bluuebunny/crossref_metadata_2025 huggingface dataset:
Opioid Receptor Ligands
Authors: McCurdy Christopher R. , Prisinzano Thomas E.
Published: April 2021

Opioid agonists, exemplified by morphine, have been the most prescribed class of drugs for the management of moderate to severe pain for many years. These drugs have significant liabilities of addiction and constipation over long‐term use and acute overdoses can result in respiratory depression. For over thousands of years, opium and opium‐derived drugs have nonetheless been utilized for their therapeutic and recreational benefits. Due to their liabilities, medicinal chemists and clinicians have worked for years to discover novel agents or treatment courses that would be devoid of these side effects. Still to this day, there are no agents that meet these criteria. Therefore, efforts continue vigorously in the quest for drugs with potent analgesic effects without abuse or side‐effect potential. Many chemical classes have been sought after in this quest and the range from peptides to synthetic compounds to natural products. Morphine offered a template that was rigid and able to provide an enormous amount of structure–function relationships that many of the market analgesics are based on. To complicate matters, the endogenous opioid system is comprised of four distinct receptor subtypes. These receptors are all members of the G‐protein superfamily and are designated as mu (μ, MOP), delta (δ, DOP), kappa (κ, KOP), and nociception (ORL1, NOP). It has been realized over the years that a combination of activities at these receptors may result in agents that could be devoid of liabilities. Intensive efforts have been directed at improved probes for each receptor subtype and combinations of agonists and antagonists for combinations of these receptors. This review will discuss the structure–activity relationships, as they are currently understood, with regard to each of the major classes of compounds that interact with these protein targets.
PET and SPECT in Drug Development
Authors: Welch Andy , Tavares Adriana A. S. , Pimlott Sally , Sutherland Andrew
Published: April 2021

Positron emission tomography (PET) and single‐photon emission computed tomography (SPECT) are noninvasive molecular imaging techniques that can be used to provide functional information in the living human body. They use radiolabeled compounds that bind to specific sites on a biological target, known as radiotracers, enabling us to visualize and characterize specific aspects of a biological process. This article describes these techniques and how they can be utilized in the drug development process.
Cryo‐Electron Microscopy in Drug Discovery and Development: Opportunities and Challenges
Authors: Gomez‐Llorente Yacob , Hong Chuan , Scapin Giovanna
Published: April 2021

While utilization of structural information has been a staple technology in drug discovery for many years, electron microscopy creates opportunities that have been thus far out of reach for the conventional techniques, like the visualization of very large molecular complexes in solution or obtaining high‐resolution structural data for small molecules from microcrystals. These opportunities come at a cost: hardware is extremely expensive, software is ever‐changing, and constantly challenged by new developments in the hardware and requests by the users, and IT departments are faced with significant requirements for storage and computational power. Nevertheless, the establishment of centralized facilities, commercial consortia, and cooperative research centers is well positioned to provide access to Cryo‐EM to an expanded base of researchers, from academia as well as from industry. Understanding of the requirements, advantages, and limitations of this technique becomes then necessary to ensure correct decision‐making processes and resource allocation when undertaking a structure‐guided drug design project.
Angiogenesis Inhibitors
Authors: Shi Lei
Published: April 2021

Angiogenesis, the formation of new capillary blood vessels from preexisting vasculature, plays an essential role in organ growth and wound repair. However, pathological angiogenesis is a hallmark of various cancers and a range of nonneoplastic diseases including ischaemic and inflammatory disorders. Angiogenesis is a complicated multistep process that precisely mediated by the balance between pro‐ and antiangiogenic factors. Concentrated efforts in this area of research have led to the discovery of a growing number of angiogenesis‐related molecules and the complex interactions among these molecules. The integrated understanding of molecular mechanism of angiogenesis process involved in tumor growth and metastasis has identified angiogenesis as a promising target for cancer therapy. Over the past two decades, dozens of antiangiogenic drugs have been approved for the treatment of a variety of cancers. So far, hundreds of thousands of cancer patients have benefited from antiangiogenesis treatments but limited efficacy and resistance remain outstanding problems.

This article will focus on tumor angiogenesis‐related signaling molecules and pathways, development of antiangiogenic agents for the treatment of various tumors, and challenge of antiangiogenic therapy of tumors.
Immuno‐Oncology
Authors: Buesking Andrew W. , Mayes Patrick A. , Combs Andrew P.
Published: April 2021

The ability to avoid immune surveillance and destruction is one of the hallmarks of cancer. Identification of ligands that can prevent immune cells from killing malignant cells was the pivotal discovery for which the 2018 Nobel Prize in Medicine was awarded and initiated the current era in cancer immunotherapy. As a result, a number of antibody‐based approaches including checkpoint inhibitors and bispecific antibodies have been explored. More recently, small molecule drugs have emerged as a complementary approach. Small molecules can offer unique advantages over antibody therapies including access to intracellular targets, opportunities for oral dosing, higher relative exposures in the brain, and increased penetration into tumors. This article provides a brief overview of antibody approaches and then summarizes nine immuno‐oncology targets for which small molecule modulators have been described in the peer‐review literature.
Therapeutic Approaches for Nonalcoholic Steatohepatitis (NASH)
Authors: Glatthar Ralf , Arch Robert H.
Published: April 2021

