bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterologous vaccination utilizing viral vector and protein platforms confers complete protection against SFTSV
Authors: Kim Jae-Yong , Jeon Kyeongseok , Hong Jung Joo , Park Sang-In , Cho Hyeonggon , Park Hyo-Jung , Kwak Hye Won , Park Hyeong-Jun , Bang Yoo-Jin , Lee Yu-Sun , Bae Seo-Hyeon , Kim So-Hee , Hwang Kyung-Ah , Jung Dae-Im , Cho Seong Hoo , Seo Sang Hwan , Kim Green , Oh Hanseul , Lee Hwal-Yong , Kim Ki Hyun , Lim Hee-Young , Jeon Pyeonghwa , Lee Joo-Yeon , Chung Junho , Lee Sang-Myeong , Ko Hae Li , Song Manki , Cho Nam-Hyuk , Lee Young-suk , Hong So-Hee , Nam Jae-Hwan
Published: May 2023

Severe fever with thrombocytopenia syndrome virus was first discovered in 2009 as the causative agent of severe fever with thrombocytopenia syndrome. Despite its potential threat to public health, no prophylactic vaccine is yet available. This study developed a heterologous prime-boost strategy comprising priming with recombinant replication-deficient human adenovirus type 5 (rAd5) expressing the surface glycoprotein, Gn, and boosting with Gn protein. This vaccination regimen induced balanced Th1/Th2 immune responses and resulted in potent humoral and T cell-mediated responses in mice. It elicited high neutralizing antibody titers in both mice and non-human primates. Transcriptome analysis revealed that rAd5 and Gn proteins induced adaptive and innate immune pathways, respectively. This study provides immunological and mechanistic insight into this heterologous regimen and paves the way for future strategies against emerging infectious diseases.
Comprehensive motivational framework to drive paddy farmers towards pluriactivity
Authors: Moumenihelali Hadi , Abbasi Enayat , Karbasioun Mostafa
Published: May 2023

Pluriactivity is a livelihood strategy in line with rural resilience. It is a phenomenon of farming in conjunction with other gainful activities. In pluriactivity, the desire and motivation of setting up an extra business and taking necessary actions are crucial. Therefore, the main aim of this study was to identify the underlying components of pluriactive paddy farmers’ motivation and also the factors affecting them. The study was implemented based on the quantitative data obtained from 182 pluriactive paddy farmers. The results of the exploratory factor analysis accentuated that there are three components in each of the pull and push typologies. The components related to pull motivation included personal aspirations and pursuit (C1), proper conditions and facilities (C2) and growth and service markets (C3). Likewise, the components related to push motivation included financial status and job creation improvement (C4), uncertainty and risk mitigation (C5) and paddy farming economic enhancement (C6). Also, it was revealed that two motivational components of personal aspirations and pursuits (C1) and financial status and job creation improvement (C4) are attributed to paddy farmer’s age of the pluriactivity initiation and also the farm size variables. It is imperative to consider both pull and push strategies in directing paddy farmers towards extension and development of pluriactivity in rural areas to enable farmers achieve sustainable livelihood in line with rural resilience.
Plasma metabolomics reveals major changes in carbohydrate, lipid, and protein metabolism of abruptly weaned beef calves
Authors: González Luciano A. , Carvalho Julia G. S. , Kuinchtner Bruno C. , Dona Anthony C. , Baruselli Pietro S. , D’Occhio Michael J.
Published: May 2023

1H NMR-based metabolomics was used to study the effect of abrupt weaning on the blood metabolome of beef calves. Twenty Angus calves (258 ± 5 kg BW; 5 to 6 months old) were randomly assigned to a non-weaned (NW) group that remained grazing with their dam or a weaned (W) group that underwent abrupt separation from their dam to a separate paddock on d 0 of the study. Body weight, behaviour, and blood samples for cortisol and metabolomics were measured at d 0, 1, 2, 7, and 14 of the study. On d 1 and 2, W calves spent less time grazing and ruminating, and more time vocalising and walking, had a greater concentration of cortisol, NEFA, 3-hydroxybutyrate, betaine, creatine, and phenylalanine, and lesser abundance of tyrosine (P < 0.05) compared to NW calves. Compared to NW calves at d 14, W calves had greater (P < 0.01) relative abundance of acetate, glucose, allantoin, creatinine, creatine, creatine phosphate, glutamate, 3-hydroxybutyrate, 3-hydroxyisobutyrate, and seven AA (alanine, glutamate, leucine, lysine, phenylalanine, threonine and valine) but lesser (P < 0.05) relative abundance of low density and very low-density lipids, and unsaturated lipids. Both PCA and OPLS-DA showed no clustering or discrimination between groups at d 0 and increasing divergence to d 14. Blood metabolomics is a useful tool to quantify the acute effects of stress in calves during the first 2 days after abrupt weaning, and longer-term changes in carbohydrate, lipid and protein metabolism due to nutritional changes from cessation of milk intake and greater reliance on forage intake.
Skeletal muscle overexpression of sAnk1.5 in transgenic mice does not predispose to type 2 diabetes
Authors: Pierantozzi E. , Raucci L. , Buonocore S. , Rubino E. M. , Ding Q. , Laurino A. , Fiore F. , Soldaini M. , Chen J. , Rossi D. , Vangheluwe P. , Chen H. , Sorrentino V.
Published: May 2023

