CRISPRlnc: a machine learning method for lncRNA-specific single-guide RNA design of CRISPR/Cas9 system.

CRISPR/Cas9 is a promising RNA-guided genome editing technology, which consists of a Cas9 nuclease and a single-guide RNA (sgRNA). So far, a number of sgRNA prediction softwares have been developed. However, they were usually designed for protein-coding genes without considering that long non-coding RNA (lncRNA) genes may have different characteristics. In this study, we first evaluated the performances of a series of known sgRNA-designing tools in the context of both coding and non-coding datasets. Meanwhile, we analyzed the underpinnings of their varied performances on the sgRNA's specificity for lncRNA including nucleic acid sequence, genome location and editing mechanism preference. Furthermore, we introduce a support vector machine-based machine learning algorithm named CRISPRlnc, which aims to model both CRISPR knock-out (CRISPRko) and CRISPR inhibition (CRISPRi) mechanisms to predict the on-target activity of targets. CRISPRlnc combined the paired-sgRNA design and off-target analysis to achieve one-stop design of CRISPR/Cas9 sgRNAs for non-coding genes. Performance comparison on multiple datasets showed that CRISPRlnc was far superior to existing methods for both CRISPRko and CRISPRi mechanisms during the lncRNA-specific sgRNA design. To maximize the availability of CRISPRlnc, we developed a web server (http://predict.crisprlnc.cc) and made it available for download on GitHub.

Synthesis and Assembly of Photoresponsive Colloidal Tubes.

Inspired by the sophisticated multicomponent and multistage assembly of proteins and their mixtures in living cells, this study rationally designs and fabricates photoresponsive colloidal tubes that can self-assemble and hybrid-assemble when mixed with colloidal spheres and rods. Time-resolved observation and computer simulation reveal that the assembly is driven by phoretic attraction originating from osmotic pressures. These pressures are induced by the chemical concentration gradients generated by the photochemical reaction caused by colloidal tubes in a H2O2 solution under ultraviolet (UV) irradiation. The assembled structure is dictated by the size and shape of the constituent colloids as well as the intensity of the UV irradiation. Additionally, the resulting assembly can undergo self-propelled motion originating from the broken symmetry of the surrounding concentration gradients. This motion can be steered by a magnetic field and used for microscale cargo delivery. The study demonstrates a facile synthesis method for colloidal tubes and highlights their unique potential for controlled, hierarchical self-assembly and hybrid-assembly.

Internal motion within ultrafast asynchronous dual wavelength mode-locked lasers.

Realtime spectroscopy access to ultrafast fiber lasers provides new opportunities for exploring complex soliton interaction dynamics. In this study, we employ a time-stretch technique that enables real-time access to both spectral and temporal dynamics, revealing rich nonlinear processes in asynchronous dual wavelength mode-locked pulses in an ultrafast fiber laser. Due to the different group velocities of the two wavelengths, the mode-locked solitons centered at different wavelengths periodically collide with each other. We recorded the entire process of soliton establishment, stabilization, and disappearance, shedding light on the mystery of stable transmission of dual-wavelength mode-locked pulses. These processes were observed for the first time in an ultrafast fiber laser, and the experimental evidence provides important insights into the understanding of nonlinear dynamics in fiber lasers, as well as the potential for improving laser performance for application in dual-comb spectroscopy.

A two-sample Mendelian randomization study of mutual relations of six types of diets in atopic dermatitis.