Nonalcoholic fatty liver disease (NAFLD), the most prevalent liver disease worldwide, is the hepatic manifestation of metabolic syndrome, which often also includes obesity, type 2 diabetes, and dyslipidemia. While NAFLD was thought to be nonprogressive, it has been shown in several studies that 12–40% of NAFLD patients develop its progressive form nonalcoholic steatohepatitis (NASH), which is characterized by inflammatory changes that can lead to progressive liver damage, fibrosis, cirrhosis, and hepatocellular carcinoma. There are presently no approved pharmacological agents for the treatment of NAFLD and NASH, but numerous agents are currently being investigated in clinical trials. These innovative therapies include three main approaches: inhibiting or reducing hepatic fat accumulation; ameliorating oxidative stress, inflammation, and apoptosis; and improving hepatic fibrosis by inhibition of fibrogenesis or promoting fibrolysis. This article provides a brief introduction to the underlying disease features and describes the medicinal chemistry and current status of the main low‐molecular‐weight pharmacological agents currently in development for NASH.
Molecular Genetics of Hyperaldosteronism
Authors: Scholl Ute I
Published: April 2021

Primary aldosteronism features excessive production of the adrenal steroid hormone aldosterone, which causes hypertension. Common causes are aldosterone‐producing adenomas (benign tumours) and bilateral hyperaldosteronism. Almost all aldosterone‐producing adenomas carry somatic mutations in known disease genes, including
KCNJ5
(a potassium channel),
CACNA1D
and
CACNA1H
(calcium channels),
ATP1A1
and
AT2B3
(ATPase subunits) and
CLCN2
(a chloride channel). These mutations directly or indirectly cause increased intracellular calcium, elevated aldosterone production and proliferation. Mutations in
CTNNB1
(β‐catenin) are less understood. Bilateral hyperaldosteronism appears to be due to somatic mutations in the so‐called aldosterone‐producing cell clusters, with
CACNA1D
and
ATP1A1
as frequently mutated genes. Familial hyperaldosteronism (FH) is rare. FH‐I, ‐II, ‐III and ‐IV are caused by germline mutations in
CYP11B2
(aldosterone synthase),
CLCN2
,
KCNJ5
and
CACNA1H
, respectively, and a syndrome that includes neurologic abnormalities is due to germline mutations in
CACNA1D
. These observations suggest pathways for the development of novel diagnostic and therapeutic strategies.

Key Concepts

Primary aldosteronism is the most common cause of secondary hypertension, caused by aldosterone‐producing adenomas or bilateral adrenal hyperplasia.

Genetic studies have demonstrated that primary aldosteronism is largely genetic in aetiology.

Somatic mutations in the potassium channel
KCNJ5
explain about 40% of aldosterone‐producing adenomas.

Mutations in
KCNJ5
are associated with female gender, early onset and larger tumour size.

Other somatic mutations in aldosterone‐producing adenomas affect the
CACNA1D
,
ATP1A1
,
ATP2B3
,
CLCN2
,
CACNA1H
and
CTNNB1
genes.

The shared common final pathway of somatic mutations in aldosterone‐producing adenomas is increased calcium signalling, which causes excessive aldosterone production and proliferation.

Bilateral hyperaldosteronism appears to be due to the so‐called aldosterone‐producing cell clusters, which carry somatic mutations in genes implicated in aldosterone‐producing adenomas.

Rare forms of familial hyperaldosteronism (FH) include FH‐I, ‐II, ‐III and ‐IV, caused by germline mutations in
CYP11B2
,
CLCN2
,
KCNJ5
and
CACNA1H
, respectively. PASNA syndrome (primary aldosteronism, seizures and neurologic abnormalities) is due to
de novo
germline mutations in
CACNA1D
.

The identification of the molecular mechanisms of primary aldosteronism suggests pathways for the development of novel diagnostic and therapeutic strategies.
Study on the Fine Grain Size and Microhardness at the Interface of AZ31/Mg‐Y Composites
Authors: Xian Yihong , He Weijun , Chen Wenhuan , Chen Zejun , Jiang Bin , Liu Qing
Published: April 2021

AZ31/Mg‐Y/AZ31 composites are fabricated by hot rolling bonding. To identify the formation mechanism of the microstructure in the interface adjacent region, additional hot rolling or/and diffusion annealing are also conducted on the base of the initial AZ31/Mg‐Y/AZ31 composite. Scanning electron microscopy, energy dispersive spectroscopy, and electron backscatter diffraction are used to characterize the microstructures and chemical compositional distributions. Vicker's microhardness tests are conducted to determine the local mechanical property. It is found that in the Mg–Y layer of the AZ31/Mg‐Y/AZ31 composite, the grain size in the interface‐adjacent region is much finer than that in the central part. Much finer Al2Y particles compared with those in the traditional Mg–Al–Y alloys are formed in the interface‐adjacent region. The formation of the fine grain in the interface‐adjacent region may be mainly related to the Al2Y particles rather than the accommodation deformation between layers. Both the grain refinement and the formation of Al2Y particles contribute to strengthening of the Mg–Y layer. The results in this work may provide a novel method to prepare fine and dispersed high‐melting‐point particles in Mg alloys, thus leading to strong and high‐thermal‐stability Mg alloys.
Organic Synaptic Transistors: The Evolutionary Path from Memory Cells to the Application of Artificial Neural Networks
Authors: Shao Lin , Zhao Yan , Liu Yunqi
Published: April 2021

