Taking a color photo: A homozygous 25-bp deletion in Bace2 may cause brown-and-white coat color in giant pandas.

Brown-and-white giant pandas (hereafter brown pandas) are distinct coat color mutants found exclusively in the Qinling Mountains, Shaanxi, China. However, its genetic mechanism has remained unclear since their discovery in 1985. Here, we identified the genetic basis for this coat color variation using a combination of field ecological data, population genomic data, and a CRISPR-Cas9 knockout mouse model. We de novo assembled a long-read-based giant panda genome and resequenced the genomes of 35 giant pandas, including two brown pandas and two family trios associated with a brown panda. We identified a homozygous 25-bp deletion in the first exon of Bace2, a gene encoding amyloid precursor protein cleaving enzyme, as the most likely genetic basis for brown-and-white coat color. This deletion was further validated using PCR and Sanger sequencing of another 192 black giant pandas and CRISPR-Cas9 edited knockout mice. Our investigation revealed that this mutation reduced the number and size of melanosomes of the hairs in knockout mice and possibly in the brown panda, further leading to the hypopigmentation. These findings provide unique insights into the genetic basis of coat color variation in wild animals.

Evolutionary Conservation Genomics Reveals Recent Speciation and Local Adaptation in Threatened Takins.

Incorrect species delimitation will lead to inappropriate conservation decisions, especially for threatened species. The takin (Budorcas taxicolor) is a large artiodactyl endemic to the Himalayan-Hengduan-Qinling Mountains and is well known for its threatened status and peculiar appearance. However, the speciation, intraspecies taxonomy, evolutionary history, and adaptive evolution of this species still remain unclear, which greatly hampers its scientific conservation. Here, we de novo assembled a high-quality chromosome-level genome of takin and resequenced the genomes of 75 wild takins. Phylogenomics revealed that takin was positioned at the root of Caprinae. Population genomics based on the autosome, X chromosome, and Y chromosome SNPs and mitochondrial genomes consistently revealed the existence of two phylogenetic species and recent speciation in takins: the Himalayan takin (B. taxicolor) and the Chinese takin (B. tibetana), with the support of morphological evidence. Two genetically divergent subspecies were identified in both takin species, rejecting three previously proposed taxonomical viewpoints. Furthermore, their distribution boundaries were determined, suggesting that large rivers play important roles in shaping the genetic partition. Compared with the other subspecies, the Qinling subspecies presented the lowest genomic diversity, higher linkage disequilibrium, inbreeding, and genetic load, thus is in urgent need of genetic management and protection. Moreover, coat color gene (PMEL) variation may be responsible for the adaptive coat color difference between the two species following Gloger's rule. Our findings provide novel insights into the recent speciation, local adaptation, scientific conservation of takins, and biogeography of the Himalaya-Hengduan biodiversity hotspot.

Establishment and validation of serum lipid-based nomogram for predicting the risk of prostate cancer.

BACKGROUND: This study aimed to explore the value of combined serum lipids with clinical symptoms to diagnose prostate cancer (PCa), and to develop and validate a Nomogram and prediction model to better select patients at risk of PCa for prostate biopsy. METHODS: Retrospective analysis of 548 patients who underwent prostate biopsies as a result of high serum prostate-specific antigen (PSA) levels or irregular digital rectal examinations (DRE) was conducted. The enrolled patients were randomly assigned to the training groups (n = 384, 70%) and validation groups (n = 164, 30%). To identify independent variables for PCa, serum lipids (TC, TG, HDL, LDL, apoA-1, and apoB) were taken into account in the multivariable logistic regression analyses of the training group, and established predictive models. After that, we evaluated prediction models with clinical markers using decision curves and the area under the curve (AUC). Based on training group data, a Nomogram was developed to predict PCa. RESULTS: 210 (54.70%) of the patients in the training group were diagnosed with PCa. Multivariate regression analysis showed that total PSA, f/tPSA, PSA density (PSAD), TG, LDL, DRE, and TRUS were independent risk predictors of PCa. A prediction model utilizing a Nomogram was constructed with a cut-off value of 0.502. The training and validation groups achieved area under the curve (AUC) values of 0.846 and 0.814 respectively. According to the decision curve analysis (DCA), the prediction model yielded optimal overall net benefits in both the training and validation groups, which is better than the optimal net benefit of PSA alone. After comparing our developed prediction model with two domestic models and PCPT-RC, we found that our prediction model exhibited significantly superior predictive performance. Furthermore, in comparison with clinical indicators, our Nomogram's ability to predict prostate cancer showed good estimation, suggesting its potential as a reliable tool for prognostication. CONCLUSIONS: The prediction model and Nomogram, which utilize both blood lipid levels and clinical signs, demonstrated improved accuracy in predicting the risk of prostate cancer, and consequently can guide the selection of appropriate diagnostic strategies for each patient in a more personalized manner.

