Synthesis and Properties of RNA Modified with Thioamide Internucleoside Linkage.

Recent success of RNA therapeutics has reinvigorated interest in chemical modifications of RNA. As exemplified by the phosphorothioates, modifications of sugar-phosphate backbone have been remarkably impactful but relatively underexplored in therapeutic RNAs. The present study reports synthesis, thermal stability, and RNA interference activity of RNAs modified with thioamide linkages. Compared to the previously studied amide-modified RNA, thioamide linkages strongly destabilized a short self-complementary RNA model duplex. However, in short interfering RNAs amides and thioamides had a similar effect on duplex stability and target RNA cleavage activity and specificity. Hence, the thioamide may be added to the toolbox of chemical biologist as a useful backbone modification well tolerated by the RNA interference machinery.

Complete retrieval of multi-level Stokes vector signal by an InP-based photonic integrated circuit.

An integrated Stokes vector receiver (SVR) that can retrieve state of polarization of light in the three-dimensional (3D) Stokes space has widespread applications, such as short-reach communication links, polarization-sensitive imaging, and sensing. While various approaches have been demonstrated to date, monolithic integration of polarization components on InP has been a challenging issue. In this paper, we develop a novel 4-port SVR circuit integrated on a compact InP chip to retrieve complete Stokes parameters of incoming light with various intensity and degree-of-polarization. By judiciously designing the lengths and positions of asymmetric waveguide sections, we demonstrate that the SV of signal can be projected onto four vertices of a regular tetrahedron inscribed in the Poincaré sphere. Additionally, we employ this device in decoding 10-Gbaud 4-ary and 8-ary Stokes-vector-modulated signals in the 3D Stokes space.

Reconfigurable all-optical on-chip MIMO three-mode demultiplexing based on multi-plane light conversion.

We present, to the best of our knowledge, the first experimental demonstration of reconfigurable all-optical on-chip multi-input-multi-output three-mode demultiplexing based on multi-plane light conversion. The demultiplexer consists of cascaded phase shifter arrays and multimode interference couplers integrated on a compact silicon chip. By optimizing the phase shifters, reconfigurable three-mode demultiplexing is experimentally realized with wavelength-dependent loss of less than 3 dB and modal crosstalk of less than -10 dB over a 23 nm optical bandwidth. Error-free mode demultiplexing of 40 Gbps non-return-to-zero signal is also demonstrated.

Polarization-analyzing circuit on InP for integrated Stokes vector receiver.

Stokes vector modulation and direct detection (SVM/DD) has immense potentiality to reduce the cost burden for the next-generation short-reach optical communication networks. In this paper, we propose and demonstrate an InGaAsP/InP waveguide-based polarization-analyzing circuit for an integrated Stokes vector (SV) receiver. By transforming the input state-of-polarization (SOP) and projecting its SV onto three different vectors on the Poincare sphere, we show that the actual SOP can be retrieved by simple calculation. We also reveal that this projection matrix has a flexibility and its deviation due to device imperfectness can be calibrated to a certain degree, so that the proposed device would be fundamentally robust against fabrication errors. A proof-of-concept photonic integrated circuit (PIC) is fabricated on InP by using half-ridge waveguides to successfully demonstrate detection of different SOPs scattered on the Poincare sphere.

Synthesis of an Aminooxy Derivative of the Tetrasaccharide Repeating Unit of Streptococcus dysgalactiae 2023 Polysaccharide for a PS A1 Conjugate Vaccine.

A highly efficient and stereocontrolled synthesis of an aminooxy derivative of the tetrasaccharide repeating unit of a rhamnose-rich polysaccharide isolated from the cell envelop of bovine mastitis Streptococcus dysgalactiae 2023 is reported for the first time. The synthesis was accomplished utilizing a stereoselective and convergent [2 + 2] glycosylation strategy inclusive of a disaccharide Schmidt donor and an inclusive rhamnose disaccharide acceptor. The synthetic aminooxy tetrasaccharide was conjugated to T-cell stimulating immunogen PS A1 from Bacteroides fragilis ATCC 25285/NCTC 9343 via a physiologically stable oxime linkage to furnish the first semisynthetic bacterial-based immunogen construct targeting S. dysgalactiae 2023. The synthetic tetrasaccharide was assembled in 19 steps with a ∼5.0% overall yield.

