bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of fulvestrant plus enzalutamide in ER+/HER2− advanced breast cancer
Authors: Elias Anthony D. , Spoelstra Nicole S. , Staley Alyse W. , Sams Sharon , Crump Lyndsey S. , Vidal Gregory A. , Borges Virginia F. , Kabos Peter , Diamond Jennifer R. , Shagisultanova Elena , Afghahi Anosheh , Mayordomo Jose , McSpadden Tessa , Crawford Gloria , D’Alessandro Angelo , Zolman Kathryn L. , van Bokhoven Adrie , Zhuang Yonghua , Gallagher Rosa I. , Wulfkuhle Julia D. , Petricoin III Emanuel F. , Gao Dexiang , Richer Jennifer K.
Published: May 2023

This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2− breast cancer (BC). Eligible patients were women with ECOG 0–2, ER+/HER2− measurable or evaluable metastatic BC. Prior fulvestrant was allowed. Fulvestrant was administered at 500 mg IM on days 1, 15, 29, and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily. Fresh tumor biopsies were required at study entry and after 4 weeks of treatment. The primary efficacy endpoint of the trial was the clinical benefit rate at 24 weeks (CBR24). The median age was 61 years (46–87); PS 1 (0–1); median of 4 prior non-hormonal and 3 prior hormonal therapies for metastatic disease. Twelve had prior fulvestrant, and 91% had visceral disease. CBR24 was 25% (7/28 evaluable). Median progression-free survival (PFS) was 8 weeks (95% CI: 2–52). Adverse events were as expected for hormonal therapy. Significant (p < 0.1) univariate relationships existed between PFS and ER%, AR%, and PIK3CA and/or PTEN mutations. Baseline levels of phospho-proteins in the mTOR pathway were more highly expressed in biopsies of patients with shorter PFS. Fulvestrant plus enzalutamide had manageable side effects. The primary endpoint of CBR24 was 25% in heavily pretreated metastatic ER+/HER2− BC. Short PFS was associated with activation of the mTOR pathway, and PIK3CA and/or PTEN mutations were associated with an increased hazard of progression. Thus, a combination of fulvestrant or other SERD plus AKT/PI3K/mTOR inhibitor with or without AR inhibition warrants investigation in second-line endocrine therapy of metastatic ER+ BC.
A superior extracellular matrix binding motif to enhance the regenerative activity and safety of therapeutic proteins
Authors: Alshoubaki Yasmin K. , Lu Yen-Zhen , Legrand Julien M. D. , Karami Rezvan , Fossat Mathilde , Salimova Ekaterina , Julier Ziad , Martino Mikaël M.
Published: May 2023

Among therapeutic proteins, cytokines and growth factors have great potential for regenerative medicine applications. However, these molecules have encountered limited clinical success due to low effectiveness and major safety concerns, highlighting the need to develop better approaches that increase efficacy and safety. Promising approaches leverage how the extracellular matrix (ECM) controls the activity of these molecules during tissue healing. Using a protein motif screening strategy, we discovered that amphiregulin possesses an exceptionally strong binding motif for ECM components. We used this motif to confer the pro-regenerative therapeutics platelet-derived growth factor-BB (PDGF-BB) and interleukin-1 receptor antagonist (IL-1Ra) a very high affinity to the ECM. In mouse models, the approach considerably extended tissue retention of the engineered therapeutics and reduced leakage in the circulation. Prolonged retention and minimal systemic diffusion of engineered PDGF-BB abolished the tumour growth-promoting adverse effect that was observed with wild-type PDGF-BB. Moreover, engineered PDGF-BB was substantially more effective at promoting diabetic wound healing and regeneration after volumetric muscle loss, compared to wild-type PDGF-BB. Finally, while local or systemic delivery of wild-type IL-1Ra showed minor effects, intramyocardial delivery of engineered IL-1Ra enhanced cardiac repair after myocardial infarction by limiting cardiomyocyte death and fibrosis. This engineering strategy highlights the key importance of exploiting interactions between ECM and therapeutic proteins for developing effective and safer regenerative therapies.
Nicotinamide ameliorates mitochondria-related neuronal apoptosis and cognitive impairment via the NAD+/SIRT3 pathway
Authors: Hao Keke , Chen Fashuai , Zhao Linyao , Xu Shilin , Xiong Ying , Xu Rui , Xie Xinhui , Huang Huan , Shu Chang , Liu Zhongchun , Wang Huiling , Wang Gaohua
Published: May 2023