Quantum Image Processing Algorithm Using Line Detection Mask Based on NEQR.

Line detection is a fundamental technique in image processing. It can extract the required information, while the information that does not need attention can be ignored, thus reducing the amount of data. At the same time, line detection is also the basis of image segmentation and plays an important role in this process. In this paper, we implement a quantum algorithm based on a line detection mask for novel enhanced quantum representation (NEQR). We build a quantum algorithm for line detection in different directions and design a quantum circuit for line detection. The detailed module designed is also provided. On a classical computer, we simulate the quantum method, and the simulation results prove the feasibility of the quantum method. By analyzing the complexity of quantum line detection, we find that the computation complexity of the proposed method is improved compared to some similar edge detection algorithms.

Human safety study of a selective neuronal adenylate cyclase 1 inhibitor NB001 which relieves the neuropathic pain and blocks ACC in adult mice.

Calcium-dependent, neuronal adenylyl cyclase subtype 1 (AC1) is critical for cortical potentiation and chronic pain. NB001 is a first-in-class drug acting as a selective inhibitor against AC1. The present study delineated the pharmacokinetic (PK) properties of human-used NB001 (hNB001) formulated as immediate-release tablet. This first-in-human (FIH) study was designed as randomized, double-blind, placebo-controlled trial. hNB001 showed placebo-like safety and good tolerability in healthy volunteers. A linear dose-exposure relationship was demonstrated at doses between 20 mg and 400 mg. The relatively small systemic exposure of hNB001 in human showed low bioavailability of this compound through oral administration, which can be improved through future dosage research. Food intake had minimal impact on the absorption of hNB001 tablet. Animal experiments further confirmed that hNB001 had strong analgesic effect in animal models of neuropathic pain. In brain slice prepared from the anterior cingulate cortex (ACC), bath application of hNB001 blocked the induction of long-term potentiation (LTP). These results from both rodents and human strongly suggest that hNB001 can be safely used for the future treatment of different types of chronic pain in human patients.

Overexpression of TaLAX3-1B alters the stomatal aperture and improves the salt stress resistance of tobacco.

BACKGROUND: Stomata, which play important roles in both optimizing photosynthesis efficiency and adapting to stress, are closely related to IAA and ABA. In plants, the auxin influx carrier LAX3 has been found to play roles in development and stress tolerance. However, the function of LAX3 in stomata and in response to salt stress remains largely unknown. METHODS AND RESULTS: Here, we show that overexpression of wheat TaLAX3-1B in tobacco results in a decrease in stomatal aperture and a relatively closed state of the stomata. In addition, the stomatal movement of the OxTaLAX3-1B lines was less sensitive to ABA than that of the WT. Consistently, compared with the WT, the OxTaLAX3-1B lines showed significantly higher expression of stomate-, IAA- and ABA-related genes and endogenous IAA and ABA contents. Furthermore, compared with the WT, the OxTaLAX3-1B lines exhibited higher proline content, salt stress-related gene expression and ROS antioxidant enzyme activity but lower MDA content and ROS accumulation after salt treatment. CONCLUSIONS: The present results suggest that TaLAX3-1B plays a positive role in regulating stomatal closure and enhancing salt stress tolerance.

Resveratrol and lycium barbarum polysaccharide improve Qinling giant panda (Ailuropoda melanoleuca Qinlingensis) sperm quality during cryopreservation.

