Chemical Optimization Research Articles

Abstract 3933: ORM-5029: A first-in-class targeted protein degradation therapy using antibody neodegrader conjugate (AnDC) for HER2-expressing breast cancer

Abstract Targeted protein degradation (TPD) molecules, including IMiD-based molecular glues and heterobifunctional degraders have expanded the breadth of therapeutic options through both their catalytic mechanism of action and ability to degrade previously “undruggable” target proteins. To increase the efficacy vs. tolerability window of protein degradation and improve drug delivery we combine the catalytic approach of targeted protein degradation with the precision of tumor targeting therapeutic antibodies. Here, we describe the development of ORM-5029, a highly potent and selective GSPT1 degrader targeting HER2-expressing tumor cells. We first screened a panel of cell lines to identify tumors where treatment with a selective, membrane-permeable, molecular glue (SMol007) would exhibit the most potent GSPT1 degradation, integrated stress response, and ultimately apoptosis. HER2+ breast cancer cell lines were more sensitive to GSPT1 degradation than the average IC50 for all cell lines tested. Several of our GSPT1 degrader molecules were tested in HER2-positive tumor models and displayed a consistent pattern of potent cytotoxicity. An unbiased global proteomics evaluation of changes in abundance identified SMol006 as a specific GSPT1 degrader, with no significant depletion of over 6500 other proteins detected. To evaluate whether antibody delivery could provide a potency increase of Smol006 and other GSTP1 degrader payloads, we conjugated these payloads to the HER2-targeting antibodies, trastuzumab and pertuzumab. Given the comparable activity of both antibodies and frequent use of trastuzumab as the antibody domain of several ADCs, we selected pertuzumab as our targeting antibody. Further medicinal chemistry optimization and evaluation of many linker-payloads led to the identification of our first preclinical AnDC candidate ORM-5029, which is composed of SMol006, a highly-potent GSPT1 degrader conjugated to pertuzumab via a clinically-validated Val-Cit PABc linker. ORM-5029 treatment in the HER2-expressing cell lines showed 10-1000 fold superiority in potency compared to SMol006, Kadcyla and/or Enhertu treatment. We evaluated ORM-5029 in several in vivo xenograft models and observed robust efficacy, following a single-dose treatment testing as low as 3 mg/kg. In the BT474 xenograft model, treatment with ORM-5029 demonstrated single-dose activity superior to Kadcyla, and comparable to Enhertu when given at an equivalent dose. In an HCC1569 xenograft model, tumor growth inhibition correlated with the degree and duration of GSPT1 depletion and changes in expression of previously described integrated stress response biomarker genes. ORM-5029 is currently in preclinical development as a potential first-in-class targeted protein degrader therapy with HER2-targeted delivery. Citation Format: James Palacino, Chen Bai, Yong Yi, Anna Skaletskaya, Khuloud Takrouri, Wesley Wong, Min-Soo Kim, Dong-Ki Choi, Da-Young Kim, Yeonhee Yang, Jiae Kook, Pedro Lee, Hangyeol Jeong, Sang-Mi Jee, Jiyun Park, Ki-Hwan Chang, Nathan Fishkin, Peter U. Park. ORM-5029: A first-in-class targeted protein degradation therapy using antibody neodegrader conjugate (AnDC) for HER2-expressing breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3933.

Abstract ND08: NXP800: A first-in-class orally active, small-molecule HSF1 pathway inhibitor