Genome-wide association studies (GWAS) and cis-expression quantitative trait locus (cis-eQTL) analyses indicated an association of the rs508419 single nucleotide polymorphism (SNP) with type 2 diabetes (T2D). rs508419 is localized in the muscle-specific internal promoter (P2) of the ANK1 gene, which drives the expression of the sAnk1.5 isoform. Functional studies showed that the rs508419 C/C variant results in increased transcriptional activity of the P2 promoter, leading to higher levels of sAnk1.5 mRNA and protein in skeletal muscle biopsies of individuals carrying the C/C genotype. To investigate whether sAnk1.5 overexpression in skeletal muscle might predispose to T2D development, we generated transgenic mice (TgsAnk1.5/+) in which the sAnk1.5 coding sequence was selectively overexpressed in skeletal muscle tissue. TgsAnk1.5/+ mice expressed up to 50% as much sAnk1.5 protein as wild-type (WT) muscles, mirroring the difference reported between individuals with the C/C or T/T genotype at rs508419. However, fasting glucose levels, glucose tolerance, insulin levels and insulin response in TgsAnk1.5/+ mice did not differ from those of age-matched WT mice monitored over a 12-month period. Even when fed a high-fat diet, TgsAnk1.5/+ mice only presented increased caloric intake, but glucose disposal, insulin tolerance and weight gain were comparable to those of WT mice fed a similar diet. Altogether, these data indicate that sAnk1.5 overexpression in skeletal muscle does not predispose mice to T2D susceptibility.
Study on soil erosion and its driving factors from the perspective of landscape in Xiushui watershed, China
Authors: Wen Linsheng , Peng Yun , Zhou Yunrui , Cai Guo , Lin Yuying , Li Baoyin
Published: May 2023

Soil erosion (SE) is one of the most serious disasters in the world, which directly damage the productivity of the land and affect human well-being. How to effectively mitigate soil erosion is a challenge faced by all countries in the world. In this study, soil erosion was quantitatively assessed base on the RULSE model in an ecologically fragile area [Xiushui watershed (XSW)], and the effects of three major categories of factors (land use/cover change, landscape fragmentation and climate) on soil erosion were investigated using correlation analysis and structural equation model. The results indicated that there was no continuous increase or decrease trend on the SE of XSW with impact of rainfall, the mean values of SE were 2205.27 t/ha, 3414.25 t/ha and 3319.44 t/ha from 2000 to 2020 and the hot areas of SE were mainly distributed around the Xiushui river channel, respectively. The expansion of urbanization (the area of impervious increased from 113.12 to 252.57 km2) aggravated landscape fragmentation, and the landscape fragmented area had some overlap with the hot zone of SE. Additionally, the LUCC factor dominated by NDVI, landscape fragmentation factor and climate factor dominated by rainfall had a directly driving effect on SE, where the path coefficient of landscape fragmentation was 0.61 (P < 0.01), respectively. We also found that except increasing forest area, improving forest quality (NDVI, canopy closure, structure) deserved emphasized in SE management, and the effect of landscape fragmentation on SE also should not be ignored. Moreover, soil erosion assessment at large scales over long time periods tends to underestimate the driving force of rainfall on SE, and it is a great challenge to evaluate the effect of extreme rainfall on soil erosion at short time scales in a downscale manner. This research provides insights for ecological sustainable management and soil erosion protection policies.
Epigenome-wide association study of diabetic chronic kidney disease progression in the Korean population: the KNOW-CKD study
Authors: Sung Hye Youn , Lee Sangjun , Han Miyeun , An Woo Ju , Ryu Hyunjin , Kang Eunjeong , Park Yong Seek , Lee Seung Eun , Ahn Curie , Oh Kook-Hwan , Park Sue K. , Ahn Jung-Hyuck
Published: May 2023

Since the etiology of diabetic chronic kidney disease (CKD) is multifactorial, studies on DNA methylation for kidney function deterioration have rarely been performed despite the need for an epigenetic approach. Therefore, this study aimed to identify epigenetic markers associated with CKD progression based on the decline in the estimated glomerular filtration rate in diabetic CKD in Korea. An epigenome-wide association study was performed using whole blood samples from 180 CKD recruited from the KNOW-CKD cohort. Pyrosequencing was also performed on 133 CKD participants as an external replication analysis. Functional analyses, including the analysis of disease-gene networks, reactome pathways, and protein–protein interaction networks, were conducted to identify the biological mechanisms of CpG sites. A phenome-wide association study was performed to determine the associations between CpG sites and other phenotypes. Two epigenetic markers, cg10297223 onAGTR1and cg02990553 onKRT28indicated a potential association with diabetic CKD progression. Based on the functional analyses, other phenotypes (blood pressure and cardiac arrhythmia forAGTR1) and biological pathways (keratinization and cornified envelope forKRT28) related to CKD were also identified. This study suggests a potential association between the cg10297223 and cg02990553 and the progression of diabetic CKD in Koreans. Nevertheless, further validation is needed through additional studies.
Glycerol induced paraspinal muscle degeneration leads to hyper-kyphotic spinal deformity in wild-type mice
Authors: Noonan Alex M. , Buliung Emily , Briar K. Josh , Quinonez Diana , Séguin Cheryle A. , Brown Stephen H. M.
Published: May 2023

