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The first line of treatment for most solid tumors is surgical resection of the primary tumor with adequate negative margins. Incomplete resections with positive margins account for over 75% of local recurrences and the development of distant metastases. In cases of oral cavity squamous cell carcinoma (OSCC), the rate of successful tumor removal with adequate margins is just 15-26%. Advanced real-time imaging methods that improve detection of tumor margins can help improve success rates. Fluorescence imaging in the second near-infrared (NIR-II) window has the potential to revolutionize the field due to its superior imaging qualities, but NIR-II dyes with adequate in vivo performance and safety profiles are scarce. We report a novel high-performance organic molecule NIR-II fluorophore, XW-03-66 , with a fluorescence quantum yield (QY) of 6.0% in aqueous media. XW-03-66 self-assembles into nanoparticles (~80 nm) and has a systemic circulation half-life (t 1/2 ) of 11.3 h. In mouse models of HPV+ and HPV- OSCC, XW-03-66 outperformed indocyanine green (ICG), a clinically available NIR dye, and enabled intraoperative NIR-II image-guided resection of the tumor and adjacent draining lymph node with negative margins. In vitro and in vivo toxicity assessments revealed minimal safety concerns for in vivo applications.

Attosecond light source is a new type of light source that was born at the beginning of the 21st century, which has a short pulse, broad spectrum, high temporal and spatial coherence and wide tunability, thus being widely employed in various research fieds. From ultrafast motion of electrons in atoms to charge transfer in biological macromolecules, attosecond pulses is currently the only tool that can track and capture these ultrafast dynamics. Attosecond pulse enables us to investigate ultrafast dynamics of micro-world both in nanometer and attosecond scales. However, the mechanism of attosecond pulse generation is completely different from general ultrafast lasers. Instead, attosecond pulse is generated by a highly nonlinear interaction between strong ultrafast femtosecond laser and matter, which is called high-order harmonic generation (HHG). The mechanism of HHG can be understood by a classical three step model. First, an electron is ionized from an atom by a strong laser electric field through tunnel ionization. Then the free electron is accelerated by the laser field and gains energy. Finally, the electron recombines with the parent ion when the laser field changes its sign with emission of a photon, whose energy equals its kinetic energy gained in the laser field plus ionization potential of the atom. Apparently, HHG is strongly affected by the laser waveform. Several key parameters of driving laser, such as wavelength, intensity, and carrier envelope phase strongly affect the process of HHG. Thus, the characteristics of attosecond pulses are determined by the driving laser. The rapid development of attosecond pulse technology strongly depends on the development of driving laser technology. In the beginning, chirped pulse amplification (CPA) technology greatly promoted the development of attosecond light sources. The femtosecond CPA systems based on Ti:sapphire crystal has been the main driving laser to generate attosecond light pulses. The driving laser wavelength is in the near infrared region near 800 nm, which generally has a pulse duration of multiple optical cycles. By employing post-compression technology to shorten pulse durations of CPA systems to few-cycle, isolated attosecond pulses in the extreme ultraviolet (XUV) can be generated, which is called the first generation of attosecond light source. Recently, optical parametric amplification (OPA) systems have been widely used as driving laser due to its flexible wavelength tunability. Using OPA, longer driving laser wavelength up to the midinfrared (MIR) can be obtained, which pushes the attosecond pulses to the soft X-ray region, and has been called the second generation of attosecond light sources. Due to broad spectrum and higher photon energy, attosecond pulses have a shorter duration in the soft X-ray region compared with XUV region, given that the temporal chirp is properly compensated. In 2017, reseachers generated soft X-ray isolated attosecond pulses, which was driven by mid-infrared pulses centered at 1.8 µm. These attosecond pulses, whose duration reaches 53 as and spectrum surpasses carbon K-edge, provide a tool for studying the ultrafast dynamics of diamond, graphene and other carbon materials. In this paper, we start with the principle of attosecond pulses generation based on HHG. Then, we introduce different technologies and their development for obtaining driving laser pulses for HHG. Finally, we introduce prospect on development of driving laser pulses for attosecond pulses generation.