Emerging evidence suggests that mitochondria play a central role in mental health disorders including schizophrenia. Here we investigated whether nicotinamide (NAM) normalized cognitive impairment via a mechanism involving the mitochondrial Sirtuin 3 (SIRT3) pathway. The 24 h maternal separation (MS) rat model was used to mimic schizophrenia-associate phenotypes. Schizophrenia-like behaviors and memory impairments were detected using the pre-pulse inhibition test, novel object recognition test, and Barnes maze test, and neuronal apoptosis was characterized using multiple assays. SIRT3 activity was inhibited pharmacologically or by knockdown in HT22 cells, and BV2 microglia and SIRT3-knockdown HT22 cells were co-cultured in vitro. Mitochondrial molecules were measured by western blotting, and mitochondrial damage was measured with reactive oxygen species and mitochondrial membrane potential assays. Proinflammatory cytokines were assayed by ELISA and microglial activation was detected by immunofluorescence. MS animals showed behavioral and cognitive impairment and increased neuronal apoptosis. Supplementation with NAM or administration of honokiol, a SIRT3 activator, reversed all of the changes in behavioral and neuronal phenotypes. Administration of the SIRT3 inhibitor 3-TYP in control and NAM-treated MS rats caused behavioral and neuronal phenotypes similar to MS. In vitro, inhibition of SIRT3 activity with 3-TYP or by knockdown in HT22 cells increased ROS accumulation and caused neuronal apoptosis in a single-culture system. In co-culture systems, SIRT3 knockdown in HT22 cells activated BV2 microglia and increased levels of TNF-α, IL-6, and IL-1β. The administration of NAM blocked these alterations. Taken together, these data suggest that NAM can rescue neuronal apoptosis and microglial over-activation through the nicotinamide adenine dinucleotide (NAD+)-SIRT3-SOD2 signaling pathway, furthering our understanding of the pathogenesis of schizophrenia and providing avenues for novel treatments.
Computational methods of EEG signals analysis for Alzheimer’s disease classification
Authors: Vicchietti Mário L. , Ramos Fernando M. , Betting Luiz E. , Campanharo Andriana S. L. O.
Published: May 2023

Computational analysis of electroencephalographic (EEG) signals have shown promising results in detecting brain disorders, such as Alzheimer’s disease (AD). AD is a progressive neurological illness that causes neuron cells degeneration, resulting in cognitive impairment. While there is no cure for AD, early diagnosis is critical to improving the quality of life of affected individuals. Here, we apply six computational time-series analysis methods (wavelet coherence, fractal dimension, quadratic entropy, wavelet energy, quantile graphs and visibility graphs) to EEG records from 160 AD patients and 24 healthy controls. Results from raw and wavelet-filtered (alpha, beta, theta and delta bands) EEG signals show that some of the time-series analysis methods tested here, such as wavelet coherence and quantile graphs, can robustly discriminate between AD patients from elderly healthy subjects. They represent a promising non-invasive and low-cost approach to the AD detection in elderly patients.
Small intestinal microbiota composition altered in obesity-T2DM mice with high salt fed
Authors: Kerem Goher , Yu Xiangfang , Ismayi Aynur , Teng Bin , Udduttula Anjaneyulu , Liu Chang , Yu Zhongjia , Tohty Dilbar , Zhang Jian V. , Ren Pei-Gen
Published: May 2023

Obesity has become a global concern because of increasing the risk of many diseases. Alterations in human gut microbiota have been proven to be associated with obesity, yet the mechanism of how the microbiota are altered by high salt diet (HSD) remains obscure. In this study, the changes of Small Intestinal Microbiota (SIM) in obesity-T2DM mice were investigated. High-throughput sequencing was applied for the jejunum microbiota analysis. Results revealed that high salt intake (HS) could suppress the body weight (B.W.) in some extent. In addition, significant T2DM pathological features were revealed in high salt-high fat diet (HS-HFD) group, despite of relatively lower food intake. High-throughput sequencing analysis indicated that the F/B ratio in HS intake groups increased significantly (P < 0.001), whereas beneficial bacteria, such as lactic acid or short chain fatty acid producing bacteria, were significantly decreased in HS-HFD group (P < 0.01 or P < 0.05). Furthermore, Halorubrum luteum were observed in small intestine for the first time. Above results preliminary suggested that in obesity-T2DM mice, high dietary salt could aggravate the imbalance of composition of SIM to unhealthy direction.
Clinicopathologic characteristics of second primary squamous cell carcinoma in patients with nasopharyngeal carcinoma after intensity-modulated radiotherapy
Authors: Wang Xi , Wang Shunlan , Cao Yang , Li Chunqiao , Fang Caishan , He Weiping , Guo Zhuming
Published: May 2023