Degenerative spinal disorders, including kyphotic deformity, are associated with a range of degenerative characteristics of the paraspinal musculature. It has therefore been hypothesized that paraspinal muscular dysfunction is a causative factor for degenerative spinal deformity; however, experimental studies demonstrating causative relationships are lacking. Male and female mice received either glycerol or saline injections bilaterally along the length of the paraspinal muscles at four timepoints, each separated by 2 weeks. Immediately after sacrifice, micro-CT was performed to measure spinal deformity; paraspinal muscle biopsies were taken to measure active, passive and structural properties; and lumbar spines were fixed for analysis of intervertebral disc (IVD) degeneration. Glycerol-injected mice demonstrated clear signs of paraspinal muscle degeneration and dysfunction: significantly (p < 0.01) greater collagen content, lower density, lower absolute active force, greater passive stiffness compared to saline-injected mice. Further, glycerol-injected mice exhibited spinal deformity: significantly (p < 0.01) greater kyphotic angle than saline-injected mice. Glycerol-injected mice also demonstrated a significantly (p < 0.01) greater IVD degenerative score (although mild) at the upper-most lumbar level compared to saline-injected mice. These findings provide direct evidence that combined morphological (fibrosis) and functional (actively weaker and passively stiffer) alterations to the paraspinal muscles can lead to negative changes and deformity within the thoracolumbar spine.
Aerosol demasking enhances climate warming over South Asia
Authors: Nair H. R. C. R. , Budhavant Krishnakant , Manoj M. R. , Andersson August , Satheesh S. K. , Ramanathan V. , Gustafsson Örjan
Published: May 2023

Anthropogenic aerosols mask the climate warming caused by greenhouse gases (GHGs). In the absence of observational constraints, large uncertainties plague the estimates of this masking effect. Here we used the abrupt reduction in anthropogenic emissions observed during the COVID-19 societal slow-down to characterize the aerosol masking effect over South Asia. During this period, the aerosol loading decreased substantially and our observations reveal that the magnitude of this aerosol demasking corresponds to nearly three-fourths of the CO2-induced radiative forcing over South Asia. Concurrent measurements over the northern Indian Ocean unveiled a ~7% increase in the earth’s surface-reaching solar radiation (surface brightening). Aerosol-induced atmospheric solar heating decreased by ~0.4 K d−1. Our results reveal that under clear sky conditions, anthropogenic emissions over South Asia lead to nearly 1.4 W m−2heating at the top of the atmosphere during the period March–May. A complete phase-out of today’s fossil fuel combustion to zero-emission renewables would result in rapid aerosol demasking, while the GHGs linger on.
White spot syndrome virus (WSSV) modulates lipid metabolism in white shrimp
Authors: Ng Yen Siong , Cheng Cheng-Shun , Ando Masahiro , Tseng Yi-Ting , He Shu-Ting , Li Chun-Yuan , Cheng Shu-Wen , Chen Yi-Min , Kumar Ramya , Liu Chun-Hung , Takeyama Haruko , Hirono Ikuo , Wang Han-Ching
Published: May 2023

In addition to the Warburg effect, which increases the availability of energy and biosynthetic building blocks in WSSV-infected shrimp, WSSV also induces both lipolysis at the viral genome replication stage (12 hpi) to provide material and energy for the virus replication, and lipogenesis at the viral late stage (24 hpi) to complete virus morphogenesis by supplying particular species of long-chain fatty acids (LCFAs). Here, we further show that WSSV causes a reduction in lipid droplets (LDs) in hemocytes at the viral genome replication stage, and an increase in LDs in the nuclei of WSSV-infected hemocytes at the viral late stage. In the hepatopancreas, lipolysis is triggered by WSSV infection, and this leads to fatty acids being released into the hemolymph. β-oxidation inhibition experiment reveals that the fatty acids generated by WSSV-induced lipolysis can be diverted into β-oxidation for energy production. At the viral late stage, WSSV infection leads to lipogenesis in both the stomach and hepatopancreas, suggesting that fatty acids are in high demand at this stage for virion morphogenesis. Our results demonstrate that WSSV modulates lipid metabolism specifically at different stages to facilitate its replication.
A scalable sparse neural network framework for rare cell type annotation of single-cell transcriptome data
Authors: Cheng Yuqi , Fan Xingyu , Zhang Jianing , Li Yu
Published: May 2023

Automatic cell type annotation methods are increasingly used in single-cell RNA sequencing (scRNA-seq) analysis due to their fast and precise advantages. However, current methods often fail to account for the imbalance of scRNA-seq datasets and ignore information from smaller populations, leading to significant biological analysis errors. Here, we introduce scBalance, an integrated sparse neural network framework that incorporates adaptive weight sampling and dropout techniques for auto-annotation tasks. Using 20 scRNA-seq datasets with varying scales and degrees of imbalance, we demonstrate that scBalance outperforms current methods in both intra- and inter-dataset annotation tasks. Additionally, scBalance displays impressive scalability in identifying rare cell types in million-level datasets, as shown in the bronchoalveolar cell landscape. scBalance is also significantly faster than commonly used tools and comes in a user-friendly format, making it a superior tool for scRNA-seq analysis on the Python-based platform.
N6-methyladenosine helps Apostichopus japonicus resist Vibrio splendidus infection by targeting coelomocyte autophagy via the AjULK-AjYTHDF/AjEEF-1α axis
Authors: Liu Jiqing , Shao Yina , Li Dongdong , Li Chenghua
Published: May 2023

