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Light-based neuromodulation systems offer exceptional spatiotemporal resolution combined with the elimination of physical tether to communicate with neurons. Currently, optical neuromodulation systems ranging from the nano to the centimeter scale enable neural activity control from the single cell to the organ level in retina, heart, spinal cord, and brain, facilitating a wide range of experiments in intact and freely moving animals in different contexts, such as during social interactions and behavioral tasks. Nanotransducers (e.g., metallic nanoparticles, silicon nanowires, and polymeric nanoparticles) and microfabricated photodiodes convert light to electrical, thermal, and mechanical stimuli that can allow remote and non-contact stimulation of neurons. Moreover, integrated devices composed of nano and microscale optoelectronic components comprise fully implantable and wirelessly powered smart optoelectronic systems that exhibit multimodal and closed-loop operation. In this review, we first discuss the material platforms, stimulation mechanisms, and applications of passive systems, i.e., nanotransducers and microphotodiodes. Then, we review the use of organic and inorganic light-emitting diodes for optogenetics and implantable wireless optoelectronic systems that enable closed-loop optogenetic neuromodulation through the use of light-emitting diodes, wireless power transfer circuits, and feedback loops. Exploration of materials and mechanisms together with the presented applications from both research and clinical perspectives in this review provides a comprehensive understanding of the optical neuromodulation field with its advantages and challenges to build superior systems in the future., Brain Research Program of the National Research Foundation (NRF); Korean government (MSIT); European Research Council (ERC); European Union (EU); Horizon Europe; Research and Innovation Programme; Scientific and Technological Research Council of Turkey (TÜBİTAK)

The maintenance of vaginal microbiota is an important factor to achieve optimum pregnancy outcomes. The study aims to describe the alterations in the composition of vaginal microbiota in pregnant women with coronavirus disease 2019 (COVID-19). This was a prospective case-control study. Vaginal swabs were collected from uninfected pregnant women (n = 28) and pregnant women with COVID-19 (n = 19) during the active phase of infection and within a month after recovering from infection. The vaginal microbiota on the swabs was examined by 16S rRNA gene sequencing. Shannon index indicates that alpha diversity is significantly higher in women with COVID-19 (p = 0.012). There was a significant decrease in Firmicutes (p = 0.014) with an increase in Bacteroidota (p = 0.018) phyla and a decrease in Lactobacillus (p = 0.007) genus in women with COVID-19 than those of uninfected pregnant women. The relative abundance of L. crispatus, L. iners, L. gasseri, and L. jensenii were lower in the COVID-19 group than in uninfected pregnant women. In subgroup analysis, the amount of Ureaplasma spp. was higher in women with moderate/severe than those of asymptomatic/mild disease (p = 0.036). The study revealed that vaginal dysbiosis with low abundance of Lactobacillus species occurred in pregnant women infected with severe acute respiratory syndrome coronavirus-2. These findings may lead to new studies to elucidate the risk of pregnancy adverse outcomes related to COVID-19., Scientific and Technological Council of Turkey (TÜBİTAK)

“Smart” polymers are polymers that respond to certain external stimuli. Specifically, pH- and temperature-responsive polymers have been explored extensively for cancer drug delivery. However, pH-responsive polymers do not provide adequate specificity for tumors, and temperature-responsive polymers do not sufficiently differentiate cancerous and healthy cells. Alternatively, we have been engineering polymers that respond to the Warburg effect. The Warburg effect describes cancer cells’ preference in generating energy through aerobic glycolysis instead of oxidative phosphorylation; the direct result of the Warburg effect is the increased concentration of lactate in the local tumor environment. We have incorporated thermophilic lactate dehydrogenase (LDH) as a lactate recognition moiety in a network of poly(N-isopropylacrylamide) (NIPAm) and N,N’-methylenebisacrylamide (BIS) as cancer-specific delivery platform using lactate as stimulus. DLS measurements and TEM images have confirmed that the protein-polymer hybrid nanoparticles resulted in monodisperse particles with average hydrodynamic diameters of 177 ± 0.8 nm at 37°C. Circular dichroism (CD) and kinetic assays showed that the incorporated LDH remained correctly folded and active in the polymer, demonstrating intact protein structure within the polymer. Upon addition of lactate, the particle hydrodynamic diameter swelled up to 99.2 ± 13.5 %, showing the material’s stimuli-responsive behavior. Furthermore, we showed that by incorporating mutant LDH with weaker binding compared to wtLDH did not induce swelling.