BACKGROUND: In the continuous endeavor to find safe and efficient treatments for Atopic Dermatitis (AD), there remains a considerable focus on dietary adjustments. Nevertheless, the limited availability of research and conflicting findings in the academic literature pose a hurdle in establishing conclusive recommendations. METHOD: Mendelian randomization (MR) was applied to the most comprehensive genome-wide association studies (GWAS) data on tea intake (447 485), green tea intake (n = 64 949), flavored milk intake (n = 64 941), never eat eggs, dairy, wheat, sugar: Wheat products(n = 461 046), never eat eggs, dairy, wheat, sugar: Sugar or foods/drinks containing sugar (n = 461 046), never eat eggs, dairy, wheat, sugar: I eat all of the above (n = 461 046) and atopic dermatitis (n = 218 467). We used the inverse-variance weighted method (IVW) as the primary method. RESULTS: The IVW analyses have demonstrated an increased tea intake was genetically associated with a reduced risk of AD (odds ratio [OR]: 0.646, 95% confidence interval [CI]: 0.430-0.968, p = 0.034). Furthermore, green tea intake was significantly negatively associated with AD (IVW OR: 0.986, 95% CI: 0.975-0.998; p = 0.024) in the IVW model. AD risk could be reduced by never eating wheat products (IVW OR: 8.243E-04, 95% CI: 7.223E-06-9.408E-02, p = 0.003). There was no association between never eating eggs, dairy, wheat, sugar: Sugar, or foods/drinks containing sugar, I eat all of the above and AD. CONCLUSIONS: Our MR study suggests a causal relationship between tea intake, green tea intake, and the avoidance of eating wheat products with atopic dermatitis. Our findings recommend that preventing and managing atopic dermatitis may be achieved by never eating wheat products while increasing tea and green tea intake.

Calreticulin, a potential coregulator of immune checkpoints and biomarker associated with tumor microenvironment and clinical prognostic significance in breast invasive carcinoma.

As a promising immune checkpoint of immunogenic cell death (ICD) and multifunctional calcium-binding molecular chaperone, calreticulin (CALR) has been attracting increasing attention. CALR mainly locates in cellular endoplasmic reticulum and significantly affects cell proliferation, invasion, induction of apoptosis, and angiogenesis in breast invasive carcinoma (BRCA). CALR overexpression might be correlated with a worse outcome. Nonetheless, it remains obscure how CALR correlates with immune infiltration and survival prognosis of BRCA. In this study, we investigated CALR expression utilizing RNAseq data from the cancer genome atlas (TCGA) and genotype-tissue expression (GTEx) database. The prognostic value of CALR was analyzed using clinical survival data. Enrichment analysis was conducted using the R package "clusterProfiler." We downloaded the immune cell infiltration score of TCGA samples from published articles and online databases and performed a correlation analysis between immune cell infiltration levels and CALR expression. We further assessed the association between CALR and immunomodulators. Moreover, we also evaluated the expression of CALR in 100 formalin-fixed and paraffin-embedded breast cancer and adjacent normal breast tissue specimens. Our results found that CALR was highly expressed in BRCA, and CALR expression levels differed in pathological stages, T stages, and N stages. Besides, these results suggested that CALR overexpression may have adverse effects on the progression-free interval (PFI) and disease-free interval (DFI), which may be related to tumor proliferation, invasion, and metastasis, leading to tumor deterioration. Meanwhile, immune cell infiltration analysis revealed a correlation between the expression of CALR and the number of neutrophils and dendritic cells, suggesting that CALR was highly correlated with many immunomodulators in BRCA. Our results provide potential biomarkers of CALR in BRCA. CALR may interact synergistically with other immunomodulators to regulate the immune microenvironment, which could be utilized to develop new immunotherapy drugs.

Guidelines for the clinical application of the Xihuang pill for the prevention and treatment of breast hyperplasia diseases.

CONTEXT: The Xihuang pill (XHP) is a traditional Chinese medicine formulation that has been historically used in the prevention and treatment of proliferative breast diseases. However, there is a lack of guidelines that offer recommendations for its clinical use. OBJECTIVE: The task force from the Chinese Guangdong Pharmaceutical Association aims to develop evidence-based guidelines for XHP to prevent and treat proliferative breast diseases. METHODS: We searched six Chinese and English electronic databases, including the China National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Wanfang Medical Database, PubMed, and Embase, up to November 1, 2022. Publications (case reports, clinical observation, clinical trials, reviews) on using XHP to treat proliferative breast diseases were manually searched. The search terms were Xihuang pill, hyperplasia of the mammary gland, breast lump, and mastalgia. The writing team developed recommendations based on the best available evidence. RESULTS: Treatment should be customized based on syndrome identification. We recommend using XHP for the prevention and treatment of breast hyperplasia disease when a patient presents the following syndromes: concurrent blood stasis syndrome, concurrent phlegm-stasis syndrome, and concurrent liver fire syndrome. Safety indicators, including blood analysis and liver and kidney function monitoring, should be performed regularly during treatment. CONCLUSIONS: Current clinical evidence suggests that XHP can be used as a standalone treatment or in conjunction with other medications to prevent and manage breast hyperplasia diseases. More randomized controlled studies are warranted to establish high-quality evidence of its use.