Abstract We report the discovery of NXP800 — a first-in-class orally active HSF1 pathway inhibitor identified in our academic laboratory at the Institute of Cancer Research, London — and its progression into Phase I clinical trials in collaboration with our partner Nuvectis Pharma. HSF1 (Heat Shock Factor 1) is an ancient stress-inducible transcription factor that plays a key role in the transcriptional activation of the eukaryotic heat shock response. This leads to expression of many heat shock proteins, including molecular chaperones, and through this HSF1 acts as a master transcriptional regulator of proteostasis. Importantly, HSF1 is hijacked by cancer cells to activate a set of genes that overlaps with, but is not identical to, the classical heat shock response. The HSF1 pathway has been shown to play a key role in oncogenesis and the hallmark features of malignancy and is important in the initiation and progression of many experimental cancer models. Importantly, while HSF1 has been demonstrated to be important in mouse models of oncogenesis, knockout of the homologue of HSF1 has only modest effects in mice and flies under non-stressed laboratory conditions – supporting the potential for a therapeutic window. In addition, gene amplification, expression and activation of HSF1 has been shown to predict clinical outcome in many human cancers. Despite strong scientific rationale and pre-clinical validation, pharmaceutical exploitation has been limited because analysis of the available molecular structures of HSF1 shows it to be very difficult to drug. Because of this, we set out to discover inhibitors of the HSF1 pathway using an initial phenotypic screen that reports on the activation of the HSF1-regulated gene HSP72. This identified the bisamide series that was followed up by a detailed understanding of structure-activity relationships and medicinal chemistry optimization, particularly to improve pharmaceutical properties, leading to the selection of NXP800 (CCT361814) as the development candidate. NXP800 has good pharmacokinetic properties in mice, including oral bioavailability; also, pharmacodynamic studies show modulation of biomarkers of the HSF1 pathway and stress response in human tumour xenograft models. NXP800 exhibits striking therapeutic activity in xenografts of human ovarian clear cell ovarian cancer (OCCC) and endometrioid ovarian cancer, two serious conditions of high unmet medical need with limited treatment options – including prolonged tumour growth inhibition and regression at doses that show good toleration. The efficacy and tolerability data indicate a clear therapeutic window, supported by selectivity and safety profiting in pharmacology and kinome panels. In addition, we identified deficiency in ARID1A, a component of the SWI/SNF chromatin remodelling complex, as indicative of greater therapeutic responsiveness. This was confirmed through broader evaluation in human cancer cell line panels that also indicates therapeutic potential for NXP800 in additional cancer types. Studies to support mechanism of action and identify patient selection biomarkers will be described. A Phase 1 trial of NXP800 is now open, incorporating validated predictive, pharmacokinetic and pharmacodynamic biomarkers that provide a robust Pharmacological Audit Trail and support the prediction of dose-to-human. Citation Format: Paul Workman. NXP800: A first-in-class orally active, small-molecule HSF1 pathway inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND08.

Smooth Sidewalls on Crystalline Gold through Facet-Selective Anisotropic Reactive Ion Etching: Toward Low-Loss Plasmonic Devices.

Quantum plasmonics aims to harness the deeply subwavelength confinement provided by plasmonic devices to engineer more efficient interfaces to quantum systems in particular single emitters. Realizing this vision is hampered by the roughness-induced scattering and loss inherent in most nanofabricated devices. In this work, we show evidence of a reactive ion etching process to selectively etch gold along select crystalline facets. Since the etch is facet selective, the sidewalls of fabricated devices are smoother than the lithography induced line-edge roughness with the prospect of achieving atomic smoothness by further optimization of the etch chemistry. This opens up a route toward fabricating integrated plasmonic circuits that can achieve loss metrics close to fundamental bounds.

Some fundamental understandings of Zn-injection water chemistry on material corrosion in pressurized water reactor primary circuit

The optimization of water chemistry in pressurized water reactor (PWR) primary circuit is one of the most effective ways to achieve both safety and economy for operating PWR nuclear power plants (NPPs). Special attention has been paid to fundamental research and engineering application of Zn-injection water chemistry (ZWC) in PWR primary circuit in recent years in China due to the rapid development of nuclear power. The present paper mainly reports the status of PWR NPPs in China and some fundamental understandings of ZWC on material corrosion. Effects of temperature (T), pH at T value, Zn concentration, Zn-injection sequence and lasting time on electrochemical corrosion behavior, oxide film characteristic and stress corrosion cracking (SCC) susceptibility of nuclear-grade austenitic alloys were investigated. A modified point defect model was used to discuss the effects of ZWC on the oxide films in high-temperature pressurized water. Some water chemistry parameters in PWR primary coolant system are proposed for mitigating corrosion and SCC of nuclear-grade austenitic alloys.