BACKGROUND: Semen cryopreservation has become an essential tool for conservation efforts of the giant panda (Ailuropoda melanoleuca); however, it is severely detrimental to sperm quality. Evidence has shown that antioxidants have the potential to reverse cryopreservation-induced damage in sperm. The purpose of this study was to screen effective antioxidants that could retain sperm quality during cryopreservation and to determine the optimal dose. Seven antioxidant groups, including resveratrol (RSV = 50 µM, RSV = 100 µM, RSV = 150 µM), lycium barbarum polysaccharide (LBP = 2 mg/mL, LBP = 4 mg/mL), laminaria japonica polysaccharides (LJP = 1 mg/mL) or combination (LBP = 2 mg/mL, LJP = 1 mg/mL and RSV = 100 µM) were assessed. RESULTS: RSV, LBP, LJP, or a combination of RSV, LBP, and LJP added to the freezing medium significantly improved sperm progressive motility, plasma membrane integrity, acrosome integrity, and mitochondrial activity during the cryopreservation process. Furthermore, the activities of glutathione peroxidase and superoxide dismutase were also improved. The levels of reactive oxygen species and malondialdehyde in semen were notably reduced. Hyaluronidase activity and acrosin activity were significantly increased in LBP-treated sperm. However, sperm total motility and DNA integrity were not significantly different between the groups. CONCLUSIONS: RSV (50 µM) or LBP (2 mg/mL) are the best candidate antioxidants for inclusion in the freezing medium to improve the quality of giant panda spermatozoa during semen cryopreservation.

Inactivation of Target RNA Cleavage of a III-B CRISPR-Cas System Induces Robust Autoimmunity in Saccharolobus islandicus.

Type III CRISPR-Cas systems show the target (tg)RNA-activated indiscriminate DNA cleavage and synthesis of oligoadenylates (cOA) and a secondary signal that activates downstream nuclease effectors to exert indiscriminate RNA/DNA cleavage, and both activities are regulated in a spatiotemporal fashion. In III-B Cmr systems, cognate tgRNAs activate the two Cmr2-based activities, which are then inactivated via tgRNA cleavage by Cmr4, but how Cmr4 nuclease regulates the Cmr immunization remains to be experimentally characterized. Here, we conducted mutagenesis of Cmr4 conserved amino acids in Saccharolobus islandicus, and this revealed that Cmr4α RNase-dead (dCmr4α) mutation yields cell dormancy/death. We also found that plasmid-borne expression of dCmr4α in the wild-type strain strongly reduced plasmid transformation efficiency, and deletion of CRISPR arrays in the host genome reversed the dCmr4α inhibition. Expression of dCmr4α also strongly inhibited plasmid transformation with Cmr2αHD and Cmr2αPalm mutants, but the inhibition was diminished in Cmr2αHD,Palm. Since dCmr4α-containing effectors lack spatiotemporal regulation, this allows an everlasting interaction between crRNA and cellular RNAs to occur. As a result, some cellular RNAs, which are not effective in mediating immunity due to the presence of spatiotemporal regulation, trigger autoimmunity of the Cmr-α system in the S. islandicus cells expressing dCmr4α. Together, these results pinpoint the crucial importance of tgRNA cleavage in autoimmunity avoidance and in the regulation of immunization of type III systems.

Accelerated electrowetting-based tunable fluidic lenses.

One of the limitations in the application of electrowetting-based tunable fluidic lenses is their slow response time. We consider here two approaches for enhancing the response speed of tunable fluidic lenses: optimization of the properties of the fluids employed and modification of the time-dependent actuation voltages. Using a tubular optofluidic configuration, it is shown through simulations how one may take advantage of the interplay between liquid viscosities and surface tension to reduce the actuation time. In addition, by careful designing the actuation pulses, the response speed of both overdamped and underdamped systems may be increased by over an order of magnitude, leading to response times of several ten milliseconds. These performance improvements may significantly enhance the applicability of tunable optofluidic-based components and systems.

Tunable fluidic lens with a dynamic high-order aberration control.

Fluidic lenses based on electrowetting actuation are attractive for their wide focal tuning range, yet are limited by optical aberrations, either intrinsic to the lenses themselves or due to the optical imaging systems in which they are employed. However, the ability to control the meniscus shape that forms the lens refractive surface with a high degree of spatial accuracy will allow correction of and compensation for a wide range of these aberrations. We demonstrate here for what we believe, to the best of our knowledge, is the first time a tunable optofluidic lens controlled by 32 azimuthally placed electrodes for which most aberrations up to the fourth radial Zernike order may be corrected. Using both wavefront sensing and sensorless wavefront estimation techniques, it is shown that focal length tunability with a significant reduction in imaging aberrations and the ability to compensate for externally induced aberrations may be achieved using a single component.