The progress of neural synaptic devices is experiencing an era of explosive growth. Given that the traditional storage system has yet to overcome the von Neumann bottleneck, it is critical to develop hardware with bioinspired information processing functions and lower power consumption. Transistors based on 2D materials, metal oxides, and organic materials have been adopted to mimic the synapse of a human brain, due to their high plasticity, parallel computing, integrated storage, and system information processing. Among these materials used to build transistors, organic semiconductors are considered to be the most promising candidate for neural synaptic devices and bio‐electronics, owing to their easy processing, mechanical flexibility, low cost, good bio‐compatibility, and ductility. This review focuses on the recent advances in organic synaptic devices with various structures, materials, and working mechanisms. The applications of artificial neural networks that integrate multiple organic synaptic transistors are also concretely discussed. Finally, the challenges that organic synaptic devices currently face are discussed and future developments are forecast.
Ultrahigh Sensitive Wearable Pressure Sensors Based on Reduced Graphene Oxide/Polypyrrole Foam for Sign Language Translation
Authors: Zou Xuejing , Chai Yuqiao , Ma Hui , Jiang Qianqian , Zhang Wei , Ma Xinlei , Wang Xusheng , Lian Huiqin , Huang Xueli , Ji Junhui , Xue Mianqi
Published: April 2021

Pressure sensors have attracted worldwide attention due to their extensive application requirements in wearable devices, flexible touch display, soft robotics, and health monitoring. Although many pressure sensors have been developed, it still remains a grand challenge to achieve ultrahigh sensitivity with good stability in low‐pressure regions. Herein, the polypyrrole (PPy) is introduced to reduced graphene oxide foam (rGOF) via in situ solventless polymerization to manufacture rGO/PPyF, which significantly enhances the sensitivity and stability of the derived sensors. The as‐fabricated sensor demonstrates an ultrahigh sensitivity of 32.32 kPa−1 in the pressure region of 0–21 Pa, high resolution, and excellent cycling stability. Furthermore, the pressure sensor can transform different hand gestures to distinguishable electrical signals in sign language translation, which indicates that the pressure sensor has a bright application prospect in wearable devices and human–computer interaction.
Assessment of fixed‐duration therapies for treatment‐naïve Waldenström macroglobulinemia
Authors: Abeykoon Jithma P. , Zanwar Saurabh , Ansell Stephen M. , Muchtar Eli , He Rong , Greipp Patricia T. , King Rebecca L. , Ailawadhi Sikander , Paludo Jonas , Larsen Jeremy T. , Habermann Thomas M. , Inwards David , Go Ronald S. , Thanarajasingam Gita , Buadi Francis , Dispenzieri Angela , Thompson Carrie A. , Witzig Thomas E. , Lacy Martha , Gonsalves Wilson , Nowakowski Grzegorz S. , Dingli David , Rajkumar Sundararajan Vincent , Kyle Robert A. , Sher Taimur , Roy Vivek , Rosenthal Allison , Chanan‐Khan Asher A. , Reeder Craig , Gertz Morie A. , Kumar Shaji , Kapoor Prashant
Published: April 2021

Comparative data guiding initial therapy for Waldenström macroglobulinemia (WM), an infrequently encountered non‐Hodgkin lymphoma, are sparse. We evaluated three commonly used rituximab‐based frontline regimens: rituximab‐bendamustine (R‐Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR) in 220 treatment‐naïve patients with WM, seen at Mayo Clinic between November 1, 2000 and October 31, 2019. The median follow‐up was 4.5 (95%CI: 4–5) years. The R‐Benda cohort (n = 83) demonstrated superior overall response rate (ORR: 98%), in comparison to DRC (n = 92, ORR: 78%) or BDR (n = 45, ORR: 84%) cohorts, p = 0.003. Similarly, longer progression‐free survival (PFS) was evident with R‐Benda use [median 5.2 vs. 4.3 (DRC) and 1.8 years (BDR), p < 0.001]. The time‐to‐next therapy (TTNT) favored R‐Benda [median, not‐reached, 4.4 (DRC) and 2.6 years (BDR), p < 0.001). These endpoints were comparable between the DRC and BDR cohorts. Overall survival (OS) was similar across the three cohorts, p = 0.77. In a subset analysis of 142 patients genotyped for MYD88L265P mutation, the ORR, PFS and TTNT were unaffected by the patients' MYD88 signature within each cohort. In conclusion, ORR, PFS and TTNT with R‐Benda are superior compared to DRC or BDR in treatment‐naïve patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88L265P mutation status.
Discovery of a Potent Degrader for Fibroblast Growth Factor Receptor 1/2
Authors: Du Guangyan , Jiang Jie , Wu Qibiao , Henning Nathaniel J. , Donovan Katherine A. , Yue Hong , Che Jianwei , Lu Wenchao , Fischer Eric S. , Bardeesy Nabeel , Zhang Tinghu , Gray Nathanael S.
Published: April 2021

Aberrant activation of FGFR signaling occurs in many cancers, and ATP‐competitive FGFR inhibitors have received regulatory approval. Despite demonstrating clinical efficacy, these inhibitors exhibit dose‐limiting toxicity, potentially due to a lack of selectivity amongst the FGFR family and are poorly tolerated. Here, we report the discovery and characterization of DGY‐09‐192, a bivalent degrader that couples the pan‐FGFR inhibitor BGJ398 to a CRL2VHL E3 ligase recruiting ligand, which preferentially induces FGFR1&2 degradation while largely sparing FGFR3&4. DGY‐09‐192 exhibited two‐digit nanomolar DC50s for both wildtype FGFR2 and several FGFR2‐fusions, resulting in degradation‐dependent antiproliferative activity in representative gastric cancer and cholangiocarcinoma cells. Importantly, DGY‐09‐192 induced degradation of a clinically relevant FGFR2 fusion protein in a xenograft model. Taken together, we demonstrate that DGY‐09‐192 has potential as a prototype FGFR degrader.
Electrolyte Structure of Lithium Polysulfides with Anti‐Reductive Solvent Shells for Practical Lithium–Sulfur Batteries
Authors: Zhang Xue‐Qiang , Jin Qi , Nan Yi‐Ling , Hou Li‐Peng , Li Bo‐Quan , Chen Xiang , Jin Zhe‐Hui , Zhang Xi‐Tian , Huang Jia‐Qi , Zhang Qiang
Published: April 2021