“Smart” polymers are polymers that respond to certain external stimuli. Specifically, pH- and temperature-responsive polymers have been explored extensively for cancer drug delivery. However, pH-responsive polymers do not provide adequate specificity for tumors, and temperature-responsive polymers do not sufficiently differentiate cancerous and healthy cells. Alternatively, we have been engineering polymers that respond to the Warburg effect. The Warburg effect describes cancer cells’ preference in generating energy through aerobic glycolysis instead of oxidative phosphorylation; the direct result of the Warburg effect is the increased concentration of lactate in the local tumor environment. We have incorporated thermophilic lactate dehydrogenase (LDH) as a lactate recognition moiety in a network of poly(N-isopropylacrylamide) (NIPAm) and N,N’-methylenebisacrylamide (BIS) as cancer-specific delivery platform using lactate as stimulus. DLS measurements and TEM images have confirmed that the protein-polymer hybrid nanoparticles resulted in monodisperse particles with average hydrodynamic diameters of 177 ± 0.8 nm at 37°C. Circular dichroism (CD) and kinetic assays showed that the incorporated LDH remained correctly folded and active in the polymer, demonstrating intact protein structure within the polymer. Upon addition of lactate, the particle hydrodynamic diameter swelled up to 99.2 ± 13.5 %, showing the material’s stimuli-responsive behavior. Furthermore, we showed that by incorporating mutant LDH with weaker binding compared to wtLDH did not induce swelling.

Stimuli responsive polymers are an efficient means of targeted therapy. Compared to conventional agents, they increase bioavailability and efficacy. In particular, polymer hydrogel nanoparticles (NPs) can be designed to respond when exposed to a specific environmental stimulus such as pH or temperature. However, targeting a specific metabolite as the trigger for stimuli response could further elevate selectivity and create a new class of bioresponsive materials. In this work we describe an N-isopropylacrylamide (NIPAm) NP that responds to a specific metabolite characteristic of a hypoxic environment found in cancerous tumors. NIPAm NPs were synthesized by copolymerization with an oxamate derivative, a known inhibitor of lactate dehydrogenase (LDH). The oxamate functionalized NPs (OxNP) efficiently sequestered LDH to produce an OxNP-protein complex. When exposed to elevated concentrations of lactic acid, a substrate of LDH and a metabolite characteristic of hypoxic tumor microenvironments, OxNP-LDH complexes swelled (65%). The OxNP-LDH complexes were not responsive to structurally related small molecules. This work demonstrates a proof of concept for tuning NP responsiveness by conjugation with a key protein to target a specific metabolite of disease.

Stimuli responsive polymers are an efficient means of targeted therapy. Compared to conventional agents, they increase bioavailability and efficacy. In particular, polymer hydrogel nanoparticles (NPs) can be designed to respond when exposed to a specific environmental stimulus such as pH or temperature. However, targeting a specific metabolite as the trigger for stimuli response could further elevate selectivity and create a new class of bioresponsive materials. In this work we describe an N-isopropylacrylamide (NIPAm) NP that responds to a specific metabolite characteristic of a hypoxic environment found in cancerous tumors. NIPAm NPs were synthesized by copolymerization with an oxamate derivative, a known inhibitor of lactate dehydrogenase (LDH). The oxamate functionalized NPs (OxNP) efficiently sequestered LDH to produce an OxNP-protein complex. When exposed to elevated concentrations of lactic acid, a substrate of LDH and a metabolite characteristic of hypoxic tumor microenvironments, OxNP-LDH complexes swelled (65%). The OxNP-LDH complexes were not responsive to structurally related small molecules. This work demonstrates a proof of concept for tuning NP responsiveness by conjugation with a key protein to target a specific metabolite of disease.