Multi-Label Active Learning Algorithms for Image Classification: Overview and Future Promise.

Image classification is a key task in image understanding, and multi-label image classification has become a popular topic in recent years. However, the success of multi-label image classification is closely related to the way of constructing a training set. As active learning aims to construct an effective training set through iteratively selecting the most informative examples to query labels from annotators, it was introduced into multi-label image classification. Accordingly, multi-label active learning is becoming an important research direction. In this work, we first review existing multi-label active learning algorithms for image classification. These algorithms can be categorized into two top groups from two aspects respectively: sampling and annotation. The most important component of multi-label active learning is to design an effective sampling strategy that actively selects the examples with the highest informativeness from an unlabeled data pool, according to various information measures. Thus, different informativeness measures are emphasized in this survey. Furthermore, this work also makes a deep investigation on existing challenging issues and future promises in multi-label active learning with a focus on four core aspects: example dimension, label dimension, annotation, and application extension.

Gravity-immune liquid-filled tunable lens with reduced spherical aberration.

The performance of uniform-thickness membrane lenses is severely compromised due to the inherent trade-off between spherical aberration and the sensitivity to gravity effects. This problem can be eliminated by engineering the membrane thickness profile such that a membrane stiff enough to withstand gravity-induced deformations can be shaped into a perfect optical surface under uniform pressure load. We present here a membrane-based liquid-tunable aspherical lens capable of diffraction-limited performance at nominal focal length, with two orders-of-magnitude smaller wavefront error compared to conventional tunable lenses, regardless of the lens orientation, by use of a non-uniform thickness profile of the flexible membrane. The lens has an aperture size of 3 mm, with a nominal focal length of 8 mm and a theoretical diffraction-limited tuning range between 7.2 and 8.8 mm. Between 6 and 12 mm, the cutoff frequency remains above 50% of the diffraction limit, demonstrating a drastic reduction in spherical aberration compared to conventional liquid-tunable lenses.

Spherical aberration free liquid-filled tunable lens with variable thickness membrane.

We present an iterative design method for liquid-tunable aspherical lenses capable of diffraction-limited performance over a wide focal length range. The lenses are formed by a thin elastomer meniscus with a variable thickness profile engineered to deform into an ideal asphere under uniform pressure load. Compared to their more conventional counterparts, the proposed lenses significantly reduce spherical aberration over a larger portion of the aperture. The design procedure begins with the semi-analytical calculation of the meniscus thickness profile using large-deflection thin plate theory. This initial profile is then further optimized using coupled finite element analysis and ray-tracing simulations iteratively. We apply the developed method to design a tunable aspherical lens with 3 mm clear aperture and 8 mm optimum focal length, and numerically demonstrate the improvement in optical performance over conventional tunable-lenses over a focal length range from 6 mm to 12 mm. Using 80% of the clear aperture, the lens has better than λ/4 RMS surface error over the focal length range from 7.7 mm to 8.5 mm, corresponding to 10% tuning of focal length with diffraction-limited performance. The sources of potential fabrication errors in a practical implementation of such a lens are also analyzed in detail in terms of their influence on optical performance.

Mixed pattern matching-based traffic abnormal behavior recognition.

A motion trajectory is an intuitive representation form in time-space domain for a micromotion behavior of moving target. Trajectory analysis is an important approach to recognize abnormal behaviors of moving targets. Against the complexity of vehicle trajectories, this paper first proposed a trajectory pattern learning method based on dynamic time warping (DTW) and spectral clustering. It introduced the DTW distance to measure the distances between vehicle trajectories and determined the number of clusters automatically by a spectral clustering algorithm based on the distance matrix. Then, it clusters sample data points into different clusters. After the spatial patterns and direction patterns learned from the clusters, a recognition method for detecting vehicle abnormal behaviors based on mixed pattern matching was proposed. The experimental results show that the proposed technical scheme can recognize main types of traffic abnormal behaviors effectively and has good robustness. The real-world application verified its feasibility and the validity.

