Synthesis of Fluorinated Benzophenones, Xanthones, Acridones, and Thioxanthones by Iterative Nucleophilic Aromatic Substitution

Fluorination of fluorophores can substantially enhance their photostability and improve spectroscopic properties. To facilitate access to fluorinated fluorophores, bis(2,4,5-trifluorophenyl)methanone was synthesized by treatment of 2,4,5-trifluorobenzaldehyde with a Grignard reagent derived from 1-bromo-2,4,5-trifluorobenzene, followed by oxidation of the resulting benzyl alcohol. This hexafluorobenzophenone was subjected to sequential nucleophilic aromatic substitution reactions, first at one or both of the more reactive 4, 4′ fluorines, and second by cyclization through substitution of the less reactive 2, 2′ fluorines, using a variety of oxygen, nitrogen, and sulfur nucleophiles, including hydroxide, methoxide, amines, and sulfide. This method yields symmetrical and asymmetrical fluorinated benzophenones, xanthones, acridones, and thioxanthones, and provides scalable access to known and novel precursors to fluorinated analogues of fluorescein, rhodamine, and other derivatives. Spectroscopic studies revealed that several of these precursors are highly fluorescent, with tunable absorption and emission spectra, depending on the substituents. This approach should allow access to a wide variety of novel fluorinated fluorophores and related compounds

Efficient and Scalable Synthesis of 4-Carboxy-Pennsylvania Green Methyl Ester: A Hydrophobic Building Block for Fluorescent Molecular Probes

Fluorinated fluorophores are valuable tools for studies of biological systems. However, amine-reactive single-isomer derivatives of these compounds are often very expensive. To provide an inexpensive alternative, we report a practical synthesis of 4-carboxy-Pennsylvania Green methyl ester. Derivatives of this hydrophobic fluorinated fluorophore, a hybrid of the dyes Oregon Green and Tokyo Green, are often cell permeable, enabling labeling of intracellular targets and components. Moreover, the low pKa of Pennsylvania Green (4.8) confers bright fluorescence in acidic cellular compartments such as endosomes, enhancing its utility for chemical biology investigations. To improve access to the key intermediate 2,7-difluoro-3,6-dihydroxyxanthen-9-one, we subjected bis-(2,4,5-trifluorophenyl)methanone to iterative nucleophilic aromatic substitution by hydroxide on scales of > 40 g. This intermediate was used to prepare over 15 grams of pure 4-carboxy-Pennsylvania Green methyl ester in 28% overall yield without requiring chromatography. This compound can be converted into the amine reactive N-hydroxysuccinimidyl ester in essentially quantitative yield for the synthesis of a wide variety of fluorescent molecular probes

One Point is All You Need: Directional Attention Point for Feature Learning

We present a novel attention-based mechanism for learning enhanced point features for tasks such as point cloud classification and segmentation. Our key message is that if the right attention point is selected, then "one point is all you need" -- not a sequence as in a recurrent model and not a pre-selected set as in all prior works. Also, where the attention point is should be learned, from data and specific to the task at hand. Our mechanism is characterized by a new and simple convolution, which combines the feature at an input point with the feature at its associated attention point. We call such a point a directional attention point (DAP), since it is found by adding to the original point an offset vector that is learned by maximizing the task performance in training. We show that our attention mechanism can be easily incorporated into state-of-the-art point cloud classification and segmentation networks. Extensive experiments on common benchmarks such as ModelNet40, ShapeNetPart, and S3DIS demonstrate that our DAP-enabled networks consistently outperform the respective original networks, as well as all other competitive alternatives, including those employing pre-selected sets of attention points

Multi-objective Black Widow Algorithm Guided by Competitive Mechanism and Pheromone Mechanism

Black widow optimization algorithm (BWOA) is a swarm intelligence optimization algorithm, which has the advantages of fast convergence and high precision. However, the update strategy adopted by BWOA is too simple, and it is easy to fall into the local optimal solution. Moreover, the search ability in multi-dimensional space is lacking, the population structure is single, and the convergence and diversity of the algorithm need to be improved.  In order to improve the comprehensive performance of BWOA and make it applicable to multi-objective optimization problems, this paper proposes a multi-objective black widow optimization algorithm (MBWOA) guided by a competition mechanism and an improved pheromone mechanism. MBWOA adopts the method of dynamic allocation of populations, which divides the populations into two in the iterative process and uses different competition mechanisms to enhance the diversity of the populations in the iterative process and improve the convergence of the algorithm. At the same time, it uses the improved pheromone mechanism to guide offspring individuals that have gone through the competition mechanism to optimize in the direction of population gap, improve the distribution of population, and enhance the convergence ability of the algorithm. Using MBWOA and four comparison algorithms to conduct comparative experiments on three indicators of IGD, HV and Spread respectively, the results show that MBWOA has better convergence accuracy, convergence speed and diversity. Finally, the effectiveness of the used mechanism is confirmed by the experiments of MBWOA and the comparison algorithms on three indicators