The abnormal phosphorylation of tau is a necessary precursor to the formation of tau fibrils, a marker of Alzheimer's disease. We hypothesize that hyperphosphorylative conditions may result in unique cell surface markers. We identify and demonstrate the utility of such surrogate markers to identify the hyperphosphorylative state.

The development of imaging agents for in vivo detection of alpha-synuclein (α-syn) pathologies faces several challenges. A major gap in the field is the lack of diverse molecular scaffolds with high affinity and selectivity to α-syn fibrils for in vitro screening assays. Better in vitro scaffolds can instruct the discovery of better in vivo agents. We report the rational design, synthesis, and in vitro evaluation of a series of novel 1-indanone and 1,3-indandione derivatives from a Structure-Activity Relationship (SAR) study centered on some existing α-syn fibril binding ligands. Our results from fibril saturation binding experiments show that two of the lead candidates compounds 8 and 32 bind α-syn fibrils with binding constants (K(d)) of 9.0 and 18.8 nM, respectively, and selectivity of greater than 10x for α-syn fibrils compared with amyloid-β (Aβ) and tau fibrils. Our results demonstrate that the lead ligands avidly label all forms of α-syn on PD brain tissue sections, but only the dense core of senile plaques in AD brain tissue, respectively. These results are corroborated by ligand-antibody colocalization data from Syn211, which shows immunoreactivity towards all forms of α-syn aggregates, and Syn303, which displays preferential reactivity towards mature Lewy pathology. Our results reveal that 1-indanone derivatives have desirable properties for the biological evaluation of α-synucleinopathies.

In this Account, we give an overview of our recent efforts towards the total synthesis of two marine natural products: bryostatin 8 and (–)-exiguolide. The central theme is to highlight the power of the organosilane strategy, which was characterized with our geminal bis(silanes)-based methodologies for constructing the unique exocyclic enoate-substituted pyran rings.1 Introduction2 Background of Bryostatins and (–)-Exiguolide3 Constructing the B-Ring of Bryostatins4 Total Synthesis of (–)-Exiguolide via an Organosilane Strategy5 Constructing the C-Ring of Bryostatins6 Total Synthesis of Bryostatin 87 Conclusion

The development of imaging agents for in vivo detection of alpha-synuclein (α-syn) pathologies faces several challenges. A major gap in the field is the lack of diverse molecular scaffolds with high affinity and selectivity to α-syn fibrils for in vitro screening assays. Better in vitro scaffolds can instruct the discovery of better in vivo agents. We report the rational design, synthesis, and in vitro evaluation of a series of novel 1-indanone and 1,3-indandione derivatives from a Structure-Activity Relationship (SAR) study centered on some existing α-syn fibril binding ligands. Our results from fibril saturation binding experiments show that two of the lead candidates bind α-syn fibrils with binding constants (Kd) of 9.0 and 18.8 nM, respectively, and selectivity of greater than 10x for α-syn fibrils compared with amyloid-β (Aβ) fibrils. Our results demonstrate that the lead ligands avidly label all forms of α-syn on PD brain tissue sections, but only the dense core of senile plaques in AD brain tissue, respectively. These results are corroborated by ligand-antibody colocalization data from Syn211, which shows immunoreactivity towards all forms of α-syn aggregates, and Syn303, which displays preferential reactivity towards mature Lewy pathology. Our results reveal that 1-indanone derivatives have desirable properties for the biological evaluation of α-synucleinopathies.

In the next-generation cognitive radio networks, numerous secondary users will share the spectrum resource with the primary users. As it may not be possible to support all the communication rate requirements, there are many supporting sets for the secondary users as long as the communication rates of the primary users are guaranteed. In this paper, we study the maximum feasible set problem to access as many secondary users as possible, under the constraints of power budgets and communication rates in cognitive radio networks. In this interesting issue, the existing literature generally removes a subset of the secondary users so that the remaining users achieve the thresholds with communication rates and power budgets. However, the removal algorithms cause more interference when there are plenty of unsupported secondary users. We leverage the spectral radius of the network characteristic matrix as the admission price to access the new secondary user. Then, we design a hybrid access control algorithm to reduce the interference time and approximate the maximum network capacity. Moreover, different supported sets produce the different energy efficiency, even having the same network capacity, while all users require the high communication rates. Numerical results demonstrate that our algorithms provide the decent energy efficiency under the communication rate constraints.