Preclinical characterization of D3S-001, a highly potent, selective, and differentiated covalent inhibitor of KRAS G12C.

e15102 Background: KRAS G12C mutation is an oncogenic driver most frequently found in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and other tumor types. Covalent small molecule inhibitors such as sotorasib, recently FDA-approved, and others in clinical trials that target G12C-altered protein by irreversibly binding to the GDP-bound inactive form of KRAS are clinically active in NSCLC patients carrying this somatic mutation. However, in in vitro assays we have developed to evaluate cellular GTP-bound KRAS G12C level, these molecules did not achieve maximal KRAS G12C target inhibition at the minimum concentration (Cmin) of their respective clinically doses. We therefore hypothesize that the potency of KRAS G12C inhibitors may be further improved through medicinal chemistry optimization. Methods: A series of in vitro and in vivo studies were conducted to assess the preclinical pharmacological activity of D3S-001. The biochemical potency of D3S-001 was evaluated by SPR binding analysis. The kinetics of KRAS G12C target engagement was measured by ELISA method. The inhibitor effect of D3S-001 on phospho-ERK1/2 was determined by HTRF assay, and the anti-proliferation effect on cancer cell lines was evaluated by CTG luminescence assay. For in vivo efficacy studies, several human cancer xenograft models and a mouse syngeneic model were employed. Results: D3S-001 demonstrated an exceptionally high Kinact/KI value of 1.58^106 M-1 s-1 by SPR binding analysis. In target engagement assays, D3S-001 achieved rapid and near complete (> 95%) KRAS G12C inhibition within 2 hours at 5 nM. This rapid and effective target engagement correlated with its substantially enhanced cellular potency in both in vitro and in vivo efficacy studies. D3S-001 demonstrated single-digit nanomolar IC50 values in inhibiting cellular phospho-ERK1/2 and cell proliferation in a panel of cancer cell lines harboring the KRAS G12C mutation. D3S-001 was also high selective with no anti-proliferation effects on non-KRAS G12C mutant cell lines. In in vivo studies, D3S-001 demonstrated robust anti-tumor effects as monotherapy in KRAS G12C xenograft models with tumor regression observed at 10 mg/kg and a 30% durable complete remission (CR) rate in CT26, a KRAS G12C syngeneic model, at 30 mg/kg. When combined with an anti-PD-1 antibody, a 70% durable CR rate was achieved with no tumor re-growth observed in CR mice after rechallenging with CT26 tumor, suggesting a memory T cell-induced response. Conclusions: D3S-001 is a highly potent, selective KRAS G12C inhibitor that is differentiated by its rapid and effective target engagement. Human PK modeling predicts > 95% constant target blockage using a 200 mg QD dosing regimen, which may be important and relevant to the induction of deeper and more durable clinical response. D3S-001 will enter a first-in-human Phase 1 clinical trial in 2022.

Integrating multiscale modeling and optimization for sustainable process development

• A new approach for process development via integrated molecular modeling, process integration and mathematical optimization. • Integration of multiscale modeling and optimization as the cornerstone. • Incorporating fundamentals into process development for the best molecular transformation route. • Process integration for selecting fit-for-purpose technologies. • Mathematical optimization based on fundamental models for identifying technological breakthrough ideas. The new approach for process development proposed in this article is based on integrated molecular modeling, process integration and mathematical optimization. Molecular modeling is about achieving the best molecular transformation to maximize desired products and minimize by-products, which is accomplished via reaction chemistry optimization and catalyst development. Process integration is about selecting fit-for-purpose technologies for reaction, separation, and heat transfer systems, while mathematical optimization is about obtaining the optimal process flowsheeting and conditions to achieve the desired products with the lowest capital and operating costs as well as minimal footprint such as plot space, various emissions and wastes, hydrogen, water, and energy. When all these are integrated seamlessly, the true optimal process design can be achieved for practical applications, which will benefit the companies, communities, and environment at the same time. The cornerstone of this novel approach is the multiscale modeling and optimization integration via integrating fundamentals with the power of system integration and optimization, more specifically, integrating molecular analysis, quantum chemistry and transport mechanics with process integration and mathematical optimization for clean process development. By incorporating fundamentals into process development, it can identify the best molecular transformation routes by optimizing reaction pathways. Furthermore, mechanistic kinetic modeling such as microkinetic modeling and molecular-based kinetic Monte Carlo, which is enhanced by quantum chemistry, can help predict yield selectivity for different catalyst formula. By process integration , fit-for-purpose technologies are selected for developing hybrid systems. By mathematical optimization based on fundamental models, it can identify technological breakthrough ideas . For given multiple objective functions, mathematical combinatory optimization of the fundamental models not only determines the best-fit technology profile for an overall process based on techno-economic criteria, but also allow the process to deal with different feedstocks and make product shift based on market needs as well as the best environmental performance. In turn, this approach enables more effective feedback from development to research, as it integrated molecular based fundamentals.

