Glycosylated AIE-active Red Light-triggered Photocage with Precisely Tumor Targeting Capability for Synergistic Type I Photodynamic Therapy and CPT Chemotherapy.

Photocaging is an emerging protocol for precisely manipulating spatial and temporal behaviors over biological activity. However, the red/near-infrared light-triggered photolysis process of current photocage is largely singlet oxygen (1O2)-dependent and lack of compatibility with other reactive oxygen species (ROS)-activated techniques, which has proven to be the major bottleneck in achieving efficient and precise treatment. Herein, we reported a lactosylated photocage BT-LRC by covalently incorporating camptothecin (CPT) into hybrid BODIPY-TPE fluorophore via the superoxide anion radical (O2 -⋅)-cleavable thioketal bond for type I photodynamic therapy (PDT) and anticancer drug release. Amphiphilic BT-LRC could be self-assembled into aggregation-induced emission (AIE)-active nanoparticles (BT-LRCs) owing to the regulation of carbohydrate-carbohydrate interactions (CCIs) among neighboring lactose units in the nanoaggregates. BT-LRCs could simultaneously generate abundant O2 -⋅ through the aggregation modulated by lactose interactions, and DNA-damaging agent CPT was subsequently and effectively released. Notably, the type I PDT and CPT chemotherapy collaboratively amplified the therapeutic efficacy in HepG2 cells and tumor-bearing mice. Furthermore, the inherent AIE property of BT-LRCs endowed the photocaged prodrug with superior bioimaging capability, which provided a powerful tool for real-time tracking and finely tuning the PDT and photoactivated drug release behavior in tumor therapy.

Recent advances in sugar-based AIE luminogens and their applications in sensing and imaging.

Most fluorogens with aggregation-induced emission (AIE) characteristics are hydrophobic and most common sugars are hydrophilic and naturally nontoxic. The combination of AIEgens and sugars can construct glycosyl AIEgens with the advantages of good water-solubility, low fluorescent background and satisfactory biocompatibility. Based on the specific reaction or binding with analytes to change the conjugate system or restrict intramolecular motions, glycosyl AIEgens can be used as powerful tools for detecting bioactive molecules or imaging living cells. In this feature article, we summarize recent advances in sugar-based AIE luminogens and their applications in biosensing and imaging. The sugar units could significantly increase the solubility, biocompatibility, target activity, and chemical modifying capacity and often decrease the background fluorescence of the AIE probes. Corresponding studies not only expand the application fields of AIEgens but also provide effective tools for broad carbohydrate research.

Numerical study on the characteristics of roadway failure and instability in coal seam with rock parting.

In order to explore the mechanism of rockburst in coal seam with rock parting, a combination of on-site and numerical experiment is used to study the failure and instability process, crack propagation mechanism, and influencing factors. The following four points were addressed: (1) the instability is a process that roadway in coal seam with rock parting go through from stable locking in the initial stress unloading stage to slipping unlocking, and then to spatter ejection in slipping dynamic load disturbance stage. (2) The fracture development caused by unloading excavation of coal seam with rock parting will change from shear crack to tensile crack. In this process, coal-rock contact surface slip and coal-rock fracture are coupled with each other. (3) The greater the mining depth is, the greater the lateral pressure coefficient is, and the higher the rockburst risk is. On the contrary, the lower the risk of rockburst. (4) When choosing the support form of roadway in coal seam with rock parting, the two supporting forms of bolting (cable) and supplementary masonry support should be preferred. The results enrich the theory of the dynamics of surrounding rock fracture in coal mine, further clarify the potential dangers to mining-area roadways and working faces, and provide technical information to ensure the safe and efficient mining of bifurcated coal seam.

In Situ Self-Assembled J-Aggregate Nanofibers of Glycosylated Aza-BODIPY for Synergetic Cell Membrane Disruption and Type†I Photodynamic Therapy.

The in situ self-assembly of exogenous molecules is a powerful strategy for manipulating cellular behavior. However, the direct self-assembly of photochemically inert constituents into supramolecular nano-photosensitizers (PSs) within cancer cells for precise photodynamic therapy (PDT) remains a challenge. Herein, we developed a glycosylated Aza-BODIPY compound (LMBP) capable of self-assembling into J-aggregate nanofibers in situ for cell membrane destruction and type I PDT. LMBP selectively entered human hepatocellular carcinoma HepG2 cells and subsequently self-assembled into intracellular J-aggregate nanovesicles and nanofibers through supramolecular interactions. Detailed studies revealed that these J-aggregate nanostructures generated superoxide radicals (O2 - ⋅) exclusively through photoinduced electron transfer, thus enabling effective PDT. Furthermore, the intracellular nanofibers exhibited an aggregation-induced retention effect, which resulted in selective toxicity to HepG2 cells by disrupting their cellular membranes and synergizing with PDT for powerful tumor suppression efficacy in vivo.