To compare the clinicopathologic characteristics of second primary squamous cell carcinoma (SPSCC) in patients with nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy (IMRT) with that after radiotherapy (RT). From 49,021 patients with NPC who treated by definitive RT, we were able to identify 15 male patients with SPSCC after IMRT, and 23 male patients with SPSCC after RT. We examined the difference between groups. In IMRT group, 50.33% developed SPSCC within 3 years, whereas 56.52% developed SPSCC after more than 10 years in RT group. Receiving IMRT was related positively to an increased risk of SPSCC (HR = 4.25; P < 0.001). There was no significant correlation between receiving IMRT and the survival of SPSCC (P = 0.051). Receiving IMRT was related positively to an increased risk of SPSCC, and the latency was much shorter. A follow-up protocol, especially in the first three years, should be designed for NPC patients with IMRT.
An intelligent fuzzy-particle swarm optimization supervisory-based control of robot manipulator for industrial welding applications
Authors: Sathish Kumar A. , Naveen S. , Vijayakumar R. , Suresh V. , Asary Abdul Rab , Madhu S. , Palani Kumaran
Published: May 2023

The propensity of manufacturers to produce goods at affordable cost, with more accuracy, and at a faster rate force them to search for novel solutions, such as deploying robots in place of people in a sector that can accommodate their needs. Welding is one of the most crucial processes in the automotive industry. This process is time-consuming, subject to error, and demands skilled professionals. The robotic application can improve this area of production and quality. Other industries, such as painting and material handling, can also profit from the use of robots. This work describes the fuzzy DC linear servo controller, which functions as a robotic arm actuator. Robots have been widely employed in most productive sectors in recent years, including assembly plates, welding, tasks at higher temperatures, etc. Controlling a robot accurately is a difficult undertaking as a robot is very nonlinear with many joints that are often organized and unstructured. To carry out the effective task, an effective PID control based on fuzzy logic has been employed together with the method of Particle Swarm Optimization (PSO) approach for the estimate of the parameter. This offline technique determines the lowest number of optimal robotic arm control parameters. To verify the controller design with computer simulation, a comparative assessment of controllers is given by means of a fuzzy surveillance controller with PSO which improves the parameter gain to provide a rapid climb, a smaller overflow, no steady condition error signal, and effective torque control of the robot arm.
Noninvasive ventilation in patients with acute hypoxemic respiratory failure: a systematic review and meta-analysis of randomized controlled trials
Authors: Aswanetmanee Pantaree , Limsuwat Chok , Maneechotesuwan Kittipong , Wongsurakiat Phunsup
Published: May 2023

The clinical benefits of noninvasive ventilation (NIV) for patients with acute hypoxemic respiratory failure (AHRF) is still inconclusive. We aimed to evaluate the effect of NIV compared with conventional oxygen therapy (COT)/high-flow nasal cannula (HFNC) in this patient population. We searched for relevant studies from PubMed, Embase, Cochrane Library, ClinicalTrials.gov, CINHAL, Web of Science up to August 2019 for randomized controlled trials (RCTs) that compared NIV with COT/HFNC in AHRF. The primary outcome was the tracheal intubation rate. Secondary outcomes were intensive care unit (ICU) mortality, and hospital mortality. We applied the GRADE approach to grade the strength of the evidence. Seventeen RCTs that recruited 1738 patients were included in our meta-analysis. When comparing NIV versus COT/HFNC, the pooled risk ratio (RR) for the tracheal intubation rate was 0.68, 95% confidence interval (CI) 0.52–0.89, p = 0.005, I2 = 72.4%, low certainty of evidence. There were no significant differences in ICU mortality (pooled RR = 0.87, 95% CI 0.60–1.26), p = 0.45, I2 = 64.6%) and hospital mortality (pooled RR = 0.71, 95% CI 0.51–1.00, p = 0.05, I2 = 27.4%). Subgroup analysis revealed that NIV application with helmet was significantly associated with a lower intubation rate than NIV with face mask. NIV did not show a significant reduction in intubation rate compared to HFNC. In conclusion, NIV application in patients with medical illness and AHRF was associated with a lower risk of tracheal intubation compared to COT. NIV with helmet and HFNC are promising strategies to avoid tracheal intubation in this patient population and warrant further studies. NIV application had no effect on mortality.

