Aromatic C(sp2 )-H Functionalization by Consecutive Paired Electrolysis: Dibromination of Aryl Amines with Dibromoethane at Room Temperature.

Herein, we disclose a facile and efficient electrochemical method for the dibromination of aryl amines by double functionalization of aromatic C(sp2 )-H (both para and ortho) under metal- and external oxidant-free conditions at room temperature for the first time. The reaction is demonstrated using 1,2-dibromoethane to dibrominate a wide range of N-substituted aryl amines in a simple setup with C(+)/Pt(-) electrodes under mild reaction conditions. This transformation proceeds smoothly with a broad substrate scope affording the valuable and versatile N-substituted 2,4-dibromoanilines in moderate to excellent yields with high regioselectivity. In this paired electrolysis, cathodic reduction of 1,2-DBE followed by anodic oxidation generates bromonium intermediates, which then couple with anilines to furnish the dibrominated products. It represents a distinctive approach to challenging redox-neutral reactions. The versatility of the electrochemical ortho-, para-dibromination was reflected by unique regioselectivities for challenging aryl amines and gram-scale electrosynthesis without the use of a stoichiometric oxidant or an activating agent.

Predicting the miniaturization limit of vertical organic field effect transistor (VOFET) with perforated graphene as a source electrode.

Vertical organic field effect transistors (VOFETs) are of paramount importance due to their fast switching speed, low power consumption, and higher density on a chip compared to lateral OFETs. The low charge carrier mobility in organic semiconductors and longer channel lengths in lateral OFETs lead to higher operating voltages. The channel length in VOFETs can be less than 100 nm which reduces the size of the channel and hence the operating voltages. Another important factor in the operation of VOFETs is the thickness and width of the source electrode. The channel length, source electrode thickness and width sets the miniaturization limit of the VOFETs. The graphene monolayer can be exploited as a source electrode due to its thinness, high carrier mobility, and metallic behaviors. However, for better gate modulation, perforations in the source material are desired. Here, we simulate the VOFET having perforated graphene monolayer as a source electrode and n-type organic semiconductor N, N'-dioctyl-3,4,9,10-perylenedicarboximide (PTCDI-C8) as an active channel material, while aluminum as a drain electrode to predict the best-miniaturized device. The miniaturization limit of such a VOFET has a limit to the gate opening/perforation in which the minimum source width is 10 nm, as in the sub 10 nm range graphene starts behaving like a semiconductor. The subthreshold swing, deduced from the drain current (JD) versus gate voltage (VG) graph, advocates the limit of the organic semiconductor height/channel length to 50 nm, while 50 nm for the gate.

Regio- and Chemoselective Access to Dihydrothiophenes and Thiophenes via Halogenation/Intramolecular C(sp2)-H Thienation of α-Allyl Dithioesters at Room Temperature.

An operationally simple, practical, and efficient cascade approach employing α-allyl dithioesters and NBS/NIS has been achieved to access a series of dihydrothiophenes and thiophenes containing diverse functional groups of different electronic and steric natures in good to excellent yields at room temperature in open air. The reaction proceeds via the electrophilic addition of a halogen source (NBS/NIS) to an allylic double bond, followed by intramolecular regio- and chemoselective S-cyclization. This protocol avoids potential toxicity and tedious work-up conditions, and features easy synthesis from readily available starting materials under catalyst-free conditions. Furthermore, 4,5-dihydrothiophenes were aromatized to thiophenes by treatment with KOH in DMF at room temperature. A probable mechanism for the formation of dihydrothiophenes and thiophenes from α-allyl dithioesters has been suggested. Notably, a large-scale experiment and the transformations of products indicated the potential utility of this reaction compared to competing processes for the synthesis of 4,5-dihydrothiophenes and thiophenes.

Magnesium catalyzed [3 + 3] heteroannulation of α-enolic dithioesters with MBH acetate: access to functionalized 3,4-dihydro-2H-thiopyrans.