Colloidal antibiotic mimics: selective capture and killing of microorganisms by shape-anisotropic colloids.

The development of targeted and efficient antimicrobials for the selective killing of pathogenic bacteria is of great importance, yet remains challenging. Here, we propose a targeted approach to selectively capture and kill microorganisms with colloidal antibiotic mimics that are readily prepared by common chemical syntheses. The mimics are shape-anisotropic colloids, which can selectively capture shape-matching microorganisms due to lock-key depletion attractions. Furthermore, after being modified with gold nanoparticles (AuNPs) and irradiated with near-infrared light, the colloidal mimics can kill the selectively captured microorganisms due to the localized photothermal effect of the AuNPs. The work demonstrates the important ability of anisotropic colloids to selectively capture and precisely kill microorganisms, which holds considerable promise for safe and adaptive antibacterial therapies without the risk of antibiotic resistance.

Comparative study of the dynamics of colloidal glass and gel.

We investigate and compare the difference in the dynamics of two arrested states: colloidal glass and colloidal gel. Real-space experiments reveal two distinct nonergodicity origins for their slow dynamics, namely, cage effects for the glass and attractive bondings for the gel. Such distinct origins lead to a faster decay of the correlation function and a smaller nonergodicity parameter of the glass than those of the gel. We also find that the gel exhibits stronger dynamical heterogeneity compared with the glass due to the greater correlated motions in the gel. Moreover, a logarithmic decay in the correlation function is observed as the two nonergodicity origins merge, consistent with the mode coupling theory.

A Versatile Method for Synthesis of Light-Activated, Magnet-Steerable Organic-Inorganic Hybrid Active Colloids.

The immense potential of active colloids in practical applications and fundamental research calls for an efficient method to synthesize active colloids of high uniformity. Herein, a facile method is reported to synthesize uniform organic-inorganic hybrid active colloids based on the wetting effect of polystyrene (PS) with photoresponsive inorganic nanoparticles in a tetrahydrofuran/water mixture. The results show that a range of dimer active colloids can be produced by using different inorganic components, such as AgCl, ZnO, TiO2, and Fe2O3 nanoparticles. Moreover, the strategy provides a simple way to prepare dual-drive active colloids by a rational selection of the starting organic materials, such as magnetic PS particles that result in light and magnet dual-drive active colloids. The motions of these active colloids are quantified, and well-controlled movements are demonstrated.

Modular Two-Step Route to Sulfondiimidamides.

Sulfur functional groups are common motifs in bioactive molecules. Sulfonamides are most prevalent but related aza-derivatives, in which oxygen atoms are replaced by imidic nitrogens, such as sulfoximines and sulfonimidamides, are gaining attraction. Despite this activity, the double aza-variants of sulfonamides, termed sulfondiimidamides, are almost completely absent from the literature. The reason for this is poor synthetic accessibility. Although a recent synthesis has established sulfondiimidamides as viable motifs, the length of the route and the capricious nature of the key sulfondiimidoyl fluoride intermediates mean that direct application to discovery chemistry is challenging. Herein, we describe a two-step synthesis of sulfondiimidamides, exploiting a hypervalent iodine-mediated amination as the key step. The starting materials are organometallic reagents, an unsymmetrical sulfurdiimide, and amines. The method allowed >40 examples to be prepared, including derivatives of three sulfonamide-based drugs. The operational simplicity, broad scope, and concise nature make this route attractive for discovery chemistry applications.

Reconfiguring Self-Assembly of Photoresponsive Hybrid Colloids.