N6-Methyladenosine (m6A) modification is one of the most abundant post-transcriptional modifications that can mediate autophagy in various pathological processes. However, the functional role of m6A in autophagy regulation is not well-documented during Vibrio splendidus infection of Apostichopus japonicus. In this study, the inhibition of m6A level by knockdown of methyltransferase-like 3 (AjMETTL3) significantly decreased V. splendidus-induced coelomocyte autophagy and led to an increase in the intracellular V. splendidus burden. In this condition, Unc-51-like kinase 1 (AjULK) displayed the highest differential expression of m6A level. Moreover, knockdown of AjULK can reverse the V. splendidus-mediated autophagy in the condition of AjMETTL3 overexpression. Furthermore, knockdown of AjMETTL3 did not change the AjULK mRNA transcript levels but instead decreased protein levels. Additionally, YTH domain-containing family protein (AjYTHDF) was identified as a reader protein of AjULK and promoted AjULK expression in an m6A-dependent manner. Furthermore, the AjYTHDF-mediated AjULK expression depended on its interaction with translation elongation factor 1-alpha (AjEEF-1α). Altogether, our findings suggest that m6A is involved in resisting V. splendidus infection via facilitating coelomocyte autophagy in AjULK-AjYTHDF/AjEEF-1α-dependent manner, which provides a theoretical basis for disease prevention and therapy in A. japonicus.
ADME Optimization in Drug Discovery
Authors: McGinnity Dermot F. , Grime Ken
Published: May 2023

An acceptable human pharmacokinetic profile increases the probability of a promising candidate drug becoming a successful therapy. The development of a mechanistic understanding of the disposition of candidate drugs towards confident predictions of key properties associated with human drug absorption, metabolism, distribution and excretion (ADME) is critical. This is achievable from a consideration of physicochemical properties, data from in vitro assays with human-derived material and from in vivo animal studies. This chapter is targeted at medicinal chemists and drug design teams and provides general definitions of the fundamental PK parameters together with best practice characterization, optimization and prediction strategies employed in the authors' laboratory.
Molecular Biology for Medicinal Chemists
Authors: Ahmad N. M. , Bush E. , Nancolas B. , Macabuag N. , Racz P. I.
Published: May 2023

Molecular biology has become unavoidable in almost all the different fields of biological science. After 1953, when Watson and Crick created the model for the DNA double helix, scientists started to annotate the genome to understand it more fully, for example, how the information encoded in our genes translated to phenotypic appearances. They aimed to find answers to questions such as: how were the different genes regulated or interacted with each other? How were the different genes transcribed onto messenger molecules to enable translation of the genomic code into native protein? What were the different roles for the proteins, what type of signal transduction system were they playing a role in? This interest was further fuelled after 2000 when the human genome was sequenced and became available to everyone. This chapter will guide you through the brief history of molecular biology, provide a general overview of the basic methods to study the different cellular mechanisms and highlight some of the applications which are currently in use during drug discovery research.
Assays
Authors: Saxty Barbara , Coombs Peter J.
Published: May 2023

Identification of a disease-relevant target is the first step in drug discovery. The target and disease are then central to the design of a series of assays (assay cascade) against which compounds can be assessed for progression through the drug discovery process. Given the desired outputs and known variables, the principles of assay design and development are relatively simple. They are to build an assay that reliably estimates the activity of compounds whilst retaining a link to the disease biology and to have this assay run as often as is required to enable quick decision making. Project assay cascades typically begin with simple biochemical tests. As compounds are developed, the assays become more physiologically relevant and pharmacologically predictive. When data divergence becomes apparent, the use of orthogonal assays, even if in themselves they are not better than the primary read out, can offer the researcher insights into the mechanism of action for the selection of the best series to progress. This chapter gives an overview of commonly used assay formats in drug discovery cascades, highlighting their strengths and weaknesses and where they might be most effectively used.
In VitroBiology: Measuring Pharmacological Activity that Will Translate to Clinical Efficacy
Authors: Dougall Iain G. , Grimley Rachel L. , Strömstedt Per Erik
Published: May 2023

The creation of a candidate drug molecule is very complex and involves multiple cycles of different assays and tests across diverse scientific disciplines. Attrition is generally high, and currently only 10–20% of all drug discovery projects result in a novel drug. A leading cause of attrition is poor efficacy, which is often only discovered late when entering human trials. Therefore early, translatable assessment of whether the candidate molecule will modulate the target of interest in a safe and effective manner is critical. A key aspect of this assessment (which is sometimes not given the focus that is warranted) is the generation of detailed knowledge of the interaction between drug molecules and targets, and how this translates to disease modulation. In this chapter we will look at how quantitative in vitro pharmacology and mechanistic enzymology methods can be applied to characterize the action of novel compounds in terms of potency, specificity and deeper understanding of mechanisms of action, with reference to specific examples. A detailed knowledge of the drug–target interactions from the molecular to the cellular level enables better prediction of efficacy and safety and contributes to mechanistic PKPD modelling to aid dose setting and translation through to patients.
Patents for Medicines
Authors: Brady Paul A. , Cook Andrew
Published: May 2023