Magnesium catalysis proved to be efficient towards [3 + 3] chemo- and diastereoselective heteroannulation employing racemic Morita-Baylis-Hillman (MBH) acetate as the C3 unit and α-enolic dithioester as the C2S1 unit, leading to highly substituted 3,4-dihydro-2H-thiopyrans in excellent yields. The compatibility with a wide range of functional groups makes this domino formation of C-C and C-S bonds interesting. DFT analyses for the regioselective formation of the intermediate was performed.

Broadening the high sensitivity range of squeezing-assisted interferometers by means of two-channel detection.

For a squeezing-enhanced linear (so-called SU(2)) interferometer, we theoretically investigate the possibility to broaden the phase range of sub-shot-noise sensitivity. We show that this goal can be achieved by implementing detection in both output ports, with the optimal combination of the detectors outputs. With this modification, the interferometer has the phase sensitivity independent of the interferometer operation point and, similar to the standard dark port regime, is not affected by the laser technical (excess) noise. Provided that each detector is preceded by a phase-sensitive amplifier, this sensitivity could be also tolerant to the detection loss.

Electrochemical Synthesis of 1,2,3-Thiadiazoles from α-Phenylhydrazones.

We have developed an electrochemical approach for the synthesis of fully substituted 1,2,3-thiadiazoles from α-phenylhydrazones at room temperature, which is very challenging and complementary to the conventional thermal reactions. The key step involves anodic oxidation of phenylhydrazone derivatives at a constant current followed by N,S-heterocyclization. The protocol is remarkable in that it is free of a base and free of an external oxidant and can be converted to a gram scale for postsynthetic drug development with functional thiadiazoles. Most importantly, the electrochemical transformation reflected efficient electro-oxidation with an operationally friendly easy procedure with ample functional molecules. Cyclic voltammograms support the mechanism of this electro-oxidative cyclization process.

Long-term follow up of en face optical coherence tomography of the inner retinal surface following internal limiting membrane peeling for idiopathic macular holes.

PURPOSE: To evaluate sequential changes in the inner retinal surface using en face spectral domain optical coherence tomography (SD-OCT) following internal limiting membrane (ILM) peeling for idiopathic full thickness macular holes. METHODS: Retrospective, interventional study on 45 eyes of 42 patients with type 1 macular hole closure after a single procedure and a minimum post-operative follow up of 6 months. Best corrected visual acuity (BCVA), fundus photographs, B scan and en face SD-OCT scans were analysed pre-operatively, at 2, 6, 12 months post-operatively and then yearly. The presence or absence of concentric macular dark spots (CMDS) on the ILM slab of en face SD-OCT, their distribution pattern and course in terms of number and size of the dark spots was qualitatively assessed at each follow up. RESULTS: CMDS was identified in a total of 26 eyes (57.78%). Of these, it was detected in 21 eyes at 2 months and the remaining by 6 months. At the time of first detection, the distribution was classified as type 1 in 9 eyes (35%), type 2 in 7 eyes (27%) and type 3 in 10 eyes (38%). There was apparent increase in the number and size of the CMDS in 16 eyes (62%) no later than 12 months follow up, while 10 eyes (38%) remained stable. There was no decrease or resolution noted in any patient. The mean post-operative follow up was 19.4 months (range 6-69 months). CONCLUSION: Inner retinal defects in the form of CMDS can be picked up on en face SD-OCT between 2-6 months post-operatively. They remain stable or become more prominent upto 12 months follow up, but do not regress once present. En face SD-OCT is recommended in all cases where ILM is peeled to assess CMDS.

Brain extraction on MRI scans in presence of diffuse glioma: Multi-institutional performance evaluation of deep learning methods and robust modality-agnostic training.