Funding Information: We thank the Arkansas Nano & Bio Materials Characterization Facility at the Institute for Nano Sciences & Engineering for our imaging studies, and Prof Yoshito Kishi (Harvard University) for the kind gift of synthetic mycolactone A/B used by S.H. and R.S. W.S. is supported by Grant No. R15GM116032 from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) and startup funds from the University of Arkansas. This work was also supported in part by Grant No. P30 GM103450 from the National Institute of General Medical Sciences of the NIH and by seed money from the Arkansas Biosciences Institute (ABI). S.O’K. is the recipient of a Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral Training Programme Award (BB/J014478/ 1), and S.H. holds a Welcome Trust Investigator Award in Science (204957/Z/16/Z). The alpha-1 antitrypsin work was supported by the Alpha-1 Foundation (J.I. and M.J.I.). J.I. and M.J.H. were supported by the intramural program of NCATS, National Institutes of Health, projects 1ZIATR000048-03 (J.I.) and ZIATR000063-04 (M.J.H.). R.S. holds a Welcome Trust Investigator Award in Science (202843/Z/16/Z). C.D. received funding from the Institut Pasteur, the Institut National de la Santé et de la Recherche Med́ icale, and the Fondation Raoul Follereau. N.B.’s synthesis and chemical biology studies of mycolactone were supported by CNRS, Université de Strasbourg, Fondations Potier et Follereau, and the Investisse-ment d’Avenir (Idex Unistra). V.O.P. is supported by the Academy of Finland (Grants 289737 and 314672) and the Sigrid Juselius Foundation. Funding Information: We thank the Arkansas Nano & Bio Materials Characterization Facility at the Institute for Nano Sciences & Engineering for our imaging studies, and Prof Yoshito Kishi (Harvard University) for the kind gift of synthetic mycolactone A/B used by S.H. and R.S. W.S. is supported by Grant No. R15GM116032 from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) and startup funds from the University of Arkansas. This work was also supported in part by Grant No. P30 GM103450 from the National Institute of General Medical Sciences of the NIH and by seed money from the Arkansas Biosciences Institute (ABI). S.O'K. is the recipient of a Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral Training Programme Award (BB/J014478/1), and S.H. holds a Welcome Trust Investigator Award in Science (204957/Z/16/Z). The alpha-1 antitrypsin work was supported by the Alpha-1 Foundation (J.I. and M.J.I.). J.I. and M.J.H. were supported by the intramural program of NCATS, National Institutes of Health, projects 1ZIATR000048-03 (J.I.) and ZIATR000063-04 (M.J.H.). R.S. holds a Welcome Trust Investigator Award in Science (202843/Z/16/Z). C.D. received funding from the Institut Pasteur, the Institut National de la Sante et de la Recherche Medicale, and the Fondation Raoul Follereau. N.B.'s synthesis and chemical biology studies of mycolactone were supported by CNRS, Universite de Strasbourg, Fondations Potier et Follereau and the Investissement d'Avenir (Idex Unistra). V.O.P. is supported by the Academy of Finland (Grants 289737 and 314672) and the Sigrid Juselius Foundation. Publisher Copyright: © 2019 American Chemical Society. Ipomoeassin F is a potent natural cytotoxin that inhibits growth of many tumor cell lines with single-digit nanomolar potency. However, its biological and pharmacological properties have remained largely unexplored. Building upon our earlier achievements in total synthesis and medicinal chemistry, we used chemical proteomics to identify Sec61 alpha (protein transport protein Sec61 subunit alpha isoform 1), the pore-forming subunit of the Sec61 protein translocon, as a direct binding partner of ipomoeassin F in living cells. The interaction is specific and strong enough to survive lysis conditions, enabling a biotin analogue of ipomoeassin F to pull down Sec61 alpha from live cells, yet it is also reversible, as judged by several experiments including fluorescent streptavidin staining, delayed competition in affinity pulldown, and inhibition of TNF biogenesis after washout. Sec61 alpha forms the central subunit of the ER protein translocation complex, and the binding of ipomoeassin F results in a substantial, yet selective, inhibition of protein translocation in vitro and a broad ranging inhibition of protein secretion in live cells. Lastly, the unique resistance profile demonstrated by specific amino acid single-point mutations in Sec61 alpha provides compelling evidence that Sec61 alpha is the primary molecular target of ipomoeassin F and strongly suggests that the binding of this natural product to Sec61 alpha is distinctive. Therefore, ipomoeassin F represents the first plant-derived, carbohydrate-based member of a novel structural class that offers new opportunities to explore Sec61 alpha function and to further investigate its potential as a therapeutic target for drug discovery.