The reconfigurable self-assembly of colloidal particles allows the bottom-up creation of adaptive materials, yet significant challenges remain. Here, we demonstrate a synthesis of photoresponsive Fe2O3/polysiloxane hybrid colloids that perform a dynamically reconfigurable self-assembly. Such self-assembly is due to chemical gradients originating from the decomposition of H2O2 by the Fe2O3 component under UV irradiation. The morphology of the self-assembly includes chains and flower-structures, where the chains can be transformed in situ into flower-like structures with decreasing UV intensity. The flower-structures can be further switched by applying an external magnetic field, leading to orientationally ordered clusters. This, interestingly, leads to an asymmetrical chemical gradient surrounding the assemblies, and transforms the cluster into a micromotor exhibiting a self-propulsion steerable by the magnetic field. Our findings demonstrate a new possibility to control and reconfigure the self-assembly of colloids, which offers an important pathway for fabrications of adaptive and smart materials at the microscale.

Water in bacterial biofilms: pores and channels, storage and transport functions.

Bacterial biofilms occur in many natural and industrial environments. Besides bacteria, biofilms comprise over 70 wt% water. Water in biofilms occurs as bound- or free-water. Bound-water is adsorbed to bacterial surfaces or biofilm (matrix) structures and possesses different Infra-red and Nuclear-Magnetic-Resonance signatures than free-water. Bound-water is different from intra-cellularly confined-water or water confined within biofilm structures and bacteria are actively involved in building water-filled structures by bacterial swimmers, dispersion or lytic self-sacrifice. Water-filled structures can be transient due to blocking, resulting from bacterial growth, compression or additional matrix formation and are generally referred to as "channels and pores." Channels and pores can be distinguished based on mechanism of formation, function and dimension. Channels allow transport of nutrients, waste-products, signalling molecules and antibiotics through a biofilm provided the cargo does not adsorb to channel walls and channels have a large length/width ratio. Pores serve a storage function for nutrients and dilute waste-products or antimicrobials and thus should have a length/width ratio close to unity. The understanding provided here on the role of water in biofilms, can be employed to artificially engineer by-pass channels or additional pores in industrial and environmental biofilms to increase production yields or enhance antimicrobial penetration in infectious biofilms.

None-line-of-sight imaging enhanced with spatial multiplexing.

Non-line-of-sight (NLOS) imaging provides a fascinating way to see through obstacles. As one of the dominating NLOS imaging approaches, transient NLOS imaging uses ultrafast illumination and detection to sense hidden objects. Because ultrafast array detectors still face challenges in manufacture or cost, most existing transient NLOS imaging schemes use a point detector and therefore need a point-by-point scanning (PPS) process, rendering a relative low detection efficiency and long imaging time. In this work, we apply a passive mode single-pixel camera to implement spatial multiplexing detection (SMD) in NLOS imaging and achieve a higher efficiency of data acquisition. We analyze and demonstrate the superiority of SMD through both simulation and experiment. We also demonstrate a SMD scheme with compressed sensing (CS) strategy. A compression ratio as low as 18% is achieved. By utilizing SMD, we accomplish a boost of detection efficiency of up to 5 times compared with the traditional PPS mode. We believe that this SMD modality is certainly an important approach to prompt the development of NLOS imaging technologies.

Prediction of drug pro-arrhythmic cardiotoxicity using a semi-physiologically based pharmacokinetic model linked to cardiac ionic currents inhibition.