The lithium–sulfur (Li–S) battery is regarded as a promising secondary battery. However, constant parasitic reactions between the Li anode and soluble polysulfide (PS) intermediates significantly deteriorate the working Li anode. The rational design to inhibit the parasitic reactions is plagued by the inability to understand and regulate the electrolyte structure of PSs. Herein, the electrolyte structure of PSs with anti‐reductive solvent shells was unveiled by molecular dynamics simulations and nuclear magnetic resonance. The reduction resistance of the solvent shell is proven to be a key reason for the decreased reactivity of PSs towards Li. With isopropyl ether (DIPE) as a cosolvent, DIPE molecules tend to distribute in the outer solvent shell due to poor solvating power. Furthermore, DIPE is more stable than conventional ether solvents against Li metal. The reactivity of PSs is suppressed by encapsulating PSs into anti‐reductive solvent shells. Consequently, the cycling performance of working Li–S batteries was significantly improved and a pouch cell of 300 Wh kg−1 was demonstrated. The fundamental understanding in this work provides an unprecedented ground to understand the electrolyte structure of PSs and the rational electrolyte design in Li–S batteries.
Silylierte Schwefelsäure: Herstellung eines Tris(trimethylsilyl)oxosulfonium[(Me3Si‐O)3SO]+‐Salzes
Authors: Bläsing Kevin , Labbow Rene , Schulz Axel , Villinger Alexander
Published: April 2021

Die Chemie der silylierten Schwefelsäure, O2S(OSiMe3)2 (T2SO4, T=Me3Si; auch bekannt als Bis(trimethylsilyl)sulfat), wurde im Detail untersucht, mit dem Ziel, die formalen Autosilylierungsprodukte der silylierten Schwefelsäure, [T3SO4]+ und [TSO4]−, in Analogie zu den bekannten protonierten Spezies, [H3SO4]+ und [HSO4]−, zu synthetisieren. Die Synthese des [TSO4]−‐Ions gelingt nur, wenn eine Base, wie z. B. OPMe3, die bei der Silylierung ein schwach koordinierendes Kation bildet, mit T2SO4 umgesetzt wird, was zur Bildung von [Me3POT]+[TSO4]− führt. Die [T3SO4]+‐Salze können ausgehend von T2SO4 in der Reaktion mit [T‐H‐T]+[B(C6F5)4]− oder T+[CHB11Br6H5]− isoliert werden, aber nur, wenn ein schwach koordinierendes Anion als Gegenion verwendet wird. Alle silylierten Verbindungen konnten kristallisiert und strukturell charakterisiert werden.
Anisotropic Synthetic Allomelanin Materials via Solid‐State Polymerization of Self‐Assembled 1,8‐Dihydroxynaphthalene Dimers
Authors: Zhou Xuhao , Gong Xinyi , Cao Wei , Forman Christopher J. , Oktawiec Julia , D'Alba Liliana , Sun Hao , Thompson Matthew P. , Hu Ziying , Kapoor Utkarsh , McCallum Naneki C. , Malliakas Christos D. , Farha Omar K. , Jayaraman Arthi , Shawkey Matthew D. , Gianneschi Nathan C.
Published: April 2021

Melanosomes in nature have diverse morphologies, including spheres, rods, and platelets. By contrast, shapes of synthetic melanins have been almost entirely limited to spherical nanoparticles with few exceptions produced by complex templated synthetic methods. Here, we report a non‐templated method to access synthetic melanins with a variety of architectures including spheres, sheets, and platelets. Three 1,8‐dihydroxynaphthalene dimers (4‐4′, 2‐4′ and 2‐2′) were used as self‐assembling synthons. These dimers pack to form well‐defined structures of varying morphologies depending on the isomer. Specifically, distinctive ellipsoidal platelets can be obtained using 4‐4′ dimers. Solid‐state polymerization of the preorganized dimers generates polymeric synthetic melanins while maintaining the initial particle morphologies. This work provides a new route to anisotropic synthetic melanins, where the building blocks are preorganized into specific shapes, followed by solid‐state polymerization.
Silylated Sulfuric Acid: Preparation of a Tris(trimethylsilyl)oxosulfonium [(Me3Si−O)3SO]+ Salt
Authors: Bläsing Kevin , Labbow Rene , Schulz Axel , Villinger Alexander
Published: April 2021

The chemistry of silylated sulfuric acid, O2S(OSiMe3)2 (T2SO4, T=Me3Si; also known as bis(trimethylsilyl) sulfate), has been studied in detail with the aim of synthesizing the formal autosilylation products of silylated sulfuric acid, [T3SO4]+ and [TSO4]−, in analogy to the known protonated species, [H3SO4]+ and [HSO4]−. The synthesis of the [TSO4]− ion only succeeds when a base, such as OPMe3 that forms a weakly coordinating cation upon silylation, is reacted with T2SO4, resulting in the formation of [Me3POT]+[TSO4]−. [T3SO4]+ salts could be isolated starting from T2SO4 in the reaction with [T−H−T]+[B(C6F5)4]− or T+[CHB11Br6H5]− when a weakly coordinating anion is used as counterion. All silylated compounds could be crystallized and structurally characterized.
Iridium‐catalyzed asymmetric hydrogenation of β‐ketophosphonates with chiral ferrocenyl P,N,N‐ligands
Authors: Ma Yin‐Feng , Hou Chuan‐Jin , Wei De‐Quan , He Xinwei , Chu Ting‐Ting , Chen Xiu‐shuai , Hu Xiang‐Ping
Published: April 2021