α-Stereoselective 3-Deoxy-d-manno-oct-2-ulosonoic Acid (Kdo) O-Glycosylation with a p-Toluenethioglycoside Donor by the (p-Tol)2SO/Tf2O Preactivation Strategy.

A convenient and efficient approach was developed to synthesize α-Kdo O-glycosides based on the Tf2O/(p-Tol)2SO preactivation strategy using peracetylated Kdo thioglycoside as a donor. Under the optimized reaction conditions, several O-glycoside products, including α-(2 → 1)-, α-(2 → 2)-, α-(2 → 3)-, and α-(2 → 6)-Kdo products, were stereoselectively synthesized in high yields. Remarkably, a series of aromatic α-Kdo O-glycosides were first and successfully constructed in high yields. An SN2-like mechanism was revealed by DFT calculations and experimental results.

Malignant transformation of rectal endometriosis: Preoperative diagnosis by endorectal ultrasound guided biopsy.

The prevalence of malignant transformation of endometriotic lesions is estimated between 0.3% and 1%. Malignant transformations of endometriosis occur in the colorectum is rarer, accounting for 0.25%. Because the malignant transformation of colorectal endometriosis rarely involves mucosa, it is difficult to obtain abnormal tissue by routine endoscopic biopsy. In this case, we evaluated a patient with a rectal mass by endorectal ultrasound (ERUS) and performed endorectal ultrasound-guided biopsy (EGB). Malignant transformations of endometriosis were confirmed by histological result. For patients with rectal tumors but with negative findings on colonoscopy and biopsy, ERUS and EGB contribute to preoperative diagnosis.

Dual functional amphiphilic sugar-coated AIE-active fluorescent organic nanoparticles for the monitoring and inhibition of insulin amyloid fibrillation based on carbohydrate-protein interactions.

Amyloid-related diseases, such as Alzheimer's disease, are all considered to be related to the deposition of amyloid fibrils in the body. Insulin is a protein hormone that easily undergoes aggregation and fibrillation to form more toxic amyloid-like fibrils. So far, it is still challenging to develop a new protocol to study the ex situ detection and in situ inhibition of amyloid fibrillation. Here, we reported a modular synthetic strategy to construct nine amphiphilic sugar-coated AIE-active fluorescent organic nanoparticles (FONs, TPE2/3/4X, X = G, M or S) with glucosamine (G), mannose (M) or sialic acid (S) as a hydrophilic moiety and tetraphenylethylene (TPE) as a hydrophobic AIE core. The carbohydrate-protein interactions between insulin and TPE2/3/4X were investigated by fluorescence spectroscopy, circular dichroism spectroscopy and transmission electron microscopy. Among the nine FON AIEgens, TPE2G was screened out as the best dual functional FON for the ex situ detection and in situ inhibition of the insulin fibrillation process, indicating that the glycosyl moiety exhibited a crucial effect on the detection/inhibition of insulin fibrillation. The molecular dynamics simulation results showed that the binding mechanism between TPE2G and native insulin was through weak interactions dominated by van der Waals interactions and supplemented by hydrogen bonding interactions to stabilize an α-helix of the insulin A chain, thereby inhibiting the insulin fibrillation process. This work provides a powerful protocol for the further research of amyloid-related diseases based on carbohydrate-protein interactions.

Whole-Genome Resequencing of Worldwide Wild and Domestic Sheep Elucidates Genetic Diversity, Introgression, and Agronomically Important Loci.