Drug-induced torsades de pointes (TdP) risks are responsible for the withdrawal of many drugs from the market. Nowadays, assessments of drug-induced TdP risks are mainly based on maximum effective free therapeutic plasma concentration (EFTPCmax) and cardiac ionic current inhibitions using the human ventricular myocytes model (Tor-ORd model). Myocytes are targets of drug-induced TdP. The TdP risks may be directly linked to myocyte drug concentrations. We aimed to develop a semi-physiologically based pharmacokinetic (Semi-PBPK) model linked to cardiac ionic current inhibition (pharmacodynamics, PD) (Semi-PBPK-PD) to simultaneously predict myocyte drug concentrations and their TdP risks in humans. Alterations in action potential duration (ΔAPD90) were simulated using the Tor-ORd model and ionic current inhibition parameters based on myocyte or plasma drug concentrations. The predicted ΔAPD90 values were translated into in vivo alterations in QT interval(ΔQTc) induced by moxifloxacin, dofetilide, or sotalol. Myocyte drug concentrations of moxifloxacin, dofetilide, and sotalol gave better predictions of ΔQTc than plasma. Following validating the developed semi-PBPK-PD model, TdP risks of 37 drugs were assessed using ΔAPD90 and early afterdepolarization occurrence, which were estimated based on 10 × EFTPCmax and 10 × EFTMCmax (maximum effective free therapeutic myocyte concentration). 10 × EFTMCmax gave more sensitive and accurate predictions of pro-arrhythmic cardiotoxicity and the predicted TdP risks were also closer to clinic practice than 10 × EFTPCmax. In conclusion, pharmacokinetics and TdP risks of 37 drugs were successfully predicted using the semi-PBPK-PD model. Myocyte drug concentrations gave better predictions of ΔQTc and TdP risks than plasma.

Synthesis of Rod-Shaped ZnO/Polysiloxane Micromotors with Patch-Dependent Motion Modes.

Inorganic particles with photocatalytic properties are excellent candidates for the fabrication of micromotors. To achieve self-propulsion, the geometric and chemical symmetries of inorganic particles should be broken. However, the synthesis of micromotors with different geometric and chemical symmetries remains challenging. In this paper, a simple synthesis method is proposed to prepare rod-shaped micromotors with different patches, leading to distinct geometric and chemical symmetries. The micromotors are composed of zinc oxide (ZnO) microrods partially patched with polysiloxanes at different positions. The patches of the micromotors can be roughly regulated by varying the amount of siloxanes used in the synthesis. These micromotors are propelled in H2O2 solution by an ionic self-diffusiophoresis mechanism, which exhibits two motion modes, including linear motion and circular motion, due to different patch positions. Moreover, the degradation of organic dyes by the micromotors depending on the patches is demonstrated.

Foamy macrophages potentially inhibit tuberculous wound healing by inhibiting the TLRs/NF-κB signalling pathway.

To characterise the distribution, classification, and quantity of foamy macrophages (FMs) in tuberculous wound tissue and the relationship between FM and delayed healing of tuberculous wounds. Morphological studies were performed to explore the distribution of FM and Mycobacterium tuberculosis (Mtb) in tuberculous wounds, with acute and chronic wounds included for comparison. Phorbol-12-myristate-13-acetate stimulation-differentiated THP-1 cells were treated with Mtb to induce their differentiation into FM with oxidised low-density lipoprotein treatment serving as a control. Relative cytokine levels were determined by quantitative PCR and Western blotting. Varied co-culture combinations of Mtb, THP-1, FM, and fibroblasts were performed, and proliferation, migration, ability to contract collagen gel, and protein levels of the chemokines in the supernatants of the fibroblasts were assessed. The differentially expressed genes in human skin fibroblasts (HSFs) after co-culture with or without FM were identified using microarray. Many FM were found in the tissues of tuberculous wounds. The FM that did not engulf Mtb (NM-FM) were mainly distributed in tissues surrounding tuberculous wounds, whereas the FM that engulfed Mtb (M-FM) were dominantly located within granulomatous tissues. Co-culture experiments showed that, with the Mtb co-culture, the portions of NM-FM in the total FM grew over time. The migration, proliferation, chemokine secretion, and the ability of fibroblasts to contract collagen gel were inhibited when co-cultured with Mtb, FM, or a combination of the two. Further investigation showed that the TLRs/NF-κB signalling pathway is involved in fibroblast function under the stimulation of FM. TLRs and NF-κB agonists could reverse the phenotypic changes in HSFs after co-culture with FM. The tuberculous wound microenvironment composed of Mtb and FM may affect wound healing by inhibiting the functions of fibroblasts. FM potentially inhibit fibroblasts' function by inhibiting the TLRs/NF-κB signalling pathway in tuberculous wounds.

Efficient utilization of the electron energy of antibiotics to accelerate Fe(III)/Fe(II) cycle in heterogeneous Fenton reaction induced by bamboo biochar/schwertmannite.