Photoinduced coupled twisted intramolecular charge transfer and excited-state proton transfer via intermolecular hydrogen bonding: a DFT/TD-DFT study

We discuss theoretically the geometric and electronic structure properties of the thiazolidinedione derivative A and its hydrogen-bonded complex in dimethylformamide (DMF) solution in the S0 and S1 states. To gain insight into the photoinduced coupled excited-state proton transfer (ESPT) and twisted intramolecular charge transfer (TICT) associated with intermolecular hydrogen bonding, the potential energy profiles are provided along the Osingle bondH bond and the twisted angle. It is predicted that TICT in S1 can facilitate ESPT initiated by intermolecular hydrogen-bond strengthening in the S1 state. The coupling of ESPT and TICT is energetically preferable

Flow-through anastomosis using a T-shaped vascular pedicle for gracilis functioning free muscle transplantation in brachial plexus injury

OBJECTIVE: In gracilis functioning free muscle transplantation, the limited caliber of the dominant vascular pedicle increases the complexity of the anastomosis and the risk of vascular compromise. The purpose of this study was to characterize the results of using a T-shaped vascular pedicle for flow-through anastomosis in gracilis functioning free muscle transplantation for brachial plexus injury. METHODS: The outcomes of patients with brachial plexus injury who received gracilis functioning free muscle transplantation with either conventional end-to-end anastomosis or flow-through anastomosis from 2005 to 2013 were retrospectively compared. In the flow-through group, the pedicle comprised a segment of the profunda femoris and the nutrient artery of the gracilis. The recipient artery was interposed by the T-shaped pedicle. RESULTS: A total of 46 patients received flow-through anastomosis, and 25 patients received conventional end-to-end anastomosis. The surgical time was similar between the groups. The diameter of the arterial anastomosis in the flow-through group was significantly larger than that in the end-to-end group (3.87 mm vs. 2.06 mm, respectively,

Microstructure evolution and electrochemical properties of TiO 2 /Ti-35Nb-2Ta-3Zr micro/nano-composites fabricated by friction stir processing

Forming stable anti-corrosion surface layer and homogenized microstructure on the surface of material has become a major challenge in developing biomedical β titanium alloy. In the study, TiO 2 /Ti-35Nb-2Ta-3Zr anti-corrosion micro/nano-composites with different amount of TiO 2 particles were successfully fabricated by one-pass friction stir processing (FSP). The composition, microstructure and electrochemical properties of the material are characterized systematically. In particular, compact passive oxide films formed on surface of the material after electrochemical corrosion are elaborated from constituent, thickness and structural characteristics. Furthermore, the relationship between various FSP parameters, microstructure presented and corresponding corrosion resistance has been discussed in detail. The results show that TiO 2 /Ti-35Nb-2Ta-3Zr micro/nano-composite layers possess massive uniform β grains with homogeneous dispersive oxygen on the surface. Nanocrystallines surrounded by amorphous phases and α″ martensite accompanied with dislocations are discovered. TiO 2 /Ti-35Nb-2Ta-3Zr micro/nano-composite layers present outstanding corrosion resistance. More TiO 2 added and higher rotation speed promotes the optimization in corrosion resistance forming more compact passive films. The study displays the potential of a new micro/nano-composite with outstanding surface microstructure and corrosion resistance that serves better as a biomedical implant. © 2019 Elsevier Lt

Multidimensional difference analysis in gastric cancer patients between high and low latitude