Matrix product state pre-training for quantum machine learning

Hybrid quantum–classical algorithms are a promising candidate for developing uses for NISQ devices. In particular, parametrised quantum circuits (PQCs) paired with classical optimizers have been used as a basis for quantum chemistry and quantum optimization problems. Tensor network methods are being increasingly used as a classical machine learning tool, as well as a tool for studying quantum systems. We introduce a circuit pre-training method based on matrix product state machine learning methods, and demonstrate that it accelerates training of PQCs for both supervised learning, energy minimization, and combinatorial optimization.

Enantioselective alkylative cross-coupling of unactivated aromatic C–O electrophiles

Nonpolar alkyl moieties, especially methyl group, are frequently used to modify bioactive molecules during lead optimization in medicinal chemistry. Thus transition-metal catalyzed alkylative cross-coupling reactions by using readily available and environmentally benign C–O electrophiles have been established as powerful tools to install alkyl groups, however, the C(sp3)–C(sp2) cross-coupling via asymmetric activation of aromatic C–O bond for the synthesis of alkylated chiral compounds remains elusive. Here, we unlock a C(sp3)–C(sp2) cross-coupling via enantioselective activation of aromatic C–O bond for the efficient synthesis of versatile axially chiral 2-alkyl-2’-hydroxyl-biaryl compounds. By employing a unique chiral N-heterocyclic carbene ligand, this transformation is accomplished via nickel catalysis with good enantiocontrol. Mechanistic studies indicate that bis-ligated nickel complexes might be formed as catalytically active species in the enantioselective alkylative cross-coupling. Moreover, further derivation experiments suggest this developed methodology holds great promise for complex molecule synthesis and asymmetric catalysis.

Reclaim Mode Post Etch Residue Remover Solutions for Advanced Technology Nodes

Back-end-of-line (BEOL) processing for creation of vias and trenches in advanced technology node semiconductor manufacturing warrants a wet chemistry capable of removing post-etch residues (PERR), titanium nitride hardmask (TiN HM) and etch stop layer (ESL), while being compatible with metals, such as copper, tungsten and cobalt. In accordance with BASF’s core competency of innovating sustainable solutions with minimal environmental impact, our reclaim mode BEOL PERR chemistries allow semiconductor manufacturers to minimize not only their cost of ownership (COO) but also their waste footprint. BASF’s reclaim mode PERR chemistries, when mixed with appropriate amount of hydrogen peroxide, facilitate oxidative wet etching of TiN HM. In this paper, we demonstrate that optimization of formulation chemistry and spiking protocol extends the bath lifetime of reclaim mode PERR chemistries beyond 24hr, which is a significant improvement vis-à-vis current industry standard of single use (drain mode) chemistries. Beaker-level bath lifetime investigation of BASF’s formulation confirms that TiN etch rate (ER) and bath pH are stable for 48hr when bath is loaded with commensurate amount of Ti ions. Beaker-level performance was also corroborated by 300mm wafer level assessment. BASF’s reclaim mode PERR chemistries with bath lifetime greater than 8hr offer progressively favorable cost of ownership (COO) vis-à-vis drain mode chemistry.

Diamond Supercapacitors: Towards Durable, Safe, and Biocompatible Aqueous-Based Energy Storage.