Domestic sheep and their wild relatives harbor substantial genetic variants that can form the backbone of molecular breeding, but their genome landscapes remain understudied. Here, we present a comprehensive genome resource for wild ovine species, landraces and improved breeds of domestic sheep, comprising high-coverage (∼16.10×) whole genomes of 810 samples from 7 wild species and 158 diverse domestic populations. We detected, in total, ∼121.2 million single nucleotide polymorphisms, ∼61 million of which are novel. Some display significant (P < 0.001) differences in frequency between wild and domestic species, or are private to continent-wide or individual sheep populations. Retained or introgressed wild gene variants in domestic populations have contributed to local adaptation, such as the variation in the HBB associated with plateau adaptation. We identified novel and previously reported targets of selection on morphological and agronomic traits such as stature, horn, tail configuration, and wool fineness. We explored the genetic basis of wool fineness and unveiled a novel mutation (chr25: T7,068,586C) in the 3'-UTR of IRF2BP2 as plausible causal variant for fleece fiber diameter. We reconstructed prehistorical migrations from the Near Eastern domestication center to South-and-Southeast Asia and found two main waves of migrations across the Eurasian Steppe and the Iranian Plateau in the Early and Late Bronze Ages. Our findings refine our understanding of genome variation as shaped by continental migrations, introgression, adaptation, and selection of sheep.

Whole-genome sequence analysis unveils different origins of European and Asiatic mouflon and domestication-related genes in sheep.

The domestication and subsequent development of sheep are crucial events in the history of human civilization and the agricultural revolution. However, the impact of interspecific introgression on the genomic regions under domestication and subsequent selection remains unclear. Here, we analyze the whole genomes of domestic sheep and their wild relative species. We found introgression from wild sheep such as the snow sheep and its American relatives (bighorn and thinhorn sheep) into urial, Asiatic and European mouflons. We observed independent events of adaptive introgression from wild sheep into the Asiatic and European mouflons, as well as shared introgressed regions from both snow sheep and argali into Asiatic mouflon before or during the domestication process. We revealed European mouflons might arise through hybridization events between a now extinct sheep in Europe and feral domesticated sheep around 6000-5000 years BP. We also unveiled later introgressions from wild sheep to their sympatric domestic sheep after domestication. Several of the introgression events contain loci with candidate domestication genes (e.g., PAPPA2, NR6A1, SH3GL3, RFX3 and CAMK4), associated with morphological, immune, reproduction or production traits (wool/meat/milk). We also detected introgression events that introduced genes related to nervous response (NEURL1), neurogenesis (PRUNE2), hearing ability (USH2A), and placental viability (PAG11 and PAG3) into domestic sheep and their ancestral wild species from other wild species.

Water-soluble AIE-active Fluorescent Organic Nanoparticles: Design, Preparation and Application for Specific Detection of Cyanide in Water and Food Samples.

A dilactosyl-dicyanovinyl-functionalized tetraphenylethene (TPELC) was designed, synthesized and used for ratiometric sensing of cyanide. TPELC was comprised of three moieties (tetraphenylethylene, dicyanovinyl group and lactose unit) in one molecule, making TPELC water-soluble and aggregation-induced emission (AIE)-active and selectively reactive to cyanide. Compared with other reported fluorescent probes containing dicyanovinyl group, TPELC is the first AIE luminogen to be assembled as fluorescent organic nanoparticles (FONs) for sensing of cyanide in water without the use of surfactant or the help of organic solvents based on the nucleophilic addition reaction. The detection mechanism was verified by liquid chromatograph mass spectrometry experiments and by protonation of cyanide to reduce the nucleophilicity of cyanide. In addition, TPELC was used for detection of the cyanide content of food samples and test strips were developed to simplify the detection procedure.

Contrast-Enhanced Ultrasound Imaging Features of Focal Chemotherapy-Induced Sinusoidal Injury in Patients With Colorectal Cancer: Initial Experience.