Peptide and protein-based cancer vaccines usually fail to elicit efficient immune responses against tumors. However, delivery of these peptides and proteins as components within caged protein nanoparticles has shown promising improvements in vaccine efficacy. Advantages of protein nanoparticles over other vaccine platforms include their highly organized structures and symmetry, biodegradability, ability to be specifically functionalized at three different interfaces (inside and outside the protein cage, and between subunits in macromolecular assembly), and ideal size for vaccine delivery. In this review, we discuss different classes of virus-like particles and caged protein nanoparticles that have been used as vehicles to transport and increase the interaction of cancer vaccine components with the immune system. We review the effectiveness of these protein nanoparticles towards inducing and elevating specific immune responses, which are needed to overcome the low immunogenicity of the tumor microenvironment.

We suggest gelatin hydrogel as an electrolyte and demonstrate organic electrochemical transistors (OECTs) based on a sheet of gelatin. We also modulate electrical characteristics of the OECT with respect to pH condition of the gelatin hydrogel from acid to base and analyze its characteristics based on the electrochemical theory. Moreover, we extend the gelatin-based OECT to electrochemical logic circuits, for example, NOT, NOR, and NAND gates., Funding Agencies|Pioneer Research Center Program [NRF-2014M3C1A3053029]; National Research Foundation of Korea - Ministry of Science, ICT and Future Planning [NRF-2015K2A7A1063990]; Swedish Foundation for Strategic Research (Si-organic electronics); Advanced Functional Material Center at Linkoping University

A blood test for colorectal cancer (CRC) screening is a valuable tool to for testing asymptomatic individuals and reducing CRC-related mortality. The objective of this study was to develop and validate a novel blood test able to differentiate patients with CRC and adenomatous polyps (AP) from individuals with a negative colonoscopy. Experimental Design: A case-control, multicenter clinical study was designed to collect blood samples from patients referred for colonoscopy or surgery. Predictive algorithms were developed on 75 controls, 61 large AP (LAP) {greater than or equal to}1cm, 45 CRC, and independently validated on 74 controls, 42 LAP, 52 CRC (23 Stages I-II) as well as on 245 cases including other colorectal findings and diseases other than CRC. The test is based on a 29-gene panel expressed in peripheral blood mononuclear cells alone or in combination with established plasma tumor markers. Results: The 29-gene algorithm detected CRC and LAP with a sensitivity of 79.5% and 55.4%, respectively, with 90.0% specificity. Combination with the protein tumor markers CEA and CYFRA21-2 resulted in a specificity increase (92.2%) with a sensitivity for CRC and LAP detection of 78.1% and 52.3%, respectively. Conclusions: We report the validation of a novel blood test, Colox®, for the detection of CRC and LAP based on a 29-gene panel and the CEA and CYFRA21-1 plasma biomarkers. The performance and convenience of this routine blood test provides physicians a useful tool to test average risk individuals unwilling to undergo upfront colonoscopy.

Kyoung-Min Kim,1 Hye Min Kim,1 Won-Jae Lee,2 Chang-Woo Lee,3 Tae-il Kim,4 Jong-Kwon Lee,5 Jayoung Jeong,5 Seung-Min Paek,2 Jae-Min Oh1 1Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Gangwon-do, Republic of Korea; 2Department of Chemistry, Kyungpook National University, Taegu, Republic of Korea; 3Battelle-Korea Laboratory, International Center for Converging Technology, Korea University, Seoul, Republic of Korea; 4Department of Biosystems and Biomaterials Science and Engineering, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea; 5Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, Republic of Korea Abstract: An attempt was made to control the surface charge of colloidal silica nanoparticles with 20 nm and 100 nm diameters. Untreated silica nanoparticles were determined to be highly negatively charged and have stable hydrodynamic sizes in a wide pH range. To change the surface to a positively charged form, various coating agents, such as amine containing molecules, multivalent metal cation, or amino acids, were used to treat the colloidal silica nanoparticles. Molecules with chelating amine sites were determined to have high affinity with the silica surface to make agglomerations or gel-like networks. Amino acid coatings resulted in relatively stable silica colloids with a modified surface charge. Three amino acid moiety coatings (L-serine, L-histidine, and L-arginine) exhibited surface charge modifying efficacy of L-histidine > L-arginine > L-serine and hydrodynamic size preservation efficacy of L-serine > L-arginine > L-histidine. The time dependent change in L-arginine coated colloidal silica was investigated by measuring the pattern of the backscattered light in a Turbiscan™. The results indicated that both the 20 nm and 100 nm L-arginine coated silica samples were fairly sta