The asymmetric hydrogenation of β‐ketophosphonates with chiral Ir/P,N,N‐ligands catalyst has been developed. A series of β‐ketophosphonates were hydrogenated, and the corresponding β‐hydroxyphosphonates were obtained in high yields with good or excellent enantioselectivities under mild condition.
Grafting multi‐elements hybrid polymer brushes on graphene oxide for epoxy composite with excellent flame retardancy
Authors: Zhang Jiatian , Wu Wenqian , Lv Yan , Guo Chuanluan , Xu Yiting , Zeng Birong , Dai Lizong
Published: April 2021

In this paper, a silicon‐oxygen coupling agent (MPS) with a double bond is hydrolyzed with graphene oxide (GO) to obtain MPS‐GO. The polymerization of MPS‐GO with the phosphorus‐containing monomer (HEPO) is initiated with 2,2′‐Azobis(2‐methylpropionitrile) (AIBN) to obtain multi‐elements hybrid polymer brushes grafting graphene oxide (HM‐GO). As a flame retardant, different amounts of HM‐GO are added to obtain EP composites. In this system, the properties of composite flame retardant obviously increase with the increasing of HM‐GO. The limiting oxygen index (LOI) value of composites with 4 wt% addition of HM‐GO is 31.0%, while the LOI value of EP‐0 is only 23.9%. And the peak heat release rate (PHRR) value is reduced from 515.8 W g−1 of pure epoxy resin to 376.9 W g−1. In addition, with the increase of HM‐GO addition, the Tg value, flexural strength and flexural modulus of EP composites are improved. Through calculation, it is proved that the rising of Tg was due to the increase of crosslink density of the system. The flame retardant performance and mechanical properties of the composite materials are steadily improved, indicating that such flame retardants are dispersed well in the epoxy resin. HM‐GO is an efficient macromolecular modified graphene oxide halogen‐free flame retardant, which can improve both flame retardant properties and mechanical properties.
Structural and biological aspects of natural bridged macrobicyclic peptides from marine resources
Authors: Dahiya Rajiv , Dahiya Sunita , Kumar Priyank , Kumar Radhika V. , Dahiya Saurabh , Kumar Suresh , Saharan Renu , Basu Paramita , Mitra Arindam , Sharma Ajay , Kashaw Sushil K. , Patel Jayvadan K.
Published: April 2021

Among peptide‐based drugs, naturally occurring bicyclic compounds have been established as molecules with unique therapeutic potential. The diverse pharmacological activities associated with bicyclic peptides from marine tunicates, sponges, and bacteria render them suitable to be employed as effective surrogate between complex and small therapeutic moieties. Bicyclic peptides possess greater conformational rigidity and higher metabolic stability as compared with linear and monocyclic peptides. The antibody‐like affinity and specificity of bicyclic peptides enable their binding to the challenging drug targets. Bridged macrobicyclic peptides from natural marine resources represent an underexplored class of molecules that provides promising platforms for drug development owing to their biocompatibility, similarity, and chemical diversity to proteins. The present review explores major marine‐derived bicyclic peptides including disulfide‐bridged, histidinotyrosine‐bridged, or histidinoalanine‐bridged macrobicyclic peptides along with their structural characteristics, synthesis, structure–activity relationship, and bioproperties.The comparison of these macrobicyclic congeners with linear/monocyclic peptides along with their therapeutic potential are also briefly discussed.
High accuracy adaptive motion control for a robotic manipulator with model uncertainties based on multilayer neural network
Authors: Hu Jian , Wang Pengfei , Xu Chenchen , Zhou Haibo , Yao Jianyong
Published: April 2021

A robotic manipulator is widely used nowadays, and its high‐accuracy motion control has become a hot topic. However, since it is a very complicated control plant, there exist many structural and unstructured uncertainties in its mathematical model, which would degrade the manipulator control performance when the traditional model‐based control method such as feedback linearization control is adopted. In this paper, a practical method that combines feedback linearization control with multilayer neural network (MNN)‐based model uncertainties observer is proposed for high‐accuracy motion control of a robotic manipulator. The proposed controller not only accounts for the parametric uncertainties but also for the external disturbance. A multilayer neural network capable of online learning is designed to estimate all of the model uncertainties, which can be compensated through the feedforward cancellation technique. A weight adaption law for the online learning neural network is derived based on Lyapunov stability theory. Finally, a feedback linearization method with the MNN‐based observer is designed to stabilize the whole system. The stability proof shows that bounded stability of a manipulator system with the proposed controller is guaranteed. Extensive simulation results show that this control strategy achieves high‐accuracy tracking control in the presence of the manipulator parametric uncertainties and external disturbance.
Controller synthesis for discrete‐time positive switched T–S fuzzy systems with partially controllable subsystems
Authors: Yang Gengjiao , Hao Fei , Zhang Lin , Li Bo hu
Published: April 2021