Durable and safe energy storage is required for the next generation of miniature bioelectronic devices, in which aqueous electrolytes are preferred due to the advantages in safety, low cost, and high conductivity. While rechargeable aqueous batteries are among the primary choices with relatively low power requirements, their lifetime is generally limited to a few thousand charging/discharging cycles as the electrode material can degrade due to electrochemical reactions. Electrical double layer capacitors (EDLCs) possess increased cycling stability and power density, although with as-yet lower energy density, due to quick electrical adsorption and desorption of ions without involving chemical reactions. However, in aqueous solution, chemical reactions which cause electrode degradation and produce hazardous species can occur when the voltage is increased beyond its operation window to improve the energy density. Diamond is a durable and biocompatible electrode material for supercapacitors, while at the same time provides a larger voltage window in biological environments. For applications requiring higher energy density, diamond-based pseudocapacitors (PCs) have also been developed, which combine EDLCs with fast electrochemical reactions. Here we inspect the properties of diamond-related materials and discuss their advantages and disadvantages when used as EDLC and PC materials. We argue that further optimization of the diamond surface chemistry and morphology, guided by computational modelling of the interface, can lead to supercapacitors with enhanced performance. We envisage that such diamond-based supercapacitors could be used in a wide range of applications and in particular those requiring high performance in biomedical applications.

Machine-Learning Guided Discovery of Bioactive Inhibitors of PD1-PDL1 Interaction.

The selective activation of the innate immune system through blockade of immune checkpoint PD1-PDL1 interaction has proven effective against a variety of cancers. In contrast to six antibody therapies approved and several under clinical investigation, the development of small-molecule PD1-PDL1 inhibitors is still in its infancy with no such drugs approved yet. Nevertheless, a promising series of small molecules inducing PDL1 dimerization has revealed important spatio-chemical features required for effective PD1-PDL1 inhibition through PDL1 sequestration. In the present study, we utilized these features for developing machine-learning (ML) classifiers by fitting Random Forest models to six 2D fingerprint descriptors. A focused database of ~16 K bioactive molecules, including approved and experimental drugs, was screened using these ML models, leading to classification of 361 molecules as potentially active. These ML hits were subjected to molecular docking studies to further shortlist them based on their binding interactions within the PDL1 dimer pocket. The top 20 molecules with favorable interactions were experimentally tested using HTRF human PD1-PDL1 binding assays, leading to the identification of two active molecules, CRT5 and P053, with the IC50 values of 22.35 and 33.65 µM, respectively. Owing to their bioactive nature, our newly discovered molecules may prove suitable for further medicinal chemistry optimization, leading to more potent and selective PD1-PDL1 inhibitors. Finally, our ML models and the integrated screening protocol may prove useful for screening larger libraries for novel PD1-PDL1 inhibitors.

Virtual screening of PEBP1 inhibitors by combining 2D/3D-QSAR analysis, hologram QSAR, homology modeling, molecular docking analysis, and molecular dynamic simulations.

Human phosphatidylethanolamine binding protein 1 (hPEBP1) is a novel target affecting many cellular signaling pathways involved in the formation of metastases. It can be used in the treatment of many cases of cancer. For these reasons, pharmaceutical companies use computational approaches, including multi-QSAR (2D, 3D, and hologram QSAR) analysis, homology modeling, molecular docking analysis, and molecular dynamic simulations, to speed up the drug discovery process. In this paper, QSAR modeling was conducted using two quantum chemistry optimization methods (AM1 and DFT levels). As per PLS results, we found that the DFT/B3LYP method presents high predictability according to 2D-QSAR, CoMFA, CoMSIA, and hologram QSAR studies, with Q2 of 0.81, 0.67, 0.79, and 0.67, and external power with R2pred of 0.78, 0.58, 0.66, and 0.56, respectively. This result has been validated by CoMFA/CoMSIA graphics, which suggests that electrostatic fields combined with hydrogen bond donor/acceptor fields are beneficial to the antiproliferative activity. While the hologram QSAR models show the contributions of each fragment in improving the activity. The results from QSAR analyses revealed that ursolic acids with heterocyclic rings could improve the activities. Ramachandran plot validated the modeled PEBP1 protein. Molecular docking and MD simulations revealed that the hydrophobic and hydrogen bond interactions are dominant in the PEBP1's pocket. These results were used to predict in silico structures of three new compounds with potential anticancer activity. Similar molecular docking stability studies and molecular dynamics simulations were conducted.