Super-simple designs are used in other constructions, such as coverings, superimposed codes and perfect hash families etc. The existence of super-simple ( v , 4 , λ ) -BIBDs has been determined for λ = 2 , 3 , 4 , 5 , 6 and 9. When λ = 7 , the necessary conditions of such a design are that v ≡ 1 , 4 (mod 12) and v ≥ 16 . In this paper, we show that these necessary conditions are sufficient.

A TMSBr/InBr3-promoted Prins cyclization/homobromination reaction of dienyl alcohol with aldehyde has been developed to construct a unique cis-E THP shown as the A ring in (−)-exiguolide and the B ring in bryostatins.

Convergent total synthesis of bryostatin 8 has been accomplished by an organosilane-based strategy. The C ring is constructed stereoselectively through a geminal bis(silane)-based [1,5]-Brook rearrangement, and the B ring through geminal bis(silane)-based Prins cyclization, thus efficiently joining the northern and southern parts of the molecule.

Ipomoeassin F, a plant-derived macrolide, exhibited single-digit nanomolar growth inhibition activity against many cancer cell lines. In this report, a series of 5-oxa/aza analogues was prepared and screened for cytotoxicity. Replacement of 5-CH2 with O/NH simplified the synthesis and led to only a small activity loss. N-methylation almost completely restored the potency. Further studies with additional 5-oxa analogues suggested, for the first time, that size and flexibility of the ring also significantly influence the bioactivity of ipomoeassin F.

One of the most fundamental tasks of wireless sensor networks is to provide coverage of the deployment region. We study the coverage of a line interval with a set of wireless sensors with adjustable coverage ranges. Each coverage range of a sensor is an interval centered at that sensor whose length is decided by the power the sensor chooses. The objective is to find a range assignment with the minimum cost. There are two variants of the optimization problem. In the discrete variant, each sensor can only choose from a finite set of powers, whereas in the continuous variant, each sensor can choose power from a given interval. For the discrete variant of the problem, a polynomial-time exact algorithm is designed. For the continuous variant of the problem, NP-hardness of the problem is proved and followed by an ILP formulation. Then, constant-approximation algorithms are designed when the cost for all sensors is proportional to r κ for some constant κ ≥ 1, where r is the covering radius corresponding to the chosen power. Specifically, if κ = 1, we give a 1.25-approximation algorithm and a fully polynomial-time approximation scheme; if κ > 1, we give a 2-approximation algorithm. We also show that the approximation analyses are tight.

A [1,5]-anion relay has been achieved in 3,3-bis(silyl) benzyl enol ether. Deprotonation at the sterically more accessible benzyl position triggers an intramolecular proton transfer to generate the thermodynamically more stable 3,3-bis(silyl) allyloxy lithium. This endo-oriented allyl anion is stable at -78 °C and undergoes diastereoselective syn-addition at the γ-position with aldehydes and ketones to give monobenzyl-substituted 1,2-diols.

An intramolecular [1,4]-S- to O-silyl migration has been used to form silyl enol ethers with Z-configurational control. The silyl migration also creates a new anion center at sulfur, which can subsequently react with electrophiles to generate Z-silyl enol ethers with diverse thioether linkages. The synthetic utility of this pathway was demonstrated by modifying the Z-silyl enol ethers with aldehydes via a Mukaiyama aldol reaction or Prins cyclization to generate functionalized organosulfur compounds.