The controller synthesis problem for discrete‐time positive switched T–S fuzzy systems (PSTSFSs) is investigated in this paper. Unlike previous literature, subsystems are assumed to be partially controllable in this paper. A novel slow–fast combined mode‐dependent average dwell time (SFCMDADT) approach is proposed to obtain sufficient conditions for the stability of general positive switched nonlinear systems with partially stable subsystems. Then based on the obtained results, a parallel distributed compensation (PDC)‐based fuzzy controller is designed, and sufficient conditions for the stability of PSTSFSs with partially controllable subsystems are developed with the aid of a time‐scheduled multiple linear copositive Lyapunov function. Furthermore, sufficient conditions for the stability of the positive switched T–S fuzzy system are given respectively for the two cases that the subsystems are all controllable and all uncontrollable. Finally, two simulation examples are provided to illustrate the effectiveness of the proposed method.
The impact of COVID‐19 on stress, anxiety, and coping in youth with and without autism and their parents
Authors: Corbett Blythe A. , Muscatello Rachael A. , Klemencic Mark E. , Schwartzman Jessica M.
Published: April 2021

In the wake of COVID‐19, the world has become a more uncertain environment—a breeding ground for stress and anxiety, especially for individuals with autism spectrum disorder (ASD). The study examined stress, anxiety, and coping in a data‐driven, real‐time assessment of 122 youth with and without ASD and their parents at the height of the COVID‐19 shutdown and three‐months later. Standardized measures were administered to ascertain stress and coping explicitly related to the pandemic (RSQ COVID‐19‐Child [self‐report], Adult [self‐report from the guardian of youth], Parent [report about child]) and anxiety (STAI‐C, STAI‐A). Multivariate, univariate analyses of variance and hierarchical regression were used. ASD youth endorsed more Trait anxiety and response to specific stressors (e.g., virus). Caregivers of youth with ASD (Adults) self‐reported higher anxiety, yet scores were elevated for both groups. Adults of youth with ASD reported more stress, especially related to the virus, access to healthcare, and concern for the future. In the TD group, youth and adults used more Primary and Secondary Control Coping whereas ASD youth and adults used more Disengagement Coping. Adult stress was the primary predictor of parent perception of child stress as well as Child self‐reported stress. While the ASD group was consistently high compared to the TD group, there were no significant changes over time for stress or anxiety. Results reveal striking differences in youth with ASD and their parents regarding stress, anxiety, and coping. Findings highlight the need for essential support, access to services, and strategies to enhance psychological and emotional well‐being.

Lay Summary

This study examined stress, anxiety, and coping related to the COVID‐19 pandemic in 61 youth with autism spectrum disorder (ASD) and 61 youth with typical development (TD) and their parents. Results showed that ASD youth reported more anxiety and stress. Adults of youth with ASD indicated higher self‐reported anxiety and stress than adults of TD youth. TD youth and their parents reported using more adaptive coping strategies. Findings highlight the need for strategies to enhance psychological and emotional well‐being.
Adsorbed protein film on pump surfaces leads to particle formation during fill‐finish manufacturing
Authors: Roffi Kirk , Li Li , Pantazis Jacob
Published: April 2021

During fill‐finish manufacturing, therapeutic proteins may aggregate or form subvisible particles in response to the physical stresses encountered within filling pumps. Understanding and quantitating this risk is important since filling may be the last unit operation before the patient receives their dose. We studied particle formation from lab‐scale to manufacturing‐scale using sensitive and robust protein formulations. Filling experiments with a ceramic rotary piston pump were integrated with a rinse‐stripping method to investigate the relationship between protein adsorption and particle formation. For a sensitive protein, multilayer film formation on the piston surface correlated with high levels of subvisible particles in solution. For a robust protein formulation, adsorption and subvisible particle formation were minimal. These results support an aggregation mechanism that is initiated by adsorption to pump surfaces and propagated by mechanical and/or hydrodynamic disruption of the film. The elemental analysis confirmed that ceramic wear debris remained at trace levels and did not contribute appreciably to protein aggregation.
Determination of the Phytochemical Composition and Antioxidant Potential of Eugenia copacabanensis and Myrciaria tenella Leaves (Myrtaceae) Using a Saccharomyces cerevisiae Model
Authors: de Carvalho Martins Víctor , França Liliana Princisval , da Silva Ferreira Yasmim , Pires Daniele Cabral , de Souza Cardoso Bárbara , Pessanha de Araújo Santiago Manuela Cristina , Pacheco Sidney , da Costa Souza Marcelo , Riger Cristiano Jorge , de Oliveira Godoy Ronoel Luiz , Geraldo de Carvalho Mario
Published: April 2021

Eugenia copacabanensis and Myrciaria tenella are present in restingas of the Atlantic Forest, but little information is available about their chemical and biological potential. In this context, the hexane, dichloromethane, ethyl acetate and butanol fractions from the leaves of methanolic extract were analyzed by GC/MS and HPLC‐DAD and the antioxidant potential was determined by DPPH and ABTS assays and using a Saccharomyces cerevisiae model. Dereplication allowed the identification of 68 compounds, 42 and 41 of which, respectively, are first reported here for E. copacabanensis and M. tenella. In vivo results revealed that the ethyl acetate and butanol fractions showed expressive antioxidant protection in the BY4741 and Δgsh1 strains, with greater impact on glutathione‐deficient cells. With a high diversity of phenolic compounds, these polar fractions of E. copacabanensis and M. tenella leaves are potential protectors against intracellular oxidative stress.
Labeling and Characterization of Phenol‐Containing Glycopeptides Using Chemoselective Probes with Isotope Tags
Authors: Wang Tsung‐Shing Andrew , Wu Ruo‐Yu , Hong Yu , Wang Zhe‐Chong , Li Tsung‐Lin , Shie Jiun‐Jie , Hsu Cheng‐Chih
Published: April 2021