MP14-19 MAGNETIC CLEARANCE OF KIDNEY STONE FRAGMENTS: INITIAL IN VITRO EXPERIENCE

You have accessJournal of UrologyCME1 May 2022MP14-19 MAGNETIC CLEARANCE OF KIDNEY STONE FRAGMENTS: INITIAL IN VITRO EXPERIENCE Tianjia Jessie Ge, Timothy Chang, Kathy Mach, Shan Wang, Kunj Sheth, Simon Conti, and Joseph Liao Tianjia Jessie GeTianjia Jessie Ge More articles by this author , Timothy ChangTimothy Chang More articles by this author , Kathy MachKathy Mach More articles by this author , Shan WangShan Wang More articles by this author , Kunj ShethKunj Sheth More articles by this author , Simon ContiSimon Conti More articles by this author , and Joseph LiaoJoseph Liao More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002543.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Surgical management of stone disease aims for complete clearance. Residual stone fragments are associated with more complications, yet only 60-75% of ureteroscopic treatments achieve complete stone-free status. While residual fragments <2 mm in size are commonly deemed insignificant, up to 30% patients with “clinically insignificant fragments” experience stone-related complications. We propose a system to improve stone-free rates and surgical efficiency, in which fragments are rendered superparamagnetic and retrieved en masse with a magnetic guidewire. METHODS: Human kidney stone fragments obtained from lithotripsy (calcium phosphate (CaPO4), calcium oxalate monohydrate (CaOxM), uric acid, and struvite) were separated by size. Fragments (10-15 mg by dry weight) were rehydrated with normal saline and incubated with superparamagnetic iron oxide particles (range 7 nm to 4.5 µm diameter) possessing carboxylic acid surface chemistry for 3 minutes at 37C. A magnetic guidewire was fabricated from individual magnets within a plastic sheath (0.75 mm total diameter) and captured magnetically labeled fragments along its length in vitro. The fragments were dried and weighed to determine the capture efficiency. The speed of fragment retrieval was compared between the magnetic system and a conventional basket. RESULTS: The magnetic system cleared small fragments (<1 mm) up to twenty times faster than a standard basket in our in vitro experiments. The 7 nm nanoparticle, ferumoxytol, is FDA-approved for the treatment of iron deficiency anemia, and performed satisfactorily in capturing small calcium phosphate fragments. Larger 1 micron particles performed more consistently across different stone compositions. Capture efficiency decreases with increasing stone fragment size, owing to larger gravitational forces counteracting the magnetic attraction. CONCLUSIONS: Iron oxide particles with carboxylic acid surface chemistries, including an FDA-approved nanoparticle, bind to a variety of calcium-based kidney stones. This approach can facilitate the efficient magnetic retrieval of small stone fragments which are difficult to basket, and lead to improved stone-free rates. Further optimization of particle chemistry and magnetic forces will allow for capture of larger fragments and clinical translation. Source of Funding: Stanford Coulter Translational Grant, NIH R21 DK131776 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e240 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tianjia Jessie Ge More articles by this author Timothy Chang More articles by this author Kathy Mach More articles by this author Shan Wang More articles by this author Kunj Sheth More articles by this author Simon Conti More articles by this author Joseph Liao More articles by this author Expand All Advertisement PDF DownloadLoading ...