OBJECTIVES: Increasing studies have reported focal chemotherapy-induced sinusoidal injury (CSI) mimicking colorectal liver metastasis (CRLM) on imaging studies, resulting in unnecessary lobectomy. This study aimed to investigate the contrast-enhanced ultrasound (CEUS) imaging features of focal CSI. METHODS: We retrospectively evaluated 16 patients who had a pathologic diagnosis of focal CSI and underwent CEUS between January 2013 and January 2019. The images were compared with those obtained from 27 patients with CRLM. RESULTS: On CEUS, 14 (87.5%) focal CSIs showed heterogeneous isoenhancement, 1 (6.3%) peripheral hyperenhancement, and 1 (6.3%) homogeneous hyperenhancement during the arterial phase. Compared with the adjacent liver parenchyma, the initial enhancement time of focal CSI was earlier in 2 (12.5%), simultaneous in 9 (56.3%), and later in 5 (31.3%) patients. In the portal and late phases, all of the focal CSI cases showed hypoenhancement compared with the adjacent liver parenchyma. Focal CSI had the following CEUS findings, which were different from those of CRLM: (1) heterogeneous isoenhancement in the arterial phase (87.5% versus 0%; P < .001); (2) an initial enhancement time later than that of the liver parenchyma (mean ± SD, 0.5 ± 1.5 versus -1.5 ± 1.9; P < .001); (3) a longer time to peak (30.5 ± 5.6 versus 22.5 ± 4.4 seconds; P < .001); and (4) a later time to wash-out (51.0 ± 12.5 versus 35.0 ± 6.2 seconds; P = .002). CONCLUSIONS: Focal CSI usually shows heterogeneous isoenhancement in arterial phase and hypoenhancement in portal and late phases on CEUS, with slow contrast wash-in and wash-out, which can be helpful in the differential diagnosis with CRLM.

Assembly of Water-soluble AIE-active Fluorescent Organic Nanoparticles for Ratiometric Detection of Hypochlorite in Living Cells.

Hypochlorous acid (HOCl) plays a crucial role in many physiological processes and is widely used as bleach, deodorant and fungicide. In this work, we designed an amphiphilic hydrazone fluorescent molecule THG-1 containing hydrophilic sugar units and hydrophobic tetraphenylethylene unit for ratiometric detection of HOCl with high sensitivity and excellent selectivity based on HOCl-triggered hydrolyzation reaction and aggregation-induced emission (AIE) effect. The detection mechanism was verified by liquid chromatograph mass spectrometry experiments and scanning electron microscope (SEM) tests. Contrast experiments revealed that the numbers of lactose unit and hydrazone linker were essential for assembly of THG-1 and detection of HOCl. In addition, THG-1 was successfully used for imaging of exogenous and endogenous HOCl in living cells.

Clinical Features of COVID-19 in a Young Man with Massive Cerebral Hemorrhage-Case Report.

COVID-19 is currently a pandemic in the world, can invade multiple systems, and has a high morbidity and mortality. So far, no cases of acute cerebrovascular disease have been reported. This article reports the clinical features of a COVID-19 patient whose first symptom was cerebral hemorrhage. More importantly, after the craniotomy, the patient had high fever and it was difficult to retreat. After cerebrospinal fluid testing, it was determined that an intracranial infection had occurred. After anti-infection and plasma infusion of the recovered person, the patient's symptoms gradually improved. This case suggests that COVID-19 may infringe on cerebral blood vessels and cause cerebral hemorrhage. Transfusion of plasma from rehabilitation patients is effective for critically ill patients.

Paternal Origins and Migratory Episodes of Domestic Sheep.

The domestication and subsequent global dispersal of livestock are crucial events in human history, but the migratory episodes during the history of livestock remain poorly documented [1-3]. Here, we first developed a set of 493 novel ovine SNPs of the male-specific region of Y chromosome (MSY) by genome mapping. We then conducted a comprehensive genomic analysis of Y chromosome, mitochondrial DNA, and whole-genome sequence variations in a large number of 595 rams representing 118 domestic populations across the world. We detected four different paternal lineages of domestic sheep and resolved, at the global level, their paternal origins and differentiation. In Northern European breeds, several of which have retained primitive traits (e.g., a small body size and short or thin tails), and fat-tailed sheep, we found an overrepresentation of MSY lineages y-HC and y-HB, respectively. Using an approximate Bayesian computation approach, we reconstruct the demographic expansions associated with the segregation of primitive and fat-tailed phenotypes. These results together with archaeological evidence and historical data suggested the first expansion of early domestic hair sheep and the later expansion of fat-tailed sheep occurred ∼11,800-9,000 years BP and ∼5,300-1,700 years BP, respectively. These findings provide important insights into the history of migration and pastoralism of sheep across the Old World, which was associated with different breeding goals during the Neolithic agricultural revolution.

Whole-genome resequencing of wild and domestic sheep identifies genes associated with morphological and agronomic traits.