Brain extraction, or skull-stripping, is an essential pre-processing step in neuro-imaging that has a direct impact on the quality of all subsequent processing and analyses steps. It is also a key requirement in multi-institutional collaborations to comply with privacy-preserving regulations. Existing automated methods, including Deep Learning (DL) based methods that have obtained state-of-the-art results in recent years, have primarily targeted brain extraction without considering pathologically-affected brains. Accordingly, they perform sub-optimally when applied on magnetic resonance imaging (MRI) brain scans with apparent pathologies such as brain tumors. Furthermore, existing methods focus on using only T1-weighted MRI scans, even though multi-parametric MRI (mpMRI) scans are routinely acquired for patients with suspected brain tumors. In this study, we present a comprehensive performance evaluation of recent deep learning architectures for brain extraction, training models on mpMRI scans of pathologically-affected brains, with a particular focus on seeking a practically-applicable, low computational footprint approach, generalizable across multiple institutions, further facilitating collaborations. We identified a large retrospective multi-institutional dataset of n=3340 mpMRI brain tumor scans, with manually-inspected and approved gold-standard segmentations, acquired during standard clinical practice under varying acquisition protocols, both from private institutional data and public (TCIA) collections. To facilitate optimal utilization of rich mpMRI data, we further introduce and evaluate a novel ''modality-agnostic training'' technique that can be applied using any available modality, without need for model retraining. Our results indicate that the modality-agnostic approach1 obtains accurate results, providing a generic and practical tool for brain extraction on scans with brain tumors.

Histopathology-validated machine learning radiographic biomarker for noninvasive discrimination between true progression and pseudo-progression in glioblastoma.

BACKGROUND: Imaging of glioblastoma patients after maximal safe resection and chemoradiation commonly demonstrates new enhancements that raise concerns about tumor progression. However, in 30% to 50% of patients, these enhancements primarily represent the effects of treatment, or pseudo-progression (PsP). We hypothesize that quantitative machine learning analysis of clinically acquired multiparametric magnetic resonance imaging (mpMRI) can identify subvisual imaging characteristics to provide robust, noninvasive imaging signatures that can distinguish true progression (TP) from PsP. METHODS: We evaluated independent discovery (n = 40) and replication (n = 23) cohorts of glioblastoma patients who underwent second resection due to progressive radiographic changes suspicious for recurrence. Deep learning and conventional feature extraction methods were used to extract quantitative characteristics from the mpMRI scans. Multivariate analysis of these features revealed radiophenotypic signatures distinguishing among TP, PsP, and mixed response that compared with similar categories blindly defined by board-certified neuropathologists. Additionally, interinstitutional validation was performed on 20 new patients. RESULTS: Patients who demonstrate TP on neuropathology are significantly different (P < .0001) from those with PsP, showing imaging features reflecting higher angiogenesis, higher cellularity, and lower water concentration. The accuracy of the proposed signature in leave-one-out cross-validation was 87% for predicting PsP (area under the curve [AUC], 0.92) and 84% for predicting TP (AUC, 0.83), whereas in the discovery/replication cohort, the accuracy was 87% for predicting PsP (AUC, 0.84) and 78% for TP (AUC, 0.80). The accuracy in the interinstitutional cohort was 75% (AUC, 0.80). CONCLUSION: Quantitative mpMRI analysis via machine learning reveals distinctive noninvasive signatures of TP versus PsP after treatment of glioblastoma. Integration of the proposed method into clinical studies can be performed using the freely available Cancer Imaging Phenomics Toolkit.

Outcomes after stereotactic radiosurgery for CNS lymphoma.

BACKGROUND: The standard of care for CNS lymphoma typically includes high dose methotrexate followed by whole brain radiation therapy, but there is an increased risk of neurotoxicity with this regimen. In our institution, we offered stereotactic radiosurgery (SRS) for disease refractory to HD-MTX in a subset of patients. A search of the literature on this modality for CNS lymphoma was also conducted. METHODS: Medical records of six patients who received partial brain radiation therapy for persistent CNS lymphoma were reviewed. SRS was given via 1-3 fractions to doses of 21 or 24 Gy. PubMed, SCOPUS, and Cochrane Library databases were systematically searched for articles reporting on outcomes for CNS lymphoma treated with SRS. RESULTS: Six patients (eleven lesions) were treated with SRS for CNS lymphomas. Median follow up was 15.6 months (range 3.3-37.8). Median RT dose per lesion was 21 Gy and median time to progression was 12.7 months. Median overall survival was not reached. Four patients had distant intracranial failure with two developing local recurrence. The search strategy yielded 16 studies of which only one was prospective and included a control group. 183 out of 256 evaluated lesions (69%) responded completely to treatment and 13 of 204 patients (6%) recurred within the treatment area at last follow-up. Overall, the treatment was well tolerated. CONCLUSION: SRS may provide favorable local control in patients with refractory CNS lymphomas. A prospective trial is warranted to validate the efficacy of such an approach.