Secondary metabolites are structurally diverse natural products (NPs) and have been widely used for medical applications. Developing new tools to enrich NPs can be a promising solution to isolate novel NPs from the native and complex samples. Here, we developed native and deuterated chemoselective labeling probes to target phenol‐containing glycopeptides by the ene‐type labeling used in proteomic research. The clickable azido‐linker was included for further biotin functionalization to facilitate the enrichment of labeled substrates. Afterward, our chemoselective method, in conjunction with LC‐MS and MSn analysis, was demonstrated in bacterial cultures. A vancomycin‐related phenol‐containing glycopeptide was labeled and characterized by our labeling strategy, showing its potential in glycopeptide discovery in complex environments.
Electrochemical Transformations of Methylxanthines in Non‐Aqueous Medium
Authors: Di Matteo Paola , Bortolami Martina , Feroci Marta , Scarano Vincenzo , Petrucci Rita
Published: April 2021

Coffee, cocoa and tea are the main sources of the natural methylxanthines caffeine, theobromine and theophylline. They are the most consumed alkaloids worldwide, with both beneficial and harmful effects on health. In addition to more traditional therapeutic uses, beneficial effects related to the oxidative stress have been more recently ascribed to these compounds. Moreover, natural methylxanthines have recently attracted attention as bio‐based and renewable starting materials for organic synthesis. By using the electron as a green and sustainable reagent, organic electrochemistry provides a precious tool to carry out redox reactions for both mechanistic and synthetic purposes. The electrochemistry of natural methylxanthines was studied previously in an aqueous electrolytes, in which their chemistry is closely related to that of uric acid. Conversely, their electrochemistry in organic solvent is recent history: a few but successful examples of organic electrosyntheses and functionalizations have been reported, with promising applications in the pharmaceutical field. Moreover, some advances in molecular mechanisms might shed light on their potentialities as antioxidants. A prospective is given in the present minireview.
Hydrodehalogenation of Polychloromethanes on Silver‐Based Gas Diffusion Electrodes
Authors: Rondinini Sandra , Pargoletti Eleonora , Vertova Alberto , Minguzzi Alessandro
Published: April 2021

This work reports the electroreduction of a volatile organic halide (trichloromethane) from an airborn stream. In the past years, we highlighted the role of polycrystalline silver as powerful electrocatalyst for the electroreductive hydrodehalogenation of volatile organic halides (VOH) in water/organic solvent mixtures, from 0 to 100 % of the aqueous component. The successful conversion of trichloromethane and 1,1,1‐trichloethane to the relevant dehalogenated compounds, methane and ethane have prompted us to extend the investigations to the treatment of gaseous effluents, adopting a silver Gas Diffusion Electrode (Ag‐GDE) and the appropriate cell design. In the field of electroreduction processes the possibility of using GDE to treat gaseous effluents for the removal of volatile organic pollutants represents an electrochemical challenge, and the treatment of N2/CHCl3 gas mixtures fed into the cathodic Ag‐GDE compartment demonstrates the feasibility of the electroreductive detoxification process. Our results will be presented and discussed in terms of CHCl3 removal efficiency, selectivity and energy consumption in preparative electrolyses.
Rational Enzyme Design without Structural Knowledge: A Sequence‐Based Approach for Efficient Generation of Transglycosylases
Authors: Teze David , Zhao Jiao , Wiemann Mathias , Kazi Zubaida G. A. , Lupo Rossana , Zeuner Birgitte , Vuillemin Marlène , Rønne Mette E. , Carlström Göran , Duus Jens Ø. , Sanejouand Yves‐Henri , O'Donohue Michael J. , Nordberg Karlsson Eva , Fauré Régis , Stålbrand Henrik , Svensson Birte
Published: April 2021

Glycobiology is dogged by the relative scarcity of synthetic, defined oligosaccharides. Enzyme‐catalysed glycosylation using glycoside hydrolases is feasible but is hampered by the innate hydrolytic activity of these enzymes. Protein engineering is useful to remedy this, but it usually requires prior structural knowledge of the target enzyme, and/or relies on extensive, time‐consuming screening and analysis. Here, a straightforward strategy that involves rational rapid in silico analysis of protein sequences is described. The method pinpoints 6–12 single‐mutant candidates to improve transglycosylation yields. Requiring very little prior knowledge of the target enzyme other than its sequence, the method is generic and procures catalysts for the formation of glycosidic bonds involving various d/l‐, α/β‐pyranosides or furanosides, and exo or endo action. Moreover, mutations validated in one enzyme can be transposed to others, even distantly related enzymes.
Porous Tungsten Oxide: Recent Advances in Design, Synthesis, and Applications
Authors: Bentley John , Desai Salil , Bastakoti Bishnu Prasad
Published: April 2021

Tungsten oxide (WO3) has received ever more attention and has been highly researched over the last decade due to its being a low‐cost transition metal semiconductor with tunable, yet widely stable, band gaps. This minireview briefly highlights the challenges in the design and synthesis of porous WO3 including methods, precursors, solvent effects, crystal phases, and surface activities of the porous WO3 base material. These topics are explored while also drawing a connection of how the morphology and crystal phase affect the band gap. The shifts in band gap not only impact the optical properties of tungsten but also allow tuning to operate on different energy levels, which makes WO3 highly desirable in many applications such as supercapacitors, batteries, solar cells, catalysts, sensors, smart windows, and bioapplications.
Low‐Temperature Direct Electrochemical Methanol Reforming Enabled by CO‐Immune Mo‐Based Hydrogen Evolution Catalysts
Authors: Bau Jeremy A. , Rueping Magnus
Published: April 2021