Understanding the genetic changes underlying phenotypic variation in sheep (Ovis aries) may facilitate our efforts towards further improvement. Here, we report the deep resequencing of 248 sheep including the wild ancestor (O. orientalis), landraces, and improved breeds. We explored the sheep variome and selection signatures. We detected genomic regions harboring genes associated with distinct morphological and agronomic traits, which may be past and potential future targets of domestication, breeding, and selection. Furthermore, we found non-synonymous mutations in a set of plausible candidate genes and significant differences in their allele frequency distributions across breeds. We identified PDGFD as a likely causal gene for fat deposition in the tails of sheep through transcriptome, RT-PCR, qPCR, and Western blot analyses. Our results provide insights into the demographic history of sheep and a valuable genomic resource for future genetic studies and improved genome-assisted breeding of sheep and other domestic animals.

Water-soluble Glucosamine-coated AIE-Active Fluorescent Organic Nanoparticles: Design, Synthesis and Assembly for Specific Detection of Heparin Based on Carbohydrate-Carbohydrate Interactions.

Two water-soluble carbohydrate-coated AIE-activate fluorescent organic nanoparticles TPE3G and TPE4G were designed and synthesized for the detection of heparin. Different from the reported strategy, we not only utilized the general detection mechanism of electrostatic interactions, but also introduced the concept of carbohydrate-carbohydrate interactions (CCIs) to enrich the detection mechanism of heparin. TPE3G can serve as an efficient "turn-on" probe with higher selectivity towards heparin than TPE4G. TEM studies revealed that the micro-aggregated TPE3G was encapsulated with the heparin chain to form a complex self-assemblied composite and emits strong fluorescence. It is believed that the results illustrated in this study provide a novel strategy based on CCls to design water-soluble and more efficient bio-probes for various biological and clinical applications.

Comparison Between Levodopa-Carbidopa Intestinal Gel Infusion and Subthalamic Nucleus Deep-Brain Stimulation for Advanced Parkinson's Disease: A Systematic Review and Meta-Analysis.

Background: Currently, some advanced treatments such as Levodopa-Carbidopa intestinal gel infusion (LCIG), deep-brain stimulation (DBS), and subcutaneous apomorphine infusion have become alternative strategies for advanced Parkinson's disease (PD). However, which treatment is better for individual patients remains unclear. This review aims to compare therapeutic effects of motor and/or non-motor symptoms of advanced PD patients between LCIG and DBS. Methods: We manually searched electronic databases (PubMed, Embase, Cochrane Library) and reference lists of included articles published until April 04, 2019 using related terms, without language restriction. We included case-controlled cohort studies and randomized-controlled trials, which directly compared differences between LCIG and DBS. The Newcastle-Ottawa scale (NOS), proposed by the Cochrane Collaboration, was utilized to assess the quality of the included studies. Two investigators independently extracted data from each trial. Pooled standard-mean differences (SMDs) and relative risks (RRs) with 95% confidence intervals (CIs) were calculated by meta-analysis. Outcomes were grouped according to the part III and part IV of the Unified Parkinson Disease Rating Scale (UPDRS) and adverse events. We also descriptively reviewed some data, which were unavailable for statistical analysis. Results: This review included five cohort trials of 257 patients for meta-analysis. There were no significant differences between LCIG and subthalamic nucleus deep-brain stimulation (STN-DBS) on UPDRS-III and adverse events comparisons: UPDRS-III (pooled SMDs = 0.200, 95% CI: -0.126-0.527, P = 0.230), total adverse events (pooled RRs = 1.279, 95% CI: 0.983-1.664, P = 0.067), serious adverse events (pooled RRs = 1.539, 95% CI: 0.664-3.566, P = 0.315). Notably, the improvement of UPDRS-IV was more significant in STN-DBS groups: pooled SMDs = 0.857, 95% CI: 0.130-1.584, P = 0.021. However, the heterogeneity was moderate for UPDRS-IV (I 2 = 73.8%). Conclusion: LCIG has comparable effects to STN-DBS on motor function for advanced PD, with acceptable tolerability. More large, well-designed trials are needed to assess the comparability of LCIG and STN-DBS in the future.

A water-soluble AIE-active polyvalent glycocluster: design, synthesis and studies on carbohydrate-lectin interactions for visualization of Siglec distributions in living cell membranes.

In this work, we designed and synthesized an aggregation-induced emission (AIE)-active tetraphenylethene-decorated pseudo-trisialic acid (TPE3S) and validated its high affinity for Siglecs using microscale thermophoresis techniques. TPE3S was a unique binding-on fluorescent trivalent sialocluster which was successfully utilized for the visualization of Siglecs expressed on the surface of mammalian cells.