AWWA Water Science Author Spotlight

Having published an article in AWWA Water Science, Amir Alansari answered questions from the publication's editor-in-chief, Kenneth L. Mercer, about the research. Critical Elements of Flocculation in Drinking Water Treatment Amir Alansari and James Amburgey I'm a water treatment specialist at Stantec at their office in Winston-Salem, N.C. My research focus is primarily on coagulation chemistry and process optimization. Lately I've been working on developing new digital tools for predicting optimal coagulation conditions using artificial intelligence. It was a $5,000 stipend to participate in the Research Experiences for Undergraduates (REU) program over the summer at the University of North Carolina at Charlotte. I was in the civil and environmental engineering program and stumbled into the world of water treatment by chance. Amir won first place in the ACE19 student poster contest. Dr. Amburgey had the biggest influence on my career and on everything I have accomplished so far. I completed all three civil engineering degrees (bachelor's, master's, doctorate) working with him at the same university. In total, I spent 12 years under his mentorship, during which time I was able to freely follow my curiosity and work on whatever I wanted. The best advice I got from him was to use the time I had in graduate school to grow my skill sets as a researcher and an engineer as much as possible. My coauthor and I read a paper that was published in 1992 in Journal AWWA by Han and Lawler, where they mathematically showed that mechanical mixing played an insignificant role in the flocculation process. We recognized the implications of their work on the recommended design guidelines for flocculation; however, an extensive literature review did not yield any conclusive evidence that supported or challenged their theory. Our article presents results from a series of experiments we performed to measure the effects of various flocculation parameters (e.g., mixing duration) on settled and filtered water-turbidity removal efficiency and determine whether Han and Lawler were correct. I try my best to have a positive impact on the lives of people around me. I'd like to think that my work is contributing to the body of knowledge, even if it is a tiny contribution. Many of our current design guidelines are based on work done about four to six decades ago. There have been a lot of scientific and technological advancements since then. I believe water treatment design could benefit from a 21st-century overhaul, which would require a renewed research interest and collective effort from the research community, regulators, consulting engineers, and industry. The current funding model does not favor this type of research. It considers topics such as coagulation as matured topics, with nothing left to discover. Our research highlighted the benefits of optimizing coagulation conditions (via jar tests) using filtered turbidity as the performance metric instead of settled water turbidity. We found that jar-test mixing conditions had a significant effect on settled turbidity removals. This means that operators no longer have to “calibrate” their jar test procedures to get their results to match the full-scale process. It simplifies the optimization process by reducing the number of variables to just two—coagulant dose and coagulation pH—which ultimately means they can achieve better treatment performance while minimizing chemical usage. To learn more about Amir's research, visit his AWWA Water Science article, available online at https://doi.org/10.1002/aws2.1213.

Small Molecule Inhibitor Targeting CDT1/Geminin Protein Complex Promotes DNA Damage and Cell Death in Cancer Cells.

DNA replication initiation requires the loading of MCM2-7 complexes at the origins of replication during G1. Replication licensing renders chromatin competent for DNA replication and its tight regulation is essential to prevent aberrant DNA replication and genomic instability. CDT1 is a critical factor of licensing and its activity is controlled by redundant mechanisms, including Geminin, a protein inhibitor of CDT1. Aberrant CDT1 and Geminin expression have been shown to promote tumorigenesis in vivo and are also evident in multiple human tumors. In this study, we developed an in vitro AlphaScreen™ high-throughput screening (HTS) assay for the identification of small-molecule inhibitors targeting the CDT1/Geminin protein complex. Biochemical characterization of the most potent compound, AF615, provided evidence of specific, dose-dependent inhibition of Geminin binding to CDT1 both in-vitro and in cells. Moreover, compound AF615 induces DNA damage, inhibits DNA synthesis and reduces viability selectively in cancer cell lines, and this effect is CDT1-dependent. Taken together, our data suggest that AF615 may serve as a useful compound to elucidate the role of CDT1/Geminin protein complex in replication licensing and origin firing as well as a scaffold for further medicinal chemistry optimisation.

Solution Annealing Induces Surface Chemical Reconstruction for High-Efficiency PbS Quantum Dot Solar Cells.