A remarkable α-effect of silicon has been discovered that results in soft nucleophilicity at the Cγ of 3,3-bis(silyl) allyloxy lithium 1. The addition of 1 to α,β-unsaturated carbonyl compounds, including enals, proceeds in a 1,4- over 1,2-manner with medium to good regioselectivity, whereas the parent allyloxy lithium 4 undergoes complete 1,2-addition. The results from DFT calculations of HMPA-complexed 1 and 4 provide the rationale to explain this different regioselectivity.

Geminal bis(silyl) enal 2a is shown to be a useful scaffold for anion relay chemistry (ARC) aimed at the stereoselective synthesis of C(3),O(1)-disilylated allylic alcohols. The ARC reaction is initiated by the addition of an alkyllithium to the aldehyde and features a CuCN-promoted C(sp2)-to-O 1,4-silyl migration to generate a vinylcuprate that reacts with activated electrophiles.

The Prins cyclization/homobromination of dienyl alcohols (I) with aldehydes (II) and (VI) leads to intermediate THP bromides, which react readily with 2,5-dinitrobenzoic acid to afford cis-THP esters mainly as E-alkenes (IV) and (VII).

Detailed investigations of the retro-[1,4] Brook rearrangement of 3-silyl allyloxysilanes are described. Based on control experiments and NMR studies, rationalizations are proposed for the formation of 3,3-bissilyl enols, unusual compounds that are stable to acidic hydrolysis but that can be transformed into the corresponding aldehydes under basic hydrolysis conditions. These studies further show that the 3,3-bissilyl enolates can be O -alkylated by alkyl halides with complete chemoselectivity. This reaction provides a practical entry to various 3,3-bissilyl aldehydes and enol derivatives. As a demonstration of the synthetic utility of this approach, 3,3-bissilyl aldehyde was converted into bissilyl divinyl ketone, which can undergo an SiO 2 -promoted Nazarov reaction to give cyclic β-silyl enone smoothly.

The [1,5]-anion relay/[2,3]-Wittig rearrangement of 3,3-bis(silyl) enol allyl ethers has been developed. This reaction provides an efficient method to synthesize versatile vinyl bissilanes, which can be transformed into trisubstituted vinylsilanes through a [1,4]-Brook rearrangement/alkylation protocol using a wide range of electrophiles.

Cognitive radio is a promising technique for increasing spectrum efficiency in wireless networks. In this paper, we study power minimization problem to allow as many secondary users access the channel of primary users as possible. In this appealing issue, many considerable literatures have been studied to generally remove a subset of the secondary users such that the remaining users satisfy the constraints with power budget and Signal-to-Interference-plus-Noise Ratio (SINR). However, when the outage probability is large, i.e. there are numerous unsupported secondary users in cognitive radio networks, the removal algorithms take interference time. Instead of removing the worst secondary user, we propose a hybrid access algorithm, leveraging the characterization of the feasibility with the spectral radius, to promote the capacity and reduce the interference time. Compared with present known alternatives, numerical results show that our algorithm achieves a better capacity.

The addition of 3,3-bis(silyl)allyloxy lithium, generated from enol ether (II), to α,β-unsaturated carbonyl compounds such as (I), (IV), (VI), and (VIII), proceeds in an 1,4- over 1,2-manner with medium to good regioselectivity, whereas the parent allyloxy lithium species undergoes complete 1,2-addition.

A [1,5]-anion relay has been achieved in 3,3-bis(silyl) benzyl enol ether. Deprotonation at the sterically more accessible benzyl position triggers an intramolecular proton transfer to generate the thermodynamically more stable 3,3-bis(silyl) allyloxy lithium. This endo-oriented allyl anion is stable at −78 °C and undergoes diastereoselective syn-addition at the γ-position with aldehydes and ketones to give monobenzyl-substituted 1,2-diols.

An intramolecular [1,4]-S- to O-silyl migration has been used to form silyl enol ethers with Z-configurational control. The silyl migration also creates a new anion center at sulfur, which can subsequently react with electrophiles to generate Z-silyl enol ethers with diverse thioether linkages. The synthetic utility of this pathway was demonstrated by modifying the Z-silyl enol ethers with aldehydes via a Mukaiyama aldol reaction or Prins cyclization to generate functionalized organosulfur compounds.