The cost of developing a medicine is huge: generally over $1.5 billion. In contrast, the cost of manufacturing the medicine is small, sometimes just a few dollars or even a few cents per unit dose. The profit margin on the sales price of the medicine thus needs to be high, in order to enable the drug originator to recoup the massive cost of developing the medicine. The sales price can only be maintained if the medicine is on the market with no direct competition. Once there is competition on price, the sales price of the medicine collapses. All of the costs of the development of the drug must be recouped before that price collapse, and patents are the main tool that a drug originator has to maintain its exclusivity. Patents are thus key to the viability of a drug development company as a business. It is vital that scientists working in drug discovery gain a good working knowledge of the patent system, both to avoid costly errors, and to help flag inventions when they are made. This chapter aims to give an insight into what patents are, what they can do, and how they are obtained and used.
Target Validation for Medicinal Chemists
Authors: Thomas Matthew , Ewart Lorna
Published: May 2023

Here we explore the essential elements of novel target identification and validation in the modern era of drug discovery. We discuss the utility of in vitro and in vivo technologies in the search and deconvolution of first-in-class targets, the opportunities each can provide when used effectively, and the challenges each represent. We consider the steps which bridge validation of a target and the initiation of drug discovery. We also explore the risks carried into the drug discovery process and how more advanced chemical matter can continue to build the validation package. Each section is supported by real-world examples in which such technologies have enabled novel target validation. We also provide a case study to illustrate target validation concepts throughout the life of a drug discovery project.
Lead Generation
Authors: Narjes Frank , Pairaudeau Garry , Petrović Dušan
Published: May 2023

The lead generation phase is the stage in early drug discovery that refers to the process of identifying hit molecules that interact with the desired target, followed by a limited optimisation of those hits. During this period the project aims to identify high-quality chemical tools suitable for advanced cellular and in vivo studies which will help to strengthen the validation of the target and increase confidence in the proposed therapeutic hypothesis. This chapter gives an overview of the major hit finding approaches together with their strengths and limitations. The process of hit profiling and hit selection, as well as hit expansion, are illustrated, and complications that can be encountered during this initial phase are highlighted. The advantage of using an integrated lead generation strategy is emphasised. A well-defined lead generation strategy, where two or more complementary hit finding approaches are executed in parallel, combined with a screening cascade containing relevant biological assays, will often result in the identification of structurally diverse lead series, leading ultimately to successful clinical candidates.
Clinical Drug Development
Authors: Kraan Maarten
Published: May 2023

Clinical drug development has changed significantly over the past decades. Supported by great advances in the discovery phase, it has enabled a plethora of options and opportunities to capture the clinical benefits and risks associated with the administration of these compounds in all disease areas. An overview of types of clinical trials, different phases of drug development, targeted drugs/companion diagnostics and biomarkers, and various basic considerations/principles will provide the reader with a peek into the options and considerations during the clinical phase of development of a pharmaceutical intervention.
Medicinal Chemistry for Neglected Diseases – Malaria, Tuberculosis, Sleeping Sickness, Leishmaniasis and River Blindness
Authors: Burrows Jeremy N. , Cooper Christopher B. , Mowbray Charles , Sjö Peter
Published: May 2023

Not every life-threatening or debilitating disease has a sufficient armoury of therapies available nor a pipeline of future products to combat the remaining unmet areas of medical need. This is particularly so in the areas of infectious diseases affecting, disproportionately, those in low- and middle-income countries where market forces, namely the inability to recoup research and development costs through sales, disincentivises new discovery and product innovation. This is further exacerbated by the inevitable challenges of resistance to anti-infectious agents and thus their controlled and careful use only in cases of need. The Medicines for Malaria Venture (MMV), the Global Alliance for TB Drug Development (GATB) and Drugs for Neglected Diseases initiative (DNDi) are Product Development Partnerships that were created to address this market failure as donor-funded organisations seeking to deliver the medicines of the future for malaria, tuberculosis and many neglected tropical diseases. The science of drug discovery, despite the resource constraints, remains unchanged from commercial therapeutic areas and MMV, GATB and DNDi work with partners globally applying state-of-the-art medicinal chemistry and thinking to diseases that affect over 250 million symptomatic disease episodes each year. The discovery strategies in each disease will be illustrated with case studies that have progressed into clinical development.
New Therapeutic Chemical Modalities: Compositions, Modes-of-action, and Drug Discovery
Authors: Valeur Eric
Published: May 2023