Kyoung-Min Kim,1 Hye Min Kim,1 Won-Jae Lee,2 Chang-Woo Lee,3 Tae-il Kim,4 Jong-Kwon Lee,5 Jayoung Jeong,5 Seung-Min Paek,2 Jae-Min Oh1 1Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Gangwon-do, Republic of Korea; 2Department of Chemistry, Kyungpook National University, Taegu, Republic of Korea; 3Battelle-Korea Laboratory, International Center for Converging Technology, Korea University, Seoul, Republic of Korea; 4Department of Biosystems and Biomaterials Science and Engineering, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea; 5Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, Republic of Korea Abstract: An attempt was made to control the surface charge of colloidal silica nanoparticles with 20 nm and 100 nm diameters. Untreated silica nanoparticles were determined to be highly negatively charged and have stable hydrodynamic sizes in a wide pH range. To change the surface to a positively charged form, various coating agents, such as amine containing molecules, multivalent metal cation, or amino acids, were used to treat the colloidal silica nanoparticles. Molecules with chelating amine sites were determined to have high affinity with the silica surface to make agglomerations or gel-like networks. Amino acid coatings resulted in relatively stable silica colloids with a modified surface charge. Three amino acid moiety coatings (L-serine, L-histidine, and L-arginine) exhibited surface charge modifying efficacy of L-histidine > L-arginine > L-serine and hydrodynamic size preservation efficacy of L-serine > L-arginine > L-histidine. The time dependent change in L-arginine coated colloidal silica was investigated by measuring the pattern of the backscattered light in a Turbiscan™. The results indicated that both the 20 nm and 100 nm L-arginine coated silica samples were fairly sta

The problem of robust dynamic pricing of an abstract commodity, whose inventory is specified at an initial time but never subsequently replenished, originally studied by Perakis and Sood (2006) in discrete time, is considered from the perspective of continuous time. We use a multiplicative demand function to model the uncertain demand, and develop a robust counterpart to replace the uncertain demand constraint. The sellers' robust best response problem yields a generalized Nash equilibrium problem, which can be formulated as an equivalent, continuous-time quasi-variational inequality. We demonstrate that, for appropriate regularity conditions, a generalized robust Nash equilibrium exists. We show that the quasi-variational inequality may be replaced by an equivalent variational inequality, and use a fixed-point algorithm to solve the variational inequality. We also demonstrate how explicit time lags associated with price updating in real-world decision environments, as well as specific pricing decision rules, may be introduced to create a dual time scale formulation and the associated solutions computed. We illustrate, via numerical examples, how robust pricing based on our DPFI formulation offers generally superior and never inferior worst case performance compared to nominal pricing.

A blood test for colorectal cancer (CRC) screening is a valuable tool to for testing asymptomatic individuals and reducing CRC-related mortality. The objective of this study was to develop and validate a novel blood test able to differentiate patients with CRC and adenomatous polyps (AP) from individuals with a negative colonoscopy. Experimental Design: A case-control, multicenter clinical study was designed to collect blood samples from patients referred for colonoscopy or surgery. Predictive algorithms were developed on 75 controls, 61 large AP (LAP) {greater than or equal to}1cm, 45 CRC, and independently validated on 74 controls, 42 LAP, 52 CRC (23 Stages I-II) as well as on 245 cases including other colorectal findings and diseases other than CRC. The test is based on a 29-gene panel expressed in peripheral blood mononuclear cells alone or in combination with established plasma tumor markers. Results: The 29-gene algorithm detected CRC and LAP with a sensitivity of 79.5% and 55.4%, respectively, with 90.0% specificity. Combination with the protein tumor markers CEA and CYFRA21-2 resulted in a specificity increase (92.2%) with a sensitivity for CRC and LAP detection of 78.1% and 52.3%, respectively. Conclusions: We report the validation of a novel blood test, Colox®, for the detection of CRC and LAP based on a 29-gene panel and the CEA and CYFRA21-1 plasma biomarkers. The performance and convenience of this routine blood test provides physicians a useful tool to test average risk individuals unwilling to undergo upfront colonoscopy.