The discharge of antibiotics evokes environmental health crisis, and is also a waste of organic energy. Currently, heterogeneous Fenton for antibiotics removal has attracted growing attentions due to wide pH range and no iron sludge production, however, it often suffers from a low formation rate of Fe(II), resulting in difficult application of heterogeneous Fenton technology in sewage treatment. To overcome this drawback, bamboo biochar (BB) is coupled with schwertmannite (Sch) through Acidithiobacillus ferrooxidans-mediated Fe(II) oxidation reaction to obtain a heterogeneous catalyst (Sch/BB) with high adsorption performance and Fenton activity. According to the analysis of experimental results, electrons around C (from BB) can easily transfer to Fe by Fe-O-C bonds to expedite ≡Fe(III)/≡Fe(II) cycle, while electrons of antibiotics adsorbed on Sch/BB surface are effectively utilized to maintain the efficient regeneration of ≡Fe(II) through BB electron shuttle or Fe-O-C bonds between Sch/BB and pollutants, further causing a superior Fenton activity (98% antibiotics removal) of Sch/BB. Moreover, due to its excellent adsorption performance, Sch/BB as filter materials can effectively remove dye pollutants in flow wastewater. These findings provided a high-activity and practical heterogeneous Fenton catalyst for pollutants degradation, while a new perspective for efficient utilization of the electrons of organic pollutants was given.

2D Colloidal Crystals with Anisotropic Impurities.

We report a study of 2D colloidal crystals with anisotropic ellipsoid impurities using video microscopy. It is found that at low impurity densities, the impurity particles behave like floating disorder with which the quasi-long-range orientational order survives and the elasticity of the system is actually enhanced. There is a critical impurity density above which the 2D crystal loses the quasi-long-range orientational order. At high impurity densities, the 2D crystal breaks into polycrystalline domains separated by grain boundaries where the impurity particles aggregate. This transition is accompanied by a decrease in the elastic moduli, and it is associated with strong heterogeneous dynamics in the system. The correlation length vs impurity density in the disordered phase exhibits an essential singularity at the critical impurity density.

Shape-Tunable Janus Micromotors via Surfactant-Induced Dewetting.

The ability to tune shapes of micromotors is challenging yet crucial for creating intelligent and functional micromachines with shape-dependent dynamics. Here, we demonstrate a facile strategy to synthesize Janus micromotors in large quantity whose shapes can be precisely tuned by a surfactant-induced dewetting strategy. The Janus micromotor is composed of a TiO2 microparticle partially encapsulated within a polysiloxane microsphere. A range of particle shapes, from approximately spherical to snowman, is achieved, and the shape-tunable dynamics of the micromotors are quantified. Our strategy is versatile and can be applicable to other photoactive materials, such as ZnO and Fe2O3 nanoparticles, demonstrating a general approach to synthesize Janus micromotors with controllable shapes. Such shape-tunable micromotors provide colloidal model systems for fundamental research on active matter, as well as building blocks for the fabrication of micromachines.

2D isotropic-nematic transition in colloidal suspensions of ellipsoids.

Liquid crystals are important condensed matter systems for technological applications, as well as for fundamental studies. An important unresolved issue is the nature of the phase transition in a two-dimensional (2D) liquid crystal system. In contrast to numerous computational studies reported in the last few decades, there have been no convincing experiments to verify these numerical results. Anisotropic colloids provide an excellent experimental model system to study phase transitions, such as crystallization and glass transition in condensed matter physics with single particle resolution. However, using colloids to probe the two-dimensional liquid crystal transition remains a challenge, since the condensed anisotropic colloids usually become stuck in the metastable glassy state rather than approaching their equilibrium liquid crystal phase. Here we report a method of using an external magnetic field to assist a colloidal system of super-paramagnetic anisotropic particles to overcome the local free energy barriers in the metastable states and approach the equilibrium phase. The experiments demonstrate a 2D isotropic-nematic phase transition with increasing packing density. The effects of the anisotropy of the colloidal particles on the 2D isotropic-nematic transition are explored. Our experimental results are compared with those from previous computational work, and quantitative agreements are reached.