An active learning approach with uncertainty, representativeness, and diversity.

Big data from the Internet of Things may create big challenge for data classification. Most active learning approaches select either uncertain or representative unlabeled instances to query their labels. Although several active learning algorithms have been proposed to combine the two criteria for query selection, they are usually ad hoc in finding unlabeled instances that are both informative and representative and fail to take the diversity of instances into account. We address this challenge by presenting a new active learning framework which considers uncertainty, representativeness, and diversity creation. The proposed approach provides a systematic way for measuring and combining the uncertainty, representativeness, and diversity of an instance. Firstly, use instances' uncertainty and representativeness to constitute the most informative set. Then, use the kernel k-means clustering algorithm to filter the redundant samples and the resulting samples are queried for labels. Extensive experimental results show that the proposed approach outperforms several state-of-the-art active learning approaches.

Mechano-triggered eradication of dentinal tubule biofilm via in situ generation of nanoscale sonosensitizer by the tailored irrigation formulation.

The efficient elimination of bacteria within the dentinal tubules has been hindered by the poor deposition and short residence of disinfecting agents. Meanwhile, the current irrigant (e.g., NaClO, 5.25 %) shows severe adverse effects on the surrounding soft tissues because of its inherent high irritancy. To address this issue, this work reports an in situ generated sonosensitizer to handle the biofilm in dentinal tubules with minimal adverse effects. The production of nanoscale sonosensitizer involves the concurrent delivery of H2O2 (0.01 %), ferrocene derivative (Fc), and indocyanine green (ICG). With ultrasound treatment, the reaction between H2O2 and Fc liberated Fe3+ that was further complexed with ICG to generate the nanoscale sonosensitizer in situ, followed by singlet oxygen production for potent disinfecting action. Because the above cascade reactions occur within the confined dentinal tubules, the generated ICG-Fe3+ nanosensitizer would show prolonged retention therein. The anti-bacterial potency of nanosensitizer was demonstrated in petrodish and ex vivo biofilm models. Meanwhile, the transmission electron microscope imaging of biofilm and cytotoxicity assay in L929 fibroblast cells proved the superiority of nanosensitizer against NaClO regarding adverse effects. The current work opens new avenues of biofilm elimination in dentinal tubules, showing a high translation potential.

Phacoemulsification combined with goniosynechialysis versus phacoemulsification alone for patients with primary angle­closure disease: A meta-analysis.

This meta-analysis aims to systematically compare the efficacy between phacoemulsification (PE) combined with goniosynechialysis (GSL) and PE alone for primary angle-closure disease (PACD) patients. All the data were searched from the PubMed, EMBASE and the Cochrane Library. The Cochrane Handbook was used to evaluate the quality of the included studies. Additionally, this meta-analysis was performed by using the Revman 5.4 software. Nine randomized controlled trials (RCTs) were included in this study. Compared with PE alone group, PE+GSL could result significant reduction in the IOP (MD, 1.81; p = 0.002). In the instrumental subgroup, also more reduction of IOP was shown in the PE+GSL group (MD, 2.11; p = 0.02). In the viscogonioplasty (VGP) subgroup, there was not no statistical difference between PE alone group and PE+GSL group (MD, 1.53; p = 0.11). Also, more reduction of peripheral anterior synechiae (PAS) was shown in the PE+GSL group (MD,59.15; p<0.00001). For the change in angle open distance (AOD)500, AOD 750, trabecular-iris space (TISA)500, number of glaucoma medications and best corrected visual acuity (BCVA), there was no difference between two groups (p = 0.25, 0.35, 0.17, 0.56, 0.08). For TISA 750, more improvement was shown in the PE+GSL group (p<0.00001). Instrumental separation had better effect on lowering IOP when it combined with PE. Both instrumental separation and VGP could reduce postoperative PAS. The operation of GSL has no obvious effect on postoperative vision.