The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42018087342).
Optimizing maternal and neonatal outcomes through tight control management of inflammatory bowel disease during pregnancy: a pilot feasibility study
Authors: Jogendran Rohit , O’Connor Katie , Jeyakumar Ajani , Tandon Parul , Nguyen Geoffrey C. , Maxwell Cynthia , Huang Vivian
Published: May 2023

A home point-of care FCP test (IBDoc) and a self-reported clinical disease activity program (IBD Dashboard) may improve routine monitoring of IBD activity during pregnancy. We aimed to evaluate the feasibility of tight control management using remote monitoring in pregnant patients with IBD. Pregnant patients (< 20 weeks) with IBD were prospectively enrolled from Mount Sinai Hospital between 2019 and 2020. Patients completed the IBDoc and IBD Dashboard at three core time points. Disease activity was measured clinically using the Harvey–Bradshaw Index (mHBI) for CD and partial Mayo (pMayo) for UC, or objectively using FCP. A feasibility questionnaire was completed in the third trimester. Seventy-seven percent of patients (24 of 31) completed the IBDoc and IBD Dashboard at all core time points. Twenty-four patients completed the feasibility questionnaires. All survey respondents strongly preferred using the IBDoc over standard lab-based testing and would use the home kit in the future. Exploratory analysis identified discordance rates of more than 50% between clinical and objective disease activity. Tight control management using remote monitoring may be feasible among pregnant patients with IBD. A combination of both clinical scores and objective disease markers may better predict disease activity.
The change in metabolic activity of a large benthic foraminifera as a function of light supply
Authors: Lintner Michael , Lintner Bianca , Schagerl Michael , Wanek Wolfgang , Heinz Petra
Published: May 2023

We studied metabolic activity of the symbiont-bearing large benthic foraminifer Heterostegina depressa under different light conditions. Besides the overall photosynthetic performance of the photosymbionts estimated by means of variable fluorescence, the isotope uptake (13C and 15N) of the specimens (= holobionts) was measured. Heterostegina depressa was either incubated in darkness over a period of 15 days or exposed to an 16:8 h light:dark cycle mimicking natural light conditions. We found photosynthetic performance to be highly related to light supply. The photosymbionts, however, survived prolonged darkness and could be reactivated after 15 days of darkness. The same pattern was found in the isotope uptake of the holobionts. Based on these results, we propose that 13C-carbonate and 15N-nitrate assimilation is mainly controlled by the photosymbionts, whereas 15N-ammonium and 13C-glucose utilization is regulated by both, the symbiont and the host cells.
Immobilization of Cr3+, Cd2+, and Pb2+ added to calcareous soil amended with composted agro-industrial residues
Authors: Khedr Mai , Emran Mohamed , Gispert Maria , Rashad Mohamed
Published: May 2023

The bioavailability of trace metals in soils poses a major threat to the environment, especially with massive mineral fertilizers added to increase plant yield. A plot experiment was conducted for the effectiveness evaluation of compost and vermicompost, recycled from agro-industrial wastes, in immobilizing chromium, cadmium, and lead added to calcareous soil (artificially contaminated). Moreover, immobilization efficiency was compared to the natural occurrence of these metals in the soil without metal addition (uncontaminated soil). In both soils, amendments and mineral fertilizers were applied at three different levels alone and combined to each other. The experimental design was arranged in factorial complete randomized blocks using contamination, organic and mineral fertilizer levels, and their combination as categorical factors. The distribution of metal fractions and their bioavailability in soils and bioaccumulation in wheat grains were evaluated. Soil alkalinity, the contents of soil organic carbon and nitrogen, available phosphorus, and soil micronutrients were significantly improved under vermicompost and compost compared to mineral fertilizer and control. Vermicompost was more effective than compost in reducing metals bioavailability in contaminated soils by increasing the immobilized organic fractions, but it regressed when combined with mineral fertilizers. The bioavailability of the naturally occurring metal levels in uncontaminated soil did not change significantly compared to contaminated soil. Likewise, wheat yield, plant biomass, and nutrient enrichment in wheat grains improved due to enhanced soil nutrient availability. These composted agro-industrial residues, by-products from food industries, can be classified as environmentally-friendly soil amendments for their great potential to enrich soil nutrients, reduce mineral fertilizer addition, enhance plant growth, and stabilize Cr, Cd, and Pb in contaminated calcareous soils under wheat plants.
The potency of bacteriophages isolated from chicken intestine and beef tribe to control biofilm-forming bacteria, Bacillus subtilis
Authors: Wardani Agustin Krisna , Buana Efendi Oulan Gustav Hakim Nata , Sutrisno Aji
Published: May 2023