Self-cleaning structural colors by TiO2/Ti nanostructures.

Structural colors are fascinating due to their stability in comparison with dyes and pigments; nevertheless, environmental pollutants contaminate surfaces and redefine structural colors. To overcome this problem, cleaning of the surface is necessary at regular intervals, which is cumbersome and costly. We have circumvented this issue in this article and fabricated scalable self-cleaning structural colors. The structural colors are generated by TiO2 nanorods and thin films on Ti sputtered glass and flexible polyethylene terephthalate substrates employing a glancing angle deposition (GLAD) technique. Theoretical calculations based on thin film interference validate the experimental results and suggest Al, Ni, Co, and Cu as an alternative of Ti for generating structural colors. Structural colors are transformed to a superhydrophilic state, i.e., a self-cleaning state, via UV exposure and annealing at elevated temperatures. In addition to a self-cleaning state, annealing could control the opaqueness and color tunability of the structural colors. A permanent wettability state in between the superhydrophobic and superhydrophilic states of the structural colors is controlled by the GLAD technique. Moreover, the structural colors are demonstrated for information encryption and optical ethanol sensing applications.

Cu(I)-Catalyzed Oxygen and Nitrogen Nucleophiles Triggered Regioselective Synthesis of Furo/Pyrrolo-Annulated Quinolines.

Cu(I)-catalyzed intramolecular annulation of o-ethynylquinoline-3-carbaldehydes leads to the synthesis of alkoxy/imidazole-substituted 1,3-dihydrofuro[3,4-b]quinolines via C-O and C-N bond formation. The scope of the reaction was further extended to o-ethynylquinoline-3-carbonitriles for the synthesis of alkoxy-substituted 3H-pyrrolo[3,4-b]quinolines using alcohols as nucleophiles. These reactions are regioselectively favoring the 5-exo-dig cyclizations in all the annulation processes.

Copper-Catalyzed One-Pot Cross-Dehydrogenative Thienannulation: Chemoselective Access to Naphtho[2,1-b]thiophene-4,5-diones and Subsequent Transformation to Benzo[a]thieno[3,2-c]phenazines.

A facile, cost-effective, and highly efficient copper-catalyzed, TEMPO-mediated straightforward synthesis of 2,3-disubstituted naphtho[2,1-b]thiophene-4,5-diones has been achieved via cross-dehydrogenative thienannulation. The reaction proceeded via in situ generated naphthalene-1,2-diones by dearomatization of ß-naphthols, followed by oxidative heteroannulation with α-enolic dithioesters chemoselectively in an open flask. Further, the naphtho[2,1-b]thiophene-4,5-diones undergo l-proline-catalyzed cross-dehydrative coupling with ortho-phenylenediamine enabling pentacyclic benzo[a]thieno[3,2-c]phenazines in good yields under solvent-free conditions. A mechanistic rationale for this cascade reaction sequence is well supported by the control experiments.

Access to Fully Substituted Thiazoles and 2,3-Dihydrothiazoles via Copper-Catalyzed [4 + 1] Heterocyclization of α-(N-Hydroxy/aryl)imino-ß-oxodithioesters with α-Diazocarbonyls.

An efficient chemoselective practical route to fully substituted thiazoles and 2,3-dihydrothiazoles has been devised by [4 + 1] heterocyclization of α-(N-hydroxy/aryl)imino-ß-oxodithioesters with in situ generated Cu-carbenoids of diazocarbonyls. The α-(N-hydroxy/aryl)imino-ß-oxodithioesters are readily accessible by the reaction of ß-oxodithioesters with nitrous acid/nitrosoarenes. The overall transformation involves sequential N-O/C-N bonds cleavage followed by cascade C-N/C-S bonds formation in one-pot. This new strategy allows full control over the introduction of various sensitive functional groups at different positions of the thiazole ring, broadening the arsenal of synthetic methods to obtain such scaffolds.

In(OTf)3-catalysed one-pot versatile pyrrole synthesis through domino annulation of α-oxoketene-N,S-acetals with nitroolefins.