Image-Guided Marking versus Manual Marking in Phacoemulsification with Toric Intraocular Lens (IOL) Implantation: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

PURPOSES: The purpose of this meta-analysis is to systematically compare the alignment accuracy and post uncorrected distance visual acuity (UDVA) between image-guided marking and manual marking for toric intraocular lens (IOL) in cataract surgery. METHODS: This work was done through the data searched from the PubMed, EMBASE and the Cochrane Library. The Cochrane Handbook was also used to evaluate the quality of the included studies. In addition, this meta-analysis was performed using Revman 5.4 software. RESULTS: A total of 6 randomized controlled trials (RCTs) were included. Compared with manual marking group, image-guided marking group had less toric IOL axis misalignment (MD, -1.98; 95%CI, -3.27 to -0.68; p = .003), less postoperative astigmatism (MD, -0.13; 95%CI, -0.21 to -0.05; p = .001), better postoperative UDVA (MD, -0.02; 95%CI, -0.04 to -0.01; p = .0003) and smaller difference vector (MD, -0.10; 95%CI, -0.14 to -0.06; p(0.00001). For the proportion of patients with residual refractive cylinder within 0.5 D, there was no difference between two groups (p = .07). CONCLUSION: Image-guided marking is prior to manual marking. As it can bring less toric IOL axis misalignment, less postoperative astigmatism, better postoperative UDVA and smaller difference vector for the patients with toric IOL implantation.

Rational design of unrestricted pRN1 derivatives and their application in the construction of a dual plasmid vector system for Saccharolobus islandicus.

Saccharolobus islandicus REY15A represents one of the very few archaeal models with versatile genetic tools, which include efficient genome editing, gene silencing, and robust protein expression systems. However, plasmid vectors constructed for this crenarchaeon thus far are based solely on the pRN2 cryptic plasmid. Although this plasmid coexists with pRN1 in its original host, early attempts to test pRN1-based vectors consistently failed to yield any stable host-vector system for Sa. islandicus. We hypothesized that this failure could be due to the occurrence of CRISPR immunity against pRN1 in this archaeon. We identified a putative target sequence in orf904 encoding a putative replicase on pRN1 (target N1). Mutated targets (N1a, N1b, and N1c) were then designed and tested for their capability to escape the host CRISPR immunity by using a plasmid interference assay. The results revealed that the original target triggered CRISPR immunity in this archaeon, whereas all three mutated targets did not, indicating that all the designed target mutations evaded host immunity. These mutated targets were then incorporated into orf904 individually, yielding corresponding mutated pRN1 backbones with which shuttle plasmids were constructed (pN1aSD, pN1bSD, and pN1cSD). Sa. islandicus transformation revealed that pN1aSD and pN1bSD were functional shuttle vectors, but pN1cSD lost the capability for replication. These results indicate that the missense mutations in the conserved helicase domain in pN1c inactivated the replicase. We further showed that pRN1-based and pRN2-based vectors were stably maintained in the archaeal cells either alone or in combination, and this yielded a dual plasmid system for genetic study with this important archaeal model.

Current status and trends of urinary incontinence research in recent 10 years based on VOSviewer visualized analysis: An observational study.

Urinary incontinence (UI) is prevalent and imposes significant social and economic burdens. This study reviews the literature on UI, assesses the current research status, and projects future trends. To visualize and analyze UI-related research, summarize and generalize the knowledge framework of the global UI field, and explore the current state of research and emerging trends, we conducted a comprehensive search of UI-related studies from 2014 to 2024 using the Web of Science Core Collection. Utilizing VOSviewer software, we mapped the scientific landscape and performed visual analytics on collaborative and co-citation networks, keyword co-occurrences, emergent clusters, and timeline mapping to elucidate the research dynamics. A total of 4326 publications were retrieved for further analysis. The United States ranked first in terms of the total number of publications, number of citations, and publication H-index. In terms of institutions, the University of California System had the most total citations and the highest H-index. Neurology and Urodynamics had the most articles published, the highest citation frequency, and the highest H-index. The author with the most citations and the highest average number of citations per article is Abrams P. The author with the highest H-index is Peyronnet B. Based on the keyword analysis, the articles were categorized into several main directions: epidemiological studies, diagnostic studies, treatment studies, female UI studies, and male UI studies. Epidemiology, treatment, and male UI are expected to continue as hot topics. This study demonstrates that UI research is more advanced in Europe and North America and that Neurourology and Urodynamics is the most influential journal in the field. In addition, epidemiology, treatment, and male UI will continue to be prominent topics. Our study contributes to a more comprehensive understanding of the current state of UI research and provides insights into future research directions in the field.