Colloidal quantum dots (CQDs) have a large specific surface area and a complex surface structure. Their properties in diverse optoelectronic applications are largely determined by their surface chemistry. Therefore, it is essential to investigate the surface chemistry of CQDs for improving device performance. Herein, we realized an efficient surface chemistry optimization of lead sulfide (PbS) CQDs for photovoltaics by annealing the CQD solution with concentrated lead halide ligands after the conventional solution-phase ligand exchange. During the annealing process, the colloidal solution was used to transfer heat and create a secondary reaction environment, promoting the desorption of electrically insulating oleate ligands as well as the trap-related surface groups (Pb-hydroxyl and oxidized Pb species). This was accompanied by the binding of more conductive lead halide ligands on the CQD surface, eventually achieving a more complete ligand exchange. Furthermore, this strategy also minimized CQD polydispersity and decreased aggregation caused by conventional solution-phase ligand exchange, thereby contributing to yielding CQD films with twofold enhanced carrier mobility and twofold reduced trap-state density compared with those of the control. Based on these merits, the fabricated PbS CQD solar cells showed high efficiency of 11% under ambient conditions. Our strategy opens a novel and effective avenue to obtain high-efficiency CQD solar cells with diverse band gaps, providing meaningful guidance for controlling ligand reactivity and realizing subtly purified CQDs.

Therapeutic RNA-silencing oligonucleotides in metabolic diseases.

Recent years have seen unprecedented activity in the development of RNA-silencing oligonucleotide therapeutics for metabolic diseases. Improved oligonucleotide design and optimization of synthetic nucleic acid chemistry, in combination with the development of highly selective and efficient conjugate delivery technology platforms, have established and validated oligonucleotides as a new class of drugs. To date, there are five marketed oligonucleotide therapies, with many more in clinical studies, for both rare and common liver-driven metabolic diseases. Here, we provide an overview of recent developments in the field of oligonucleotide therapeutics in metabolism, review past and current clinical trials, and discuss ongoing challenges and possible future developments.

Computing Edge Version of Resolvability and Double Resolvability of a Graph

The field of graph theory is extensively used to investigate structure models in biology, computer programming, chemistry, and combinatorial optimization. In order to work with the chemical structure, chemists require a mathematical form of the compound. The chemical structure can be depicted using nodes (which represent the atom) and links (which represent the many types of bonds). As a result, a graph theoretic explanation of this problem is to give representations for the nodes of a graph such that different nodes have unique representations. This graph theoretic study is referred to as the metric dimension. In this article, we have computed the edge version of the metric dimension and doubly resolving sets for the family of cycle with chord C n t for n ≥ 6 and 2 ≤ t ≤ ⌊ n / 2 ⌋ .

Noisy intermediate-scale quantum algorithms

A universal fault-tolerant quantum computer that can solve efficiently problems such as integer factorization and unstructured database search requires millions of qubits with low error rates and long coherence times. While the experimental advancement towards realizing such devices will potentially take decades of research, noisy intermediate-scale quantum (NISQ) computers already exist. These computers are composed of hundreds of noisy qubits, i.e. qubits that are not error-corrected, and therefore perform imperfect operations in a limited coherence time. In the search for quantum advantage with these devices, algorithms have been proposed for applications in various disciplines spanning physics, machine learning, quantum chemistry and combinatorial optimization. The goal of such algorithms is to leverage the limited available resources to perform classically challenging tasks. In this review, we provide a thorough summary of NISQ computational paradigms and algorithms. We discuss the key structure of these algorithms, their limitations, and advantages. We additionally provide a comprehensive overview of various benchmarking and software tools useful for programming and testing NISQ devices.

Cellulose Amphiphilic Materials: Chemistry, Process and Applications.

In the last decade, amphiphilic cellulose (AC) is emerging as attractive biomaterial for different therapeutic use, due to its unique chemical and physical properties. Using it as alternative to synthetic polymers, AC opens up new avenues to prepare new bio-sustainable materials with low impact in the cellular environment. Herein, most recent methods to synthesize and processing AC materials from different sources—i.e., cellulose nanofibers, bacterial cellulose, cellulose derivatives—will be discussed. By an accurate optimization of morphology and surface chemistry, it is possible to develop innovative amphiphilic platforms, promising for a wide range of biomedical applications, from drug delivery to molecular/particle adsorption.