Biofilm becomes one of the crucial food safety problems in the food industry as the formation of biofilm can be a source of contamination. To deal with the problem, an industry generally employs physical and chemical methods including sanitizers, disinfectants, and antimicrobials to remove biofilm. However, the use of these methods may bring about new problems, which are bacterial resistance in the biofilm and the risk for product contamination. New strategies to deal with bacterial biofilms are needed. Bacteriophages (phages), as a green alternative to chemical, have re-emerged as a promising approach to treat bacterial biofilm. In the present study, the potential of lytic phages which have antibiofilm activity on biofilm-forming bacteria (Bacillus subtilis), were isolated from chicken intestines and beef tripe obtained from Indonesian traditional markets using host cells obtained isolated from these samples. Phages isolation was conducted by using double layer agar technique. A lytic test of phages was administered on biofilm-forming bacteria. The difference of turbidity level between control (which were not infected by phages) and the test tubes containing host bacteria infected by phages was investigated. The infection time for the production of phages was determined based on the level of clarity of the media in the test tube with a longer lysate addition time. Three phages were isolated namely: ϕBS6, ϕBS8, and ϕUA7. It showed the ability to inhibit B. subtilis as biofilm-forming spoilage bacteria. The best inhibition results were obtained from ϕBS6. Infection with ϕBS6 in B. subtilis lead to 0.5 log cycle decreased in bacterial cells. This study showed that isolated phages might be used as a potential approach for handling the problem of biofilm formation by B. subtilis.
Theory and rationale of interpretable all-in-one pattern discovery and disentanglement system
Authors: Wong Andrew K. C. , Zhou Pei-Yuan , Lee Annie E.-S.
Published: May 2023

In machine learning (ML), association patterns in the data, paths in decision trees, and weights between layers of the neural network are often entangled due to multiple underlying causes, thus masking the pattern-to-source relation, weakening prediction, and defying explanation. This paper presents a revolutionary ML paradigm: pattern discovery and disentanglement (PDD) that disentangles associations and provides an all-in-one knowledge system capable of (a) disentangling patterns to associate with distinct primary sources; (b) discovering rare/imbalanced groups, detecting anomalies and rectifying discrepancies to improve class association, pattern and entity clustering; and (c) organizing knowledge for statistically supported interpretability for causal exploration. Results from case studies have validated such capabilities. The explainable knowledge reveals pattern-source relations on entities, and underlying factors for causal inference, and clinical study and practice; thus, addressing the major concern of interpretability, trust, and reliability when applying ML to healthcare, which is a step towards closing the AI chasm.
Harnessing big data for health equity through a comprehensive public database and data collection framework
Authors: Sabet Cameron , Hammond Alessandro , Ravid Nim , Tong Michelle Sun , Stanford Fatima Cody
Published: May 2023

The United States Department of Health and Human Services (HHS) pledged $90 million to help reduce health disparities with data-driven solutions. The funds are being distributed to 1400 community health centers, serving over 30 million Americans. Given these developments, our piece examines the reasons behind the delayed adoption of big data for healthcare equity, recent efforts embracing big data tools, and methods to maximize potential without overburdening physicians. We additionally propose a public database for anonymized patient data, introducing diverse metrics and equitable data collection strategies, providing valuable insights for policymakers and health systems to better serve communities.
Repurposed inhibitor of bacterial dihydrodipicolinate reductase exhibits effective herbicidal activity
Authors: Mackie Emily R. R. , Barrow Andrew S. , Giel Marie-Claire , Hulett Mark D. , Gendall Anthony R. , Panjikar Santosh , Soares da Costa Tatiana P.
Published: May 2023