A [1,4]-S- to O-silyl migration has been exploited to chemoselectively transform esters into ketones by using organolithium reagents, allowing multicomponent synthesis of α-thioketones. Mechanistic studies reveal that this migration proceeds in an intramolecular manner and is more favorable than the corresponding [1,5]-S- to O- and [1,3]-C- to O-silyl migrations. The resulting α-thioketones are valuable building blocks for the synthesis of cyclic or multifunctionalized organosulfur compounds.

A [1,4]-S- to O-silyl migration has been exploited to chemoselectively transform esters into ketones by using organolithium reagents, allowing multicomponent synthesis of α-thioketones. Mechanistic studies reveal that this migration proceeds in an intramolecular manner and is more favorable than the corresponding [1,5]-S- to O- and [1,3]-C- to O-silyl migrations. The resulting α-thioketones are valuable building blocks for the synthesis of cyclic or multifunctionalized organosulfur compounds.

Geminal bis(silyl) enal (I) is shown to be a useful scaffold for anion relay chemistry (ARC) aimed at the stereoselective synthesis of trisubstituted vinylsilanes.

Detailed investigations of the retro-[1,4] Brook rearrangement of 3-silyl allyloxysilanes are described. Based on control experiments and NMR studies, rationalizations are proposed for the formation of 3,3-bissilyl enols, unusual compounds that are stable to acidic hydrolysis but that can be transformed into the corresponding aldehydes under basic hydrolysis conditions. These studies further show that the 3,3-bissilyl enolates can be O -alkylated by alkyl halides with complete chemoselectivity. This reaction provides a practical entry to various 3,3-bissilyl aldehydes and enol derivatives. As a demonstration of the synthetic utility of this approach, 3,3-bissilyl aldehyde was converted into bissilyl divinyl ketone, which can undergo an SiO 2 -promoted Nazarov reaction to give cyclic β-silyl enone smoothly.

A new strategy to trisubstituted vinylsilanes is developed: the vinyl bissilanes can be transformed into trisubstituted vinylsilanes through a [1,4]-Brook rearrangement/alkylation protocol using different electrophiles.

We study the time complexity of data collection in sensor networks. A simple mathematical model for sensor networks regarded as lines, multi-lines and trees is defined and corresponding optimal schedules are provided. A lower bound of data collection time on general graph networks is also derived.

The sequential addition/Brook rearrangement/epoxide opening process proceeds with high stereoselectivity.

A highly stereoselective approach to novel tetrasubstituted (Z)-β-hydroxy-α-TMS silyl enol ethers is described. The reaction proceeds via a sequential addition/[1,2]-Brook rearrangement/epoxide-opening process of TMS-substituted oxiranyl anions with acylsilanes.

One of the most fundamental tasks of wireless sensor networks is to provide coverage of the deployment region. In this paper, we study the coverage of a line segment with a set of wireless sensors with adjustable coverage ranges. Each coverage range of a sensor is an interval centered at that sensor whose length is decided by the power the sensor chooses. The objective is to find a range assignment with the minimum cost. There are two variants of the optimization problem. In the discrete variant, each sensor can only choose from a finite set of powers while in the continuous variant, each sensor can choose power from a given interval. For the discrete variant of the problem, we present a polynomial-time exact algorithm. For the continuous variant of the problem, we develop constant-approximation algorithms when the cost for all sensors is proportional to rk for some constant k ≥ 1, where r is the covering radius corresponding to the chosen power. Specifically, if k = 1, we give a simple 1.25-approximation algorithm and a fully polynomial-time approximation scheme (FPTAS); if k > 1, we give a simple 2-approximation algorithm.

In this paper, we investigate the existence of resolvable group divisible designs (RGDDs) with block size four, group-type h^n and general index @l. The necessary conditions for the existence of such a design are n>=4, hn=0(mod4) and @lh(n-1)=0(mod3). These necessary conditions are shown to be sufficient for all @l>=2, with the definite exceptions of (@l,h,n)@?{(3,2,6)}@?{(2j+1,2,4):j>=1}. The known existence result for @l=1 is also improved.