Over the last decade, the landscape of therapeutic modalities has been deeply transformed by the development of novel chemical classes challenging the supremacy of small molecules and antibodies/biologics. Many of these New Modalities have now reached clinical stage or even market and have demonstrated the opportunity to modulate therapeutic targets through additional modes-of-action and through intervention at the DNA and RNA level beyond the classical protein level. This chapter describes the different chemical classes that make New Modalities either as single entities or as homo- or hetero-fusion and -conjugation and their associated modes-of-action. The discovery of starting of points and property optimisation is then described, focusing on the most advanced modalities, leading finally to a framework for modality selection. Overall, medicinal chemists have now access to an extended set of drug modalities to modulate biology, and even rewire biological processes with approaches such as chemically induced proximity, and this chapter serves as a guide to navigate through this exciting field.
Introduction and Overview
Authors: Blackburn G. Michael , Egli Martin , Gait Michael J. , Watts Jonathan K.
Published: May 2023

For over 60 years, we have been fascinated and stimulated by their awareness that the study of nucleic acids is central to the knowledge of life. This chapter looks at the biological importance of DNA, the origins of nucleic acids research, early structural studies on nucleic acids and also the discovery of the structure of DNA. It then focuses on the advent of molecular biology, the partnership of chemistry and biology and then the world of RNA. The chapter concludes with a section on frontiers in nucleic acid research.
Noncoding RNA
Authors: Younger Scott T.
Published: May 2023

The human genome is composed of roughly 20 000 genes that are transcribed into messenger RNAs and subsequently translated into protein products. These protein-coding genes comprise 1–2% of the sequence space in the human genome. The remaining 98% of the genome was long believed to be devoid of meaningful information and often referred to as ‘junk DNA’. However, the developments and applications of powerful genomic technologies over the past decade have illuminated a wide variety of previously unappreciated regulatory aspects of the noncoding genome. One notable observation facilitated by advances in high-throughput transcriptome profiling is that the vast majority of the human genome is transcribed into RNA. The RNA produced from noncoding regions of the genome is collectively termed noncoding RNA. Noncoding RNAs come in all shapes and sizes and they play diverse roles in the regulation of gene expression. This chapter provides an overview of several different classes of noncoding RNAs including the details of their initial discovery, the mechanisms through which they regulate gene expression and their biogenesis pathways.
In Vitro Evolution and Aptamers
Authors: de Franciscis Vittorio , Mayer Günter , Giangrande Paloma H.
Published: May 2023

We present here the fundamentals of aptamer selection, beginning with the original in vitro systematic evolution of ligands by exponential enrichment (SELEX) protocol, first described in 1990, and culminating in recent advances in aptamer selection methodologies that have fast-tracked the development of aptamers for several research and therapeutic applications. These include advances in chemistries to impart stability and reduce toxicity, methodologies that have enabled the identification of aptamers to more complex targets and novel technologies such as next-generation sequencing (NGS), to fast-track the selection process and to provide a more complete in silico analysis of aptamer sequence families and their functional properties. We have highlighted applications of aptamers as research tools and as unique reagents for diagnostic and therapeutic applications. We have concluded this survey with an overview of those aptamers that have undergone clinical development and/or evaluation and have discussed the applications of this new class of chemically-modified oligonucleotides as potential diagnostics and therapeutics for a variety of clinical indications. We believe that aptamers constitute a research field with great potential for future advances.
Covalent Modifications of Nucleic Acids and Their Repair
Authors: Blackburn G. Michael
Published: May 2023

The main DNA repair processes in humans involve direct repair (DR), base excision repair (BER), nucleotide excision repair (NER), interstrand crosslink repair (ICR) and base mismatch repair (BMR), as have been described in other chapters, in addition to homologous recombination (HR) and non-homologous end-joining (NHEJ). Studies on human repair systems have advanced rapidly, especially into UV damage, and recent studies have shown that human DNA polymerase η (Pol η) modulates susceptibility to skin cancer by promoting DNA synthesis past sunlight-induced cyclobutane pyrimidine dimers that have escaped nucleotide excision repair (NER). This bypass has low fidelity, meaning that in normal people, and especially in individuals with xeroderma pigmentosum who accumulate photodimers because they are NER-defective, the errors made by Pol η during dimer bypass may contribute to mutagenesis and to skin cancer. The depth of understanding that is now being achieved on the covalent modification of nucleic acids is awesome, both for adventitious (exogenous) and evolutionarily evolved (endogenous) modification. It is uncovering new questions and posing new challenges. A clear manifestation of this is the range of targets that have now been explored using cutting-edge methodologies that were unimaginable in earlier years. Above all, the advances made have brought us face-to-face with the amazing complexity of repair systems for our nucleic acids that supremely have made viable life on our planet.
Chemistry for Sustainable Technologies: A Foundation
Authors: Winterton Neil
Published: May 2023

Following the success of the first edition, this fully updated and revised book continues to provide an interdisciplinary introduction to sustainability issues in the context of chemistry and chemical technology. Its prime objective is to equip young chemists (and others) to more fully to appreciate, defend and promote the role that chemistry and its practitioners play in moving towards a society better able to control, manage and ameliorate its impact on the ecosphere. To do this, it is necessary to set the ideas, concepts, achievements and challenges of chemistry and its application in the context of its environmental impact, past, present and future, and of the changes needed to bring about a more sustainable yet equitable world.