In(OTf)3-catalyzed robust and sustainable one-pot access to previously unknown and synthetically demanding polysubstituted pyrroles via [3 + 2] annulation of α-oxoketene-N,S-acetals with ß-nitrostyrenes has been achieved under solvent-free conditions. The merit of this domino Michael addition/cyclization sequence is highlighted by its operational simplicity, short reaction time (5-10 min), good to excellent yields, tolerance of a large variety of functional groups, and efficiency of producing two new (C-C and C-N) bonds and one highly functionalized pyrrole ring in a single operation, which make it an ideal alternative to existing methods.

Iridium(III)-catalyzed photoredox cross-coupling of alkyl bromides with trialkyl amines: access to α-alkylated aldehydes.

A C(sp3)-C(sp3) cross coupling approach based on an iridium-photocatalytic radical process has been developed enabling the synthesis of various α-alkylated aldehydes from easily available/synthesized alkyl bromides and trialkyl amines under mild photocatalytic conditions. The synthesized aldehydes are also explored as a functional handle for various useful products such as carboxylic acid, alcohol and N-heterocycle synthesis.

Association Between Time From Surgery to Radiation Therapy and Multimodality Treatment Outcomes in HPV+ Head and Neck Cancer: A Multi-Institutional Cohort Experience.

Purpose: Oropharyngeal squamous cell cancers (OPSCCs) are traditionally managed with surgery and, if indicated, adjuvant radiation therapy (RT) with or without chemotherapy. NCCN recommends keeping the time from surgery to the start of RT (TSRT) within 6 weeks to avoid possibly compromising patient outcomes. HPV+ OPSCCs behave more favorably than HPV- OPSCCs. We hypothesized that TSRT beyond 6 weeks may not portend poorer outcomes for the former. Methods: We identified nonmetastatic, high-risk HPV+ OPSCCs treated with multimodal therapy at 2 institutions. Prolonged TSRT was defined as >6 weeks and was evaluated for association with recurrence-free survival (RFS). Radiation treatment time (RTT; time from the first to the last day of RT), total treatment package time (TTPT; time from surgery to the end of adjuvant treatments), de-escalated RT (dose ≤56 Gy), concurrent chemotherapy, smoking history, and treatment institution were evaluated as possible confounders. Results: In total, 96 patients were included. The median follow-up time was 62 months (4-123 months); 69 patients underwent transoral robotic surgeries, and 27 received open surgeries. The median postoperative RT dose was 60 Gy (50-70.8 Gy). The median TSRT, RTT, and TTPT were 38 days (11-208), 43 days (26-56 days), and 81 days (40-255 days), respectively. Ten patients failed treatment at a median of 8 months (4-64 months). Two locoregional and 4 distant failures occurred in the group without prolonged TSRT, whereas 2 locoregional and 2 distant failures were recorded in the prolonged TSRT group. Prolonged TTPT, de-escalated RT, chemotherapy, smoking history, and treatment institution were not associated with treatment failure. RTT was dropped from our analyses as no events appeared in the prolonged RTT group, and no reliable hazard ratio could be computed. Conclusions: TSRT > 6 weeks was not significantly associated with inferior outcomes in the postoperative management of HPV+ OPSCCs. Longer TSRT may facilitate better recovery from surgical toxicity, as needed, without compromising oncologic outcomes. The TSRT goal for these cancers should be investigated in future studies.

Changes in microbial community structure and yield responses with the use of nano-fertilizers of nitrogen and zinc in wheat-maize system.