Design, analysis, and transmission system performance of a 41 GHz silicon photonic modulator.

The design and characterization of a slow-wave series push-pull traveling wave silicon photonic modulator is presented. At 2 V and 4 V reverse bias, the measured -3 dB electro-optic bandwidth of the modulator with an active length of 4 mm are 38 GHz and 41 GHz, respectively. Open eye diagrams are observed up to bitrates of 60 Gbps without any form of signal processing, and up to 70 Gbps with passive signal processing to compensate for the test equipment. With the use of multi-level amplitude modulation formats and digital-signal-processing, the modulator is shown to operate below a hard-decision forward error-correction threshold of 3.8×10-3 at bitrates up to 112 Gbps over 2 km of single mode optical fiber using PAM-4, and over 5 km of optical fiber with PAM-8. Energy consumed solely by the modulator is also estimated for different modulation cases.

High-speed compact silicon photonic Michelson interferometric modulator.

We present the detailed analysis and characterization of a silicon Michelson modulator with short 500 µm phase shifters and a low VπLπ of 0.72 V-cm under reverse bias. We investigate optical modulation of reverse biased p-n and forward biased p-i-n junctions. We demonstrate for the first time that error-free operation up to 40 Gbps is possible with lumped silicon interferometric modulators. For reverse bias operation, we show that even greater bandwidth can be obtained with lower impedance drivers. Forward bias operation with pre-emphasized signals is shown to have clean eye diagrams up to 40 Gbps, however, error counting reveals a strong dependence on test patterns and that error-free operation is achievable for short pattern lengths.

Focusing-curved subwavelength grating couplers for ultra-broadband silicon photonics optical interfaces.

We report on the design and characterization of focusing-curved subwavelength grating couplers for ultra-broadband silicon photonics optical interfaces. With implementation of waveguide dispersion engineered subwavelength structures, an ultra-wide 1-dB bandwidth of over 100 nm (largest reported to date) near 1550 nm is experimentally achieved for transverse-electric polarized light. By tapering the subwavelength structures, back reflection is effectively suppressed and grating coupling efficiency is increased to -4.7 dB. A compact device footprint of 40 µm × 20 µm is realized by curving the gratings in a focusing scheme.

Adhesively bonded Ce:YIG/SOI integrated optical circulator.

A classical 3-port optical circulator is demonstrated on the silicon-on-insulator (SOI) platform. A garnet die with a magneto-optical cerium-doped yttrium iron garnet (Ce:YIG) layer is bonded on top of a Mach-Zehnder interferometer circuit using a thin adhesive bonding layer. The power transmission between different ports is characterized in the presence of an external magnetic field, transversal to the light propagation direction. An isolation of 22 dB is measured at a wavelength of 1562 nm.

Exploring Noncovalent Protease Inhibitors for the Treatment of Severe Acute Respiratory Syndrome and Severe Acute Respiratory Syndrome-Like Coronaviruses.

Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans causing zoonotic outbreaks of severe disease. Both viruses originate from a group of betacoronaviruses known as subgroup 2b. The emergence of two dangerous human pathogens from this group along with previous studies illustrating the potential of other subgroup 2b members to transmit to humans has underscored the need for antiviral development against them. Coronaviruses modify the host innate immune response in part through the reversal of ubiquitination and ISGylation with their papain-like protease (PLpro). To identify unique or overarching subgroup 2b structural features or enzymatic biases, the PLpro from a subgroup 2b bat coronavirus, BtSCoV-Rf1.2004, was biochemically and structurally evaluated. This evaluation revealed that PLpros from subgroup 2b coronaviruses have narrow substrate specificity for K48 polyubiquitin and ISG15 originating from certain species. The PLpro of BtSCoV-Rf1.2004 was used as a tool alongside PLpro of CoV-1 and CoV-2 to design 30 novel noncovalent drug-like pan subgroup 2b PLpro inhibitors that included determining the effects of using previously unexplored core linkers within these compounds. Two crystal structures of BtSCoV-Rf1.2004 PLpro bound to these inhibitors aided in compound design as well as shared structural features among subgroup 2b proteases. Screening of these three subgroup 2b PLpros against this novel set of inhibitors along with cytotoxicity studies provide new directions for pan-coronavirus subgroup 2b antiviral development of PLpro inhibitors.