Herbicide resistance represents one of the biggest threats to our natural environment and agricultural sector. Thus, new herbicides are urgently needed to tackle the rise in herbicide-resistant weeds. Here, we employed a novel strategy to repurpose a ‘failed’ antibiotic into a new and target-specific herbicidal compound. Specifically, we identified an inhibitor of bacterial dihydrodipicolinate reductase (DHDPR), an enzyme involved in lysine biosynthesis in plants and bacteria, that exhibited no antibacterial activity but severely attenuated germination of the plant Arabidopsis thaliana. We confirmed that the inhibitor targets plant DHDPR orthologues in vitro, and exhibits no toxic effects against human cell lines. A series of analogues were then synthesised with improved efficacy in germination assays and against soil-grown A. thaliana. We also showed that our lead compound is the first lysine biosynthesis inhibitor with activity against both monocotyledonous and dicotyledonous weed species, by demonstrating its effectiveness at reducing the germination and growth of Lolium rigidum (rigid ryegrass) and Raphanus raphanistrum (wild radish). These results provide proof-of-concept that DHDPR inhibition may represent a much-needed new herbicide mode of action. Furthermore, this study exemplifies the untapped potential of repurposing ‘failed’ antibiotic scaffolds to fast-track the development of herbicide candidates targeting the respective plant enzymes.
Improving the visibility of minorities through network growth interventions
Authors: Neuhäuser Leonie , Karimi Fariba , Bachmann Jan , Strohmaier Markus , Schaub Michael T.
Published: May 2023

Improving the position of minority groups in networks through interventions is a challenge of high theoretical and societal importance. However, a systematic analysis of interventions that alter the network growth process is still missing. In this work, we propose a model to examine how network growth interventions impact the position of minority nodes in degree rankings over time. We distinguish between (i) group size interventions, such as introducing quotas; and (ii) behavioural interventions, such as varying how groups connect to each other. We find that even extreme quotas do not increase minority representation in rankings if the actors in the network do not adopt homophilic behaviour. Thus, interventions need to be coordinated in order to improve the visibility of minorities. In a real-world case study, we explore which interventions can reach gender parity in academia. Our work provides a theoretical and computational framework for investigating the effectiveness of interventions in growing networks.
Metabolic handoffs between multiple symbionts may benefit the deep-sea bathymodioline mussels
Authors: Zvi-Kedem Tal , Vintila Simina , Kleiner Manuel , Tchernov Dan , Rubin-Blum Maxim
Published: May 2023

Bathymodioline mussels rely on thiotrophic and/or methanotrophic chemosynthetic symbionts for nutrition, yet, secondary heterotrophic symbionts are often present and play an unknown role in the fitness of the organism. The bathymodioline Idas mussels that thrive in gas seeps and on sunken wood in the Mediterranean Sea and the Atlantic Ocean, host at least six symbiont lineages that often co-occur. These lineages include the primary symbionts chemosynthetic methane- and sulfur-oxidizing gammaproteobacteria, and the secondary symbionts, Methylophagaceae, Nitrincolaceae and Flavobacteriaceae, whose physiology and metabolism are obscure. Little is known about if and how these symbionts interact or exchange metabolites. Here we curated metagenome-assembled genomes of Idas modiolaeformis symbionts and used genome-centered metatranscriptomics and metaproteomics to assess key symbiont functions. The Methylophagaceae symbiont is a methylotrophic autotroph, as it encoded and expressed the ribulose monophosphate and Calvin-Benson-Bassham cycle enzymes, particularly RuBisCO. The Nitrincolaceae ASP10-02a symbiont likely fuels its metabolism with nitrogen-rich macromolecules and may provide the holobiont with vitamin B12. The Urechidicola (Flavobacteriaceae) symbionts likely degrade glycans and may remove NO. Our findings indicate that these flexible associations allow for expanding the range of substrates and environmental niches, via new metabolic functions and handoffs.
Bioinformatics for Medicinal Chemistry
Authors: Manners Emma , O'Donovan Claire , Martin Maria J.
Published: May 2023

Bioinformatics is the computational processing and analysis of biological data. Structured biological data is available in open-access databases and provides a valuable source of information for drug discovery and medicinal chemistry research. In this chapter, an overview of key biological entities, their properties and databases relevant to bioinformatics analyses is presented. Medicinal chemistry resources (that also use chemoinformatics approaches) are described and we offer an insight into how these can be used to investigate the impact of chemical entities on biological molecules relevant to disease. Platforms that integrate broad drug-relevant data in a user-friendly format are also highlighted. Throughout the chapter, the example of cholesterol lowering drugs and/or their biological targets are used to highlight bioinformatics strategies and relevant data that can be extracted from freely available data repositories to illustrate how bioinformatics can be of use to the medicinal chemistry community.
Translational Science
Authors: Vaarala Outi , Liikkanen Sammeli , Moilanen Anu
Published: May 2023