Progress since 2010 is reflected by the inclusion of the latest research and thinking, selected and discussed to put the advances concisely in a much wider setting – historic, scientific, technological, intellectual and societal. The treatment also examines the complexities and additional challenges arising from public and media attitudes to science and technology and associated controversies and from the difficulties in reconciling environmental protection and global development.

While the book stresses the central importance of rigour in the collection and treatment of evidence and reason in decision-making, to ensure that it meets the needs of an extensive community of students, it is broad in scope, rather than deep. It is, therefore, appropriate for a wide audience, including all practising scientists and technologists.
Polymer Structure Characterization: From Nano to Macro Organization in Small Molecules and Polymers
Authors: Pethrick Richard A
Published: May 2023

The different physical properties displayed by low molar mass organic materials and polymers are a result of their molecular organisation. In order to understand the structure – property relationship of a material it is necessary to first look at the interactions at a molecular level. This new edition of Polymer Structure Characterization provides readers with the background needed to understand the factors that influence molecular organization and how this affects the morphology and bulk physical properties of a material.

In order to introduce the concepts, the book first looks at small molecular systems and builds up to complex macromolecular systems. The second edition has been fully revised and updated to include new examples and references. Topics covered include: organic crystals, liquid crystals, plastic crystals, polymer crystal growth, amorphous glassy materials, polymer surfaces and interfaces, colloids and molecular organization in liquids as well as two new chapters on self-assembly and biopolymer systems.

The book is intended to provide complimentary material for a range of undergraduate and postgraduate courses in materials science, molecular chemistry and chemical physics. In addition to polymer and material scientists, the book would also be of interest to chemists and physicists studying the properties of organic materials.
Green Chemistry: Principles and Case Studies
Authors: Etzkorn Felicia A
Published: May 2023

Green chemistry as a discipline is gaining increasing attention globally, with environmentally conscious students keen to learn how they can contribute to a safer and more sustainable world. Many universities now offer courses or modules specifically on green chemistry – Green Chemistry: Principles and Case Studies is an essential learning resource for those interested in mastering the subject.

Providing a comprehensive overview of the concepts of green chemistry this book engages students with a thorough understanding of what we mean by green chemistry and how it can be put into practice. Structured around the well-known 12 Principles, and firmly grounded in real-world applications and case-studies, this book shows how green chemistry is already being put into practice and prepare them to think about how they can be incorporated into their own work.

Targeted at advanced undergraduate and first-year graduate students with a background in general and organic chemistry, it is a useful resource both for students and for teachers looking to develop new courses.
History of Catalysis
Authors: Moulijn Jacob A. , van Santen Rutger A.
Published: May 2023

Catalysis has a rich history. At the end of the 19th century, catalysis emerged as a scientific discipline in harmony with industrial applications. In this chapter, the history of catalysis will be presented with a flavour of practical applications and a focus on heterogeneous (chemo)catalysis. A chronological table of the major discoveries in the field clearly shows the exciting journey to the present well-developed catalysis discipline.
Current Challenges in Catalysis
Authors: Vogt Dieter , Westwood Nicholas J.
Published: May 2023

As catalysis spans a wide range and involves many disciplines, this chapter does not aim to line out all current challenges. Many of those challenges are related to environmental issues and the urgent need for more sustainable production methods, next to important persisting fundamental questions. We want to create the mindset that is needed to tackle those challenges and give examples of recent developments. A common feature is the integration of knowledge and disciplines that goes along with vanishing disciplinary boundaries that, anyway, only exist in our heads.
Organometallic Chemistry and Elementary Steps
Authors: van Leeuwen Piet W. N. M.
Published: May 2023

The entire science of chemistry can be thought of as the underlying knowledge of catalysis, since each conversion can be subjected to catalysis, each material might function as a catalyst, each spectroscopic technique may prove useful one day in catalysis, and catalytic processes are amongst the most intriguing theoretical targets. Yet, in only a small number of pages, we will outline here what we think are the key underlying principles for catalysis. The organometallic chemistry we discuss in this chapter deals with the most often used concepts of chemical bonding related to catalysis and the organometallic reactions most frequently encountered in mechanistic treatments of catalytic reactions. For an elaborate treatment of elementary steps, the reader is referred to a specialized textbook. As the title suggests, we will mainly deal with homogeneous processes, but the same elementary reactions can also take place at the surface of solid catalysts or nanoparticles. In particular, metals or metal carbides show additional reactions that have no close analogues in organometallic chemistry, such as the dissociation of adsorbed CO in Fe or iron carbide catalysts.
Thermodynamics and Kinetics
Authors: Wilde Nicole , Gläser Roger
Published: May 2023

Thermodynamics and kinetics build the physico-chemical fundamentals for the quantitative description of chemical reactions. Hence, they are at the heart of chemical and engineering science and applications as a whole and, of course, include and govern catalytic reactions as well. In the present chapter, the most important basic principles of chemical thermodynamics are briefly presented and the relevance to catalysis is emphasized. Besides treatment of the chemical equilibrium, examples for applications in reaction engineering, mostly with respect to optimizing the maximum achievable conversion are given. In a second part, the kinetics of chemical reactions are first treated on a general level. After introducing the reaction rate, parameters for catalytic activity and stability are described. Finally, two examples for specific cases of catalytic kinetics, i.e., the Langmuir–Hinshelwood–Hougen–Watson approach and the Michaelis–Menten kinetics are presented.
Computational Catalysis
Authors: Macgregor Stuart A. , Bühl Michael , Hensen Emiel J. M.
Published: May 2023