Efficient and improved synthesis of Telmisartan.

An efficient synthesis of the angiotensin II receptor antagonist Telmisartan (1) is presented involving a cross coupling of 4-formylphenylboronic acid 10 with 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline (11) as the key step (90% yield). The benzimidazole moiety 15 was constructed regioselectively via a reductive amination-condensation sequence, replacing the alkylation of the preformed benzimidazole step in the previously published route. This methodology overcomes many of drawbacks associated with previously reported syntheses.

A short and efficient synthesis of valsartan via a Negishi reaction.

An efficient synthesis of the angiotensin-II inhibitor valsartan (Diovan®) is presented. Directed ortho-metalation of 5-phenyl-1-trityl-1H-tetrazole (6) and its Negishi coupling with aryl bromide 5 are the key steps of the synthesis. This method overcomes many of the drawbacks associated with previously reported syntheses.

Chemical synthesis and immunological evaluation of entirely carbohydrate conjugate Globo H-PS A1.

An anticancer, entirely carbohydrate conjugate, Globo H-polysaccharide A1 (Globo H-PS A1), was chemically prepared and immunologically evaluated in C57BL/6 mice. Tumor associated carbohydrate antigen Globo H hexasaccharide was synthesized in an overall 7.8% yield employing a convergent [3 + 3] strategy that revealed an anomeric aminooxy group used for conjugation to oxidized PS A1 via an oxime linkage. Globo H-PS A1, formulated with adjuvants monophosphoryl lipid A and TiterMax® Gold. After immunization an antigen specific immune response was observed in ELISA with anti-Globo H IgG/IgM antibodies. Specificity of the corresponding antibodies was determined by FACS showing cell surface binding to Globo H-positive cancer cell lines MCF-7 and OVCAR-5. The anti-Globo H antibodies also exhibited complement-dependent cellular cytotoxicity against MCF-7 and OVCAR-5 cells.

Syntheses and evaluation of glucosyl aryl thiosemicarbazide and glucosyl thiosemicarbazone derivatives as antioxidant and anti-dyslipidemic agents.

A series of N-per-O-acetyl-glucosyl arylthiosemicarbazide and thiosemicarbazone derivatives have been synthesized and evaluated for their in vivo anti-dyslipidemic and in vitro antioxidant activities. Among 16 compounds tested, 3 compounds showed potent anti-dyslipidemic activity and 6 compounds showed potent antioxidant and scavenger of oxygen free radicals activity.

A short synthesis of ±-cherylline dimethyl ether.

A synthesis of ±-cherylline dimethyl ether is reported. The key steps involved are Michael-type addition, radical azidonation of an aldehyde, Curtius rearrangement, and reduction of an isocyanate intermediate followed by Pictet-Spengler cyclization.

Synthesis and evaluation of antitubercular activity of glycosyl thio- and sulfonyl acetamide derivatives.

A series of glycosyl thioacetamide and glycosyl sulfonyl acetamide derivatives have been prepared following a convenient reaction protocol and evaluated for their antitubercular activity against Mycobacterium tuberculosis H(37)Rv. Amongst 32 compounds evaluated 3 compounds were effective in inhibiting mycobacterial growth at MIC of 6.25 microg/mL, 6 compounds at MIC of 3.125 microg/mL and 1 compound at MIC of 1.56 microg/mL. All active compounds were found nontoxic in Vero cell lines and mice bone marrow macrophages.

Efficacy of nano-hydroxyapatite prepared by an aqueous solution combustion technique in healing bone defects of goat.