Translational science transforms basic, clinical and population-based research into new therapies, bringing community level health benefits. The success factors for drug discovery are based on high quality translational science. The first success factor is target identification, which is the major focus in the pre-clinical phase of translational research. Deep understanding of the disease biology and identification of the disease driver as a drug's target increases the probability of success. The second success factor is the identification of patients who respond to the treatment. Patient selection biomarkers, genetic, biological or digital, provide a link between the target and disease subtype. Finally, understanding of unmet clinical needs in patients, and the benefits and risks of the intervention at community level, needs to be clear from the early project to the post-marketing stage. The accomplishments of translational science are determined by the accuracy of the data collected and the disease models used, i.e. translatability of the models into human disease. During the past decade translational science has advanced greatly due to the emergence of new, disruptive technologies. Digital technologies and innovative data analysis techniques are also transforming translational research. The use of data science and artificial intelligence for the analysis of real-world data from population-based studies or clinical trials opens new avenues for target ideas, biomarkers and patient stratification.
Lead Optimisation: What You Should Know!
Authors: Ward Simon E. , Davis Andrew M.
Published: May 2023

Lead Optimisation (LO) is a critical part of the drug discovery process as it is the part where all efforts that go into earlier parts of the process (Target Identification, HTS, Hit-to-Lead, Lead Identification) are crystallised into a single compound, the candidate drug. The optimisation phase is like a treasure hunt, and discovery projects can take many paths to discover their treasured molecule. In this chapter we have chosen to focus on the practicalities of how the LO project can be organised, and what different property issues the project may face as it attempts to find an efficient path forward to find a suitable candidate drug for development. This multiparameter optimisation dance can have many issues, often interconnected. We discuss approaches to many of these problems and offer advice on how project members should think about tackling issues in a holistic way. In this way we hope to support projects in understanding the right issues to tackle at the right time. We offer some tips, and examples, of successes, and suggest that identifying the issue to tackle is key to establishing robust hypotheses to test and so drive projects forward. Our goal in this chapter is to aid project thinking about the best way forward.
Pharmaceutical Properties – The Importance of Solid Form Selection
Authors: Doherty Cheryl L. , Robertson Amy L. , Clear Nicola , Docherty Robert
Published: May 2023

The selection of the solid form for development is a milestone in the conversion of a new chemical entity into a drug product. An understanding of the materials science of a new active pharmaceutical is crucial at the interface of medicinal chemistry and pharmaceutical development. The physicochemical properties of a new chemical entity that impact product performance are strongly influenced by the solid state structure of the active pharmaceutical ingredient. The formation of different solid state structures (salt, co-crystal and polymorph) provides an opportunity to eliminate undesirable properties thus enabling a rapid and successful development program. In this chapter we will link new academic progress to the best current industrial practices that medicinal chemists and pharmaceutical scientists can apply in selecting the optimal solid form, along with the related pharmaceutical properties that enable the rapid advancement of new molecules to medicines.
DNA and RNA Structure
Authors: Egli Martin
Published: May 2023

This chapter explores the foundational principles of the conformations of nucleosides, nucleotides and oligonucleotides and the structures of the various double-helical, three-stranded and four-stranded DNA molecules as well as the expanding universe of RNA tertiary structural motifs. At the lower end of the molecular scale, the pursuit of novel nucleoside and nucleotide analogues with antiviral activity and as building blocks for oligonucleotides against a multitude of therapeutic targets requires the steady generation of new structural information to guide synthetic efforts to improve drug potency and efficacy. X-ray crystallography, solution nuclear magnetic resonance, cryo-electron microscopy, spectroscopy, computational simulation and combinations of these approaches are penetrating ever more complex molecular assemblies and machines to reveal their inner workings and underlying chemical principles. Stunning improvements in optical microscopy, as well as electron microscopic tomography, neutron and electron diffraction, have set the stage for exciting structural breakthroughs and discoveries we can anticipate during the coming years. At times, structure and function seem out of step and we rely on the former to deliver a better understanding of the latter. A fine example is left-handed Z-DNA that we have described here in some detail. Over 40 years after the initial determination of the crystal structure of a Z-DNA duplex, increasing evidence has been uncovered that supports important roles of CG-repeat sequences and left-handed DNA in cell development, regulation and disease.
Nucleosides and Nucleotides
Authors: Williams David M. , Blackburn G. Michael
Published: May 2023