Hydrogen storage in the form of intermediate artificial fuels such as methanol is important for future chemical and energy applications, and the electrochemical regeneration of hydrogen from methanol is thermodynamically favorable compared to direct water splitting. However, CO produced from methanol oxidation can adsorb to H2‐evolution catalysts and drastically reduce activity. In this study, we explore the origins of CO immunity in Mo‐containing H2‐evolution catalysts. Unlike conventional catalysts such as Pt or Ni, Mo‐based catalysts display remarkable immunity to CO poisoning. The origin of this behavior in NiMo appears to arise from the apparent inability of CO to bind Mo under electrocatalytic conditions, with mechanistic consequences for the H2‐evolution reaction (HER) in these systems. This specific property of Mo‐based HER catalysts makes them ideal in environments where poisons might be present.
Co3O4−CeO2 Nanocomposites for Low‐Temperature CO Oxidation
Authors: Yang Jingxia , Yigit Nevzat , Möller Jury , Rupprechter Günther
Published: April 2021

In an effort to combine the favorable catalytic properties of Co3O4 and CeO2, nanocomposites with different phase distribution and Co3O4 loading were prepared and employed for CO oxidation. Synthesizing Co3O4‐modified CeO2 via three different sol‐gel based routes, each with 10.4 wt % Co3O4 loading, yielded three different nanocomposite morphologies: CeO2‐supported Co3O4 layers, intermixed oxides, and homogeneously dispersed Co. The reactivity of the resulting surface oxygen species towards CO were examined by temperature programmed reduction (CO‐TPR) and flow reactor kinetic tests. The first morphology exhibited the best performance due to its active Co3O4 surface layer, reducing the light‐off temperature of CeO2 by about 200 °C. In contrast, intermixed oxides and Co‐doped CeO2 suffered from lower dispersion and organic residues, respectively. The performance of Co3O4‐CeO2 nanocomposites was optimized by varying the Co3O4 loading, characterized by X‐ray diffraction (XRD) and N2 sorption (BET). The 16–65 wt % Co3O4−CeO2 catalysts approached the conversion of 1 wt % Pt/CeO2, rendering them interesting candidates for low‐temperature CO oxidation.
Synergistic DNA‐ and Protein‐Based Recognition Promote an RNA‐Templated Bio‐orthogonal Reaction
Authors: McLoughlin Niall M. , Kuepper Arne , Neubacher Saskia , Grossmann Tom N.
Published: April 2021

Biomolecular assemblies composed of proteins and oligonucleotides play a central role in biological processes. While in nature, oligonucleotides and proteins usually assemble via non‐covalent interactions, synthetic conjugates have been developed which covalently link both modalities. The resulting peptide‐oligonucleotide conjugates have facilitated novel biological applications as well as the design of functional supramolecular systems and materials. However, despite the importance of concerted protein/oligonucleotide recognition in nature, conjugation approaches have barely utilized the synergistic recognition abilities of such complexes. Herein, the structure‐based design of peptide‐DNA conjugates that bind RNA through Watson‐Crick base pairing combined with peptide‐mediated major groove recognition is reported. Two distinct conjugate families with tunable binding characteristics have been designed to adjacently bind a particular RNA sequence. In the resulting ternary complex, their peptide elements are located in proximity, a feature that was used to enable an RNA‐templated click reaction. The introduced structure‐based design approach opens the door to novel functional biomolecular assemblies.
Interstellar Enolization‐Acetaldehyde (CH3CHO) and Vinyl Alcohol (H2CCH(OH)) as a Case Study
Authors: Kleimeier N. Fabian , Kaiser Ralf I.
Published: April 2021

Owing to the unique conditions in cold molecular clouds, enols—the thermodynamically less stable tautomers of aldehydes and ketones—do not undergo tautomerization to their more stable tautomers in the gas phase because they cannot overcome tautomerization barriers at the low temperatures. Laboratory studies of interstellar analog ices have demonstrated the formation of several keto–enol tautomer pairs in astrochemically relevant ice mixtures over the last years. However, so far only one of them, acetaldehyde−vinyl alcohol, has been detected in deep space. Due to their reactivity with electrophiles, enols can play a crucial role in our understanding of the molecular complexity in the interstellar medium and in comets and meteorites. To study the enolization of aldehydes in interstellar ices by interaction with galactic cosmic rays (GCRs), we irradiated acetaldehyde ices with energetic electrons as proxies of secondary electrons generated in the track of GCRs while penetrating interstellar ices. The results indicate that GCRs can induce enolization of acetaldehyde and that intra‐ as well as intermolecular processes are relevant. Therefore, enols should be ubiquitous in the interstellar medium and could be searched for using radio telescopes such as ALMA. Once enols are detected and abundances are established, they can serve as tracers for the non‐equilibrium chemistry in interstellar ices thus eventually constraining fundamental reaction mechanisms deep inside interstellar ices.
Green Esterification of Carboxylic Acids Promoted bytert‐Butyl Nitrite
Authors: Zheng Yonggao , Zhao Yanwei , Tao Suyan , Li Xingxing , Cheng Xionglve , Jiang Gangzhong , Wan Xiaobing
Published: April 2021

In this work, the green esterification of carboxylic acids promoted bytert‐butyl nitrite has been well developed. This transformation is compatible with a broad range of substrates and exhibits excellent functional group tolerance. Various drugs and substituted amino acids are applicable to this reaction under near neutral conditions, with good to excellent yields.