The present study was undertaken to evaluate porous hydroxyapatite (HAp), the powder of which was prepared by a novel aqueous solution combustion technique, as a bone substitute in healing bone defects in vivo, as assessed by radiologic and histopathologic methods, oxytetracycline labeling, and angiogenic features in Bengal goat. Bone defects were created in the diaphysis of the radius and either not filled (group I) or filled with a HAp strut (group II). The radiologic study in group II showed the presence of unabsorbed implants which acted as a scaffold for new bone growth across the defect, and the quality of healing of the bone defect was almost indistinguishable from the control group, in which the defect was more or less similar, although the newly formed bony tissue was more organized when HAp was used. Histologic methods showed complete normal ossification with development of Haversian canals and well-defined osteoblasts at the periphery in group II, whereas the control group had moderate fibro-collagenization and an adequate amount of marrow material, fat cells, and blood vessels. An oxytetracycline labeling study showed moderate activity of new bone formation with crossing-over of new bone trabeculae along with the presence of resorption cavities in group II, whereas in the control group, the process of new bone formation was active from both ends and the defect site appeared as a homogenous non-fluoroscent area. Angiograms of the animals in the control group showed uniform angiogenesis in the defect site with establishment of trans-transplant angiogenesis, whereas in group II there was complete trans-transplant shunting of blood vessel communication. Porous HAp ceramic prepared by an aqueous combustion technique promoted bone formation over the defect, confirming their biologic osteoconductive property.

Total Synthesis of Zwitterionic Tetrasaccharide Repeating Unit from Bacteroides fragilis ATCC 25285/NCTC 9343 Capsular Polysaccharide PS A1 with Alternating Charges on Adjacent Monosaccharides.

The tetrasaccharide repeating unit of zwitterionic polysaccharide A1 (PS A1) from Bacteroides fragilis ATCC 25285/NCTC 9343 has been synthesized using a linear glycosylation approach. One key step includes an α(1,4)-stereoselective [2 + 1] glycosylation of a 2,4,6-trideoxy-2-acetamido-4-amino-d-Gal p (AAT) donor with a poorly reactive axial C4-OH disaccharide acceptor. Mild acid-mediated deacetylation and a challenging [3 + 1] glycosylation are also highlighted. The strategy is inclusive of a single-pot, three-step deprotection affording PS A1 with alternating charges on adjacent monosaccharide units.

Synthesis of an Aminooxy Derivative of the Trisaccharide Globotriose Gb3.

The synthesis of α-aminooxy trisaccharide moiety [α-d-Gal-(1,4)-ß-d-Gal-(1,4)-ß-d-Glc-α-aminooxy], related to the cell surface globotriaosylceramide (Gb3) receptor of the B subunit of the AB5 Shiga toxin of Shigella dysenteriae, has been synthesized for the first time in 11 steps with a 15% overall isolated yield. A highlight of this work entails utilizing chemically compatible synthetic transformations, including those related to glycosylation, incorporative of the succinimidyl moiety as a precursor to the aminooxy Gb3 derivative. The fully deprotected trisaccharide aminooxy compound was reacted with a carbonyl compound leading to oxime formation in quantitative yield underscoring the importance for future glyco-conjugations.

In vivo response of porous hydroxyapatite and beta-tricalcium phosphate prepared by aqueous solution combustion method and comparison with bioglass scaffolds.

Pure hydroxyapatite (HAp) and a biphasic calcium phosphate [containing 90% of beta-tri-calcium phosphate (beta-TCP) and 10% HAp] were tailored through an aqueous solution combustion synthesis. Porous struts were prepared using all the powders along with bioglass, a known bioactive material, and subsequently characterized. Sterilized struts were implanted to the lateral side of radius bone of 24 black Bengal goats of either sex, in which a blank hole was left unfilled in a group of six specimens to act as control. The bone formation response of the three implanting materials in vivo has been studied using scanning electron microscope and histological analysis in contrast with positive controls. Push-out tests were used to assess the mechanical strength at the bone-biomaterial interface. It was observed that interfacial response was strongly dependent on combinations of different physical and chemical parameters. The surface of beta-TCP exhibited similar characteristics of bone and was distinct from those of intervening apatite layer of bioglass. Lower bone ingrowth and reduced strength was observed with HAp compared to beta-TCP/bioglass-based implants. Bone formation response of the Ca-P material varied according to the composition of the implanting material, which could be tailored through this novel synthesis.