Genetic variation has been shown to affect tumor growth and progression, and the temperature at different latitudes may promote the evolution of genetic variation. Geographical data with latitudinal information is of importance to understand the interplay between genetic variants and environmental influence, such as the temperature, in gastric cancer (GC). In this study, we classified the GC samples from The Cancer Genome Atlas database into two groups based on the latitudinal information of patients and found that GC samples with low-latitude had better clinical outcomes. Further analyses revealed significant differences in other clinical factors such as disease stage and grade between high and low latitudes GC samples. Then, we analyzed the genomic and transcriptomic differences between the two groups. Furthermore, we evaluated the activity score of metabolic pathways and infiltrating immune cells in GC samples with different latitudes using the single-sample gene set enrichment analysis algorithm. These results showed that GC samples at low-latitude had lower tumor mutation burden and subclones as well as higher DNA repair activities. Meanwhile, we found that most immune cells were associated with the prognosis of low-latitude GC patients. At last, we constructed and validated an immune-related prognostic model to evaluate the prognosis of GC samples at different latitudes. This study has provided a further understanding of the geographical contribution to GC at the multiomic level and may benefit the individualized treatment of GC patients at different latitudes

Expression of miR-21 and its targets (PTEN, PDCD4, TM1) in flat epithelial atypia of the breast in relation to ductal carcinoma in situ and invasive carcinoma

<p>Abstract</p> <p>Background</p> <p>Flat epithelial atypia (FEA) of the breast is characterised by a few layers of mildly atypical luminal epithelial cells. Genetic changes found in ductal carcinoma in situ (DCIS) and invasive ductal breast cancer (IDC) are also found in FEA, albeit at a lower concentration. So far, miRNA expression changes associated with invasive breast cancer, like miR-21, have not been studied in FEA.</p> <p>Methods</p> <p>We performed miRNA in-situ hybridization (ISH) on 15 cases with simultaneous presence of normal breast tissue, FEA and/or DCIS and 17 additional cases with IDC. Expression of the miR-21 targets PDCD4, TM1 and PTEN was investigated by immunohistochemistry.</p> <p>Results</p> <p>Two out of fifteen cases showed positive staining for miR-21 in normal breast ductal epithelium, seven out of fifteen cases were positive in the FEA component and nine out of twelve cases were positive in the DCIS component. A positive staining of miR-21 was observed in 15 of 17 IDC cases. In 12 cases all three components were present in one tissue block and an increase of miR-21 from normal breast to FEA and to DCIS was observed in five cases. In three cases the FEA component was negative, whereas the DCIS component was positive for miR-21. In three other cases, normal, FEA and DCIS components were negative for miR-21 and in the last case all three components were positive. Overall we observed a gradual increase in percentage of miR-21 positive cases from normal, to FEA, DCIS and IDC. Immunohistochemical staining for PTEN revealed no obvious changes in staining intensities in normal, FEA, DCIS and IDC. Cytoplasmic staining of PDCD4 increased from normal to IDC, whereas, the nuclear staining decreased. TM1 staining decreased from positive in normal breast to negative in most DCIS and IDC cases. In FEA, the staining pattern for TM1 was similar to normal breast tissue.</p> <p>Conclusion</p> <p>Upregulation of miR-21 from normal ductal epithelial cells of the breast to FEA, DCIS and IDC parallels morphologically defined carcinogenesis. No clear relation was observed between the staining pattern of miR-21 and its previously reported target genes.</p

Novel Acid-Activated Fluorophores Reveal a Dynamic Wave of Protons in the Intestine of Caenorhabditis elegans

Unlike the digestive systems of vertebrate animals, the lumen of the alimentary canal of C. elegans is unsegmented and weakly acidic (pH ~ 4.4), with ultradian fluctuations to pH > 6 every 45 to 50 seconds. To probe the dynamics of this acidity, we synthesized novel acid-activated fluorophores termed Kansas Reds. These dicationic derivatives of rhodamine B become concentrated in the lumen of the intestine of living C. elegans and exhibit tunable pKa values (2.3–5.4), controlled by the extent of fluorination of an alkylamine substituent, that allow imaging of a range of acidic fluids in vivo. Fluorescence video microscopy of animals freely feeding on these fluorophores revealed that acidity in the C. elegans intestine is discontinuous; the posterior intestine contains a large acidic segment flanked by a smaller region of higher pH at the posterior-most end. Remarkably, during the defecation motor program, this hot spot of acidity rapidly moves from the posterior intestine to the anterior-most intestine where it becomes localized for up to 7 seconds every 45 to 50 seconds. Studies of pH-insensitive and base-activated fluorophores as well as mutant and transgenic animals revealed that this dynamic wave of acidity requires the proton exchanger PBO-4, does not involve substantial movement of fluid, and likely involves the sequential activation of proton transporters on the apical surface of intestinal cells. Lacking a specific organ that sequesters low pH, C. elegans compartmentalizes acidity by producing of a dynamic hot spot of protons that rhythmically migrates from the posterior to anterior intestine