19a, and western blotting was used to determine the expression levels of tumor necrosis factor-α, human leukocyte antigen-DR, arginase-1, CD163, CD206, interleukin-4, AMP-activated protein kinase (AMPK), p-AMPK, hypoxia-inducible factor-1α (HIF-1α), protein kinase B (AKT), p-AKT, mechanistic target of rapamycin (mTOR), and p-mTOR in TAMs. The proliferative ability of HCT-116 cells was detected using the CCK8 assay, and the migratory ability of HCT-116 cells was evaluated using the Transwell assay. The interaction between lncRNA NBR2 and miR-19a was determined using the luciferase assay. The lncRNA NBR2 was downregulated and miR-19a was highly expressed in CRC cells, accompanied by a high M2 polarization. Downregulated miR-19a promoted M1 polarization, activated AMPK, suppressed HIF-1α and AKT/mTOR signaling pathways, and promoted antitumor properties in NBR2-overexpressed TAMs, which were all reversed by the introduction of the miR-19a mimic. LncRNA NBR2 was verified to target miR-19a in macrophages according to the results of the luciferase assay. Collectively, lncRNA NBR2 may suppress the progression of CRC by downregulating miR-19a to regulate M2 macrophage polarization.

Waveguide-Integrated PdSe2 Photodetector over a Broad Infrared Wavelength Range.

Hybrid integration of van der Waals materials on a photonic platform enables diverse exploration of novel active functions and significant improvement in device performance for next-generation integrated photonic circuits, but developing waveguide-integrated photodetectors based on conventionally investigated transition metal dichalcogenide materials at the full optical telecommunication bands and mid-infrared range is still a challenge. Here, we integrate PdSe2 with silicon waveguide for on-chip photodetection with a high responsivity from 1260 to 1565 nm, a low noise-equivalent power of 4.0 pW·Hz-0.5, a 3-dB bandwidth of 1.5 GHz, and a measured data rate of 2.5 Gbit·s-1. The achieved PdSe2 photodetectors provide new insights to explore the integration of novel van der Waals materials with integrated photonic platforms and exhibit great potential for diverse applications over a broad infrared range of wavelengths, such as on-chip sensing and spectroscopy.

hKLK alleviates myocardial fibrosis in mice with viral myocarditis.

Myocardial fibrosis is the most serious complication of viral myocarditis (VMC). This study aimed to investigate the therapeutic benefits and underlying mechanisms of lentivirus-mediated human tissue kallikrein gene transfer in myocardial fibrosis in VMC mice. We established VMC mouse model via intraperitoneal injection with Coxsackie B3 virus. The effect was then assessed after treatment with vehicle, the empty lentiviral vectors (EZ.null), and the vectors expressing hKLK1 (EZ.hKLK1) via tail vein injection for 30 days, respectively. The results showed that administering EZ.hKLK1 successfully induced hKLK1 overexpression in mouse heart. Compared with EZ.null treatment, EZ.hKLK1 administration significantly reduced the heart/weight ratio, improved cardiac function, and ameliorated myocardial inflammation in VMC mice, suggesting that hKLK1 overexpression alleviates VMC in mice. EZ.hKLK1 administration also significantly abrogated the increased myocardial collagen content, type I/III collagen ratio, TGF-ß1 mRNA and protein expression in VMC mice, suggesting that hKLK1 overexpression reduces collagen accumulation and blunts TGF-ß1 signaling in the hearts of VMC mice. In conclusion, our results suggest that hKLK1 alleviates myocardial fibrosis in VMC mice, possibly by downregulating TGF-ß1 expression.

Hybrid NOMA/OFDMA visible light communication system with coordinated multiple point transmission.

In this study, a hybrid non-orthogonal multiple access / orthogonal frequency division multiple access (NOMA/OFDMA) scheme is proposed for multi-cell multi-user visible light communication (VLC) systems. Each cell is divided into several sub-cells that are multiplexed using OFDMA. Users within the same sub-cell are multiplexed by NOMA. Thus, the hybrid NOMA/OFDMA scheme takes advantage of both NOMA and OFDMA, which not only improves the spectral efficiency of OFDMA but also avoids the co-channel interference of NOMA. Moreover, coordinated multiple-point transmission based on repeated coding is introduced to eliminate multiuser interference, which also improves the received signal-to-noise ratio of edge users. In this manner, spectrum resources are fully utilized, where the frequency reuse factor is equal to 1. Furthermore, we propose a two-dimensional power-allocation algorithm for the proposed hybrid NOMA/OFDMA VLC system. Based on the fixed power allocation strategy, power is allocated jointly among sub-cells and users within sub-cells to minimize the average symbol error rate (SER). The performance of the proposed system was investigated in detail by simulation, where the SERs were evaluated under different power ratios. Simulation results also show that the SER performance of the proposed hybrid NOMA/OFDMA VLC system is significantly improved compared to the traditional NOMA and OFDMA VLC systems in different VLC networks. Finally, the proof-of-concept experiment was set up, clearly validating the superiority of the proposed system further.

Narrow-bandwidth Bragg grating filter based on Ge-Sb-Se chalcogenide glasses.

Bragg grating (BG) filters play important roles in integrated photonics such as signal processing and optical sensing. In silicon-based counterpart photonic platforms, the application of narrow-bandwidth (Δλ) filters is often restrained by fabrication limitations. In this study, narrow-bandwidth BG filters based on Ge-Sb-Se chalcogenide materials are investigated. The structure of the filter is designed by optimizing the grating period, corrugation height, and grating number. The large corrugation of chalcogenide BG is more friendly and convenient for manufacturing process. The symmetric and asymmetric corrugation filters are then fabricated and characterized. Experimental results show a half-maximum bandwidth of 0.97 nm and 0.32 nm for symmetric and asymmetric filters, respectively, which demonstrates excellent narrow-bandwidth filtering performance of chalcogenide BG.

High Q-factor, ultrasensitivity slot microring resonator sensor based on chalcogenide glasses.

In this article, the chalcogenide slot waveguide is theoretically studied, and the highest power confinement factors of the slot region and the cladding region are obtained to be 36.3% and 56.7%, respectively. A high-sensitivity chalcogenide slot microring resonator sensor is designed and fabricated by electron-beam lithography and dry etching. The structure increases the sensitivity of the sensor compared with the conventional evanescent field waveguide sensor. The cavity has achieved a quality factor of 1 × 104 by fitting the resonant peaks with the Lorentzian profile, one of the highest quality factors reported for chalcogenide slot microring resonators. The sensor sensitivity is measured to be 471 nm/RIU, which leads to an intrinsic limit of detection of 3.3 × 10--4 RIU.