The growing popularity of nano-fertilization around the world for enhancing yield and nutrient use efficiency has been realized, however its influence on soil microbial structure is not fully understood. The purpose of carrying out this study was to assess the combined effect of nano and conventional fertilizers on the soil biological indicators and crop yield in a wheat-maize system. The results indicate that the at par grain yield of wheat and maize was obtained with application of 75% of recommended nitrogen (N) with full dose of phosphorus (P) and potassium (K) through conventional fertilizers along with nano-N (nano-urea) or nano-N plus nano-Zn sprays and N100PK i.e. business as usual (recommended dose of fertilizer). Important soil microbial property like microbial biomass carbon was found statistically similar with nano fertilizer-based management (N75PK + nano-N, and N75PK + nano-N + nano-Zn) and conventional management (N100PK), during both wheat and maize seasons. The experimental data indicated that the application of foliar spray of nano-fertilizers along with 75% N as basal is a sustainable nutrient management approach with respect to growth, yield and rhizosphere biological activity. Furthermore, two foliar sprays of nano-N or nano-N + nano-Zn curtailed N requirement by 25%, furthermore enhanced soil microbial diversity and the microbial community structure. The specific microbial groups, including Actinobacteria, Bacteroidia, and Proteobacteria, were present in abundance and were positively correlated with wheat and maize yield and soil microbial biomass carbon. Thus, one of the best nutrient management approaches for sustaining productivity and maintaining sound microbial diversity in wheat-maize rotation is the combined use of nano-fertilizers and conventional fertilizers.

Predicting peritumoral glioblastoma infiltration and subsequent recurrence using deep-learning-based analysis of multi-parametric magnetic resonance imaging.

Purpose: Glioblastoma (GBM) is the most common and aggressive primary adult brain tumor. The standard treatment approach is surgical resection to target the enhancing tumor mass, followed by adjuvant chemoradiotherapy. However, malignant cells often extend beyond the enhancing tumor boundaries and infiltrate the peritumoral edema. Traditional supervised machine learning techniques hold potential in predicting tumor infiltration extent but are hindered by the extensive resources needed to generate expertly delineated regions of interest (ROIs) for training models on tissue most and least likely to be infiltrated. Approach: We developed a method combining expert knowledge and training-based data augmentation to automatically generate numerous training examples, enhancing the accuracy of our model for predicting tumor infiltration through predictive maps. Such maps can be used for targeted supra-total surgical resection and other therapies that might benefit from intensive yet well-targeted treatment of infiltrated tissue. We apply our method to preoperative multi-parametric magnetic resonance imaging (mpMRI) scans from a subset of 229 patients of a multi-institutional consortium (Radiomics Signatures for Precision Diagnostics) and test the model on subsequent scans with pathology-proven recurrence. Results: Leave-one-site-out cross-validation was used to train and evaluate the tumor infiltration prediction model using initial pre-surgical scans, comparing the generated prediction maps with follow-up mpMRI scans confirming recurrence through post-resection tissue analysis. Performance was measured by voxel-wised odds ratios (ORs) across six institutions: University of Pennsylvania (OR: 9.97), Ohio State University (OR: 14.03), Case Western Reserve University (OR: 8.13), New York University (OR: 16.43), Thomas Jefferson University (OR: 8.22), and Rio Hortega (OR: 19.48). Conclusions: The proposed model demonstrates that mpMRI analysis using deep learning can predict infiltration in the peri-tumoral brain region for GBM patients without needing to train a model using expert ROI drawings. Results for each institution demonstrate the model's generalizability and reproducibility.

Pomegranate Resembling Design of Starch Sago Beads Encapsulates Nanopyriproxyfen, Enabling Slow Release and Improved Bioactivity.

Environmental contamination by intense insecticide usage is consistently proposed as a significant contributor to major hazards; further, disturbing non-target populations provoke a grave concern worldwide as they play essential roles in ecosystems. Pyriproxyfen is one of the most widely used pesticides; however, due to its probable toxicity, its global application in large amounts may result in water concentrations that exceed regulatory pollution thresholds. Herein, we describe nanopyriproxyfen-loaded sago beads (PPX-NCB) designed for the slow release of pyriproxyfen (PPX). Our design is inspired by the composite structure of sago beads, composed of several small beads resembling a pomegranate. The microscopic beads accumulate chitosan-PPX-nanomicelles cross-linked with tripolyphosphate via physical absorption, offering adequate room for water absorption and subsequent PPX release. PPX-NCB had distinct effects on the immature egg and larva of Anopheles stephensi, limiting embryonic development in the eggs while enhancing bioactivity. It affects the integument of larvae and alters the surface hydrocarbons of eggs and larvae. In addition, PPX-NCB demonstrates an improved safety profile in non-target Daphnia magna.