A review on applications of computational chemistry in homogeneous, enzymatic and heterogeneous catalysis is presented. After a non-technical introduction into the methodological toolkit of computational chemistry (methods based on molecular and/or quantum mechanics, practical aspects of calculations), selected examples from the literature are discussed. These comprise, among others, density functional theory calculations for homogeneous metal-catalysed C–C coupling reactions, cytochrome P450 chemistry and Fischer–Tropsch reactions on solid metal catalysts.
Transition Metal Complexes and Ligand Synthesis
Authors: Nelson David J. , Nolan Steven P.
Published: May 2023

This chapter considers the ways in which N-heterocyclic carbenes and phosphines can be prepared from readily-available starting materials. The synthesis of complexes of these ligands, based on metals such as iridium, platinum, ruthenium, chromium, palladium, copper and gold, is also discussed. These species are useful for various transformations, including hydroformylation, metathesis, cross-coupling, and alkene oligomerisation.
Advanced Solution Spectroscopic Techniques
Authors: Iggo Jonathan A. , Parry Alice
Published: May 2023

The word ‘spectroscopy’ is derived from the Latin spectrum meaning ‘image’ or ‘apparition’ and the Greek skopéō meaning ‘to see’. Solution based spectroscopies can be used individually or in combination to ‘see’ the species present in a reaction solution and so aid us in the elucidation of reaction mechanisms and the development of catalyst structure–property relationships. This chapter aims to provide an overview of the available spectroscopic and spectrometric techniques for such studies – NMR, ESR, IR, Raman, UV/Vis and XAS spectroscopies and mass spectrometry – drawing on examples from the literature to illustrate the scope and limitations of each technique.
X-Ray Photoelectron Spectroscopy
Authors: Lee Adam F. , Parlett Christopher M. A. , Wilson Karen
Published: May 2023

X-ray photoelectron spectroscopy (XPS) is a key tool for the quantitative analysis of surface composition and oxidation state, and universally employed in academic and commercial settings to improve the design of heterogeneous catalysts. This section outlines the principles and application of XPS as a versatile, chemically specific analytical tool to determine the electronic structure and near surface composition of constituent elements within industrially relevant catalytic materials.
Adsorption Methods
Authors: Lee Adam F. , Parlett Christopher M. A. , Wilson Karen
Published: May 2023

The adsorption of molecules on a surface at constant temperature and pressure results in a decrease in the system entropy; thus, the enthalpy of adsorption must be negative (exothermic) to be spontaneous (i.e. Gibbs free energy ≤ 0). Gas surface collisions are either elastic, with no interaction, or inelastic, the latter being exothermic via energy transfer from the adsorbate to the adsorbent. If the energy loss is sufficient to forbid spontaneous desorption, yet no reaction occurs to form chemical bonds, adsorption is classed as physisorption. Chemisorption involves the formation of a chemical bond between the surface and the adsorbate; thus, as this involves the formation of a molecular orbital between the surface atom and the incoming molecule/atom, the resulting chemisorbed species will saturate at the monolayer. This chapter will cover both physisorption and chemisorption and the techniques employed in their analysis.
Reaction and Reactor Engineering
Authors: Lauwaert Jeroen , Thybaut Joris W. , Goguet Alexandre , Hardacre Christopher , Ola Oluwafunmilola , Maroto-Valer Mercedes
Published: May 2023

Chemical engineering aims, on the one hand, at simulating and predicting phenomena with respect to chemical reactions, such as intrinsic reaction kinetics, mass transport, sorption effects, thermodynamic and hydrodynamic phenomena and, on the other hand, at the design, construction, and optimization of the corresponding reactors in which these reactions are performed. The present chapter starts with explaining how intrinsic reaction rates of chemical transformations occurring on a heterogeneous catalyst surface may be disguised by mass and heat transfer phenomena and how the occurrence of such limitations can be diagnosed. Subsequently, adsorption phenomena are described and it is explained how to account for them in a kinetic model. The third section of this chapter comprises a strategy to extrapolate gas phase kinetics towards liquid or three-phase reactions envisaging the up-scaling from ideal laboratory scale conditions to realistic commercial applications. Next, the focus moves from reaction towards reactor engineering. First, the traditional reactor types, i.e., batch, semi-batch, plug flow, and continuous stirred tank reactors, are discussed. Subsequently, microreactors, which are characterized by a much larger surface-to-volume ratio and, hence, exhibit an enhanced mass and heat transfer, are discussed. Finally, various methods of energy input are reported. Some specific reactor types such as monolith and membrane reactors, which are able to dramatically decrease the pressure drop, are discussed in more detail in the fifth section. The final section of this chapter aims at reactor and process design. It starts with a discussion on the hierarchical design strategy of chemical processes. Subsequently, reactor selection based on the specific boundaries of the indented application is addressed. The chapter wraps up with a discussion on the phenomena that should be accounted for while designing the selected reactor, i.e., capillary condensation, the catalyst wetting efficiency, the flow regime, and axial and radial dispersion.