In this chapter we describe methods for the chemical synthesis of modified nucleosides and nucleotides. Because most naturally nucleosides and nucleotides are commercially available, syntheses have been directed at the generation of nucleosides containing modified bases and sugars and nucleotides in which oxygen atoms in the phosphate ester are replaced by other heteroatoms. The enzymatic processes associated with nucleotide metabolism are described and the roles of nucleotides in biology are discussed. Finally, the biological properties of nucleosides as antiviral and anticancer agents are highlighted.
DNA and RNA Sequencing
Authors: Booth Michael J.
Published: May 2023

The ability to detect the sequence of nucleobases in DNA or RNA is vital for understanding their function. This chapter outlines both the history of DNA and RNA sequencing and the current leading technologies. These have generated the ability to sequence billions of nucleotides simultaneously and single molecules of millions of bases in length. As of 2020, determining the sequence of a human genome takes 1 day and costs approximately $1000. Uses of sequencing beyond the detection of the underlying gene codes include mapping protein–DNA interactions, profiling gene expression and tracking modified bases. First, second and third generation technological breakthroughs have brought about a revolution in sequencing capabilities, which have had effects on scientific research and clinical medicine. Alternative technologies also have their place, including DNA fingerprinting, DNA microarrays and locating nucleic acid sequences within living cells. Interrogation of gene sequence inside a single cell is in its infancy of showing results.
Nucleic Acid Therapeutics
Authors: Watts Jonathan K.
Published: May 2023

In past decades, small molecules and therapeutic antibodies dominated the field of therapeutic development. Nucleic acids have now enabled new classes of therapeutics in diverse ways, with some 20 nucleic acid therapeutics approved and hundreds more in clinical trials. Oligonucleotides can silence gene expression by recruiting RNase H or RNA interference (RNAi) machinery and when designed to target splice sites, or splice signals within pre-mRNA, oligonucleotides can modulate splicing. Activation of gene expression can be achieved through multiple mechanisms, all of which are at an earlier stage of development than gene silencing and splice switching. A full gene can be delivered to cells using a viral vector, which can be used to provide a durable replacement copy of a defective gene or for introduction of a new function. The delivery of a modified mRNA allows transient replacement of a defective gene or introduction of a sequence only transiently needed, such as an encoded antigen. Finally, delivery of an RNA-guided clustered, regularly interspersed, short palindromic repeats (CRISPR) protein, or the RNA or DNA which encodes that protein, can be used to create permanent edits in cellular DNA. In all of these cases, platform technologies, including optimized approaches to chemical modification, have taken years or decades to develop. Nonetheless, each success informs and enables the development of new drugs, built on the same platform, but with a different sequence, and to target a different disease. The ability to use existing platform technologies and rationally-designed sequences has enabled the development of drugs for rare diseases, and even for a solo patient.
Reversible Small Molecule–Nucleic Acid Interactions
Authors: Wilson W. David , Paul Ananya
Published: May 2023

Historically, small molecules have targeted double helical DNA through intercalation and minor groove complexes. Initially, small molecules to target RNA were focused on RNAs involved in protein biosynthesis. Now, many more compounds to target diverse RNA structures have been designed or discovered. This coincides with the exciting discovery that, while only a small amount of the genome is transcribed into RNA for protein synthesis, much of the genome is used to synthesize a variety of non-coding RNAs (ncRNAs). These have important cell functions, including the involvement of ncRNAs in disease development when they undergo mutation, moreover, their dysregulation has been found to be relevant not only to tumorigenesis, but also to neurological, cardiovascular, developmental and other diseases. Although it has been known for some time that four guanine bases can associate into a tetraplex, our knowledge of how these tetraplexes associate into a variety of four-stranded DNA quadruplexes has greatly advanced. A wide variety of biological functions for these quadruplexes have been discovered. They have a major role in cancer that makes them exciting targets for development of new anticancer agents. At the beginning of our search for new small molecule targets a key structure are the four-way junction and other junction types. The design of new agents to attack these targets will provide many new insights into molecular recognition studies of nucleic acids. The new compounds generated will help us to define the cellular functions of nucleic acid structures and will provide new ideas for the development of nucleic-acid targeted therapeutics.
Feedstocks and Renewable Resources
Authors: de Vries Johannes G. , Deuss Peter J. , Barta Katalin
Published: May 2023

First, this chapter provides a systematic overview of basic feedstocks used in the petrochemical industry. The most important bulk chemicals derived from the important C2, C3, and C4 building blocks, as well as BTX (benzene, toluene, xylene), and the corresponding catalytic methods are presented. Furthermore, the use of coal and natural gas is discussed. The second part of this chapter will give a short introduction on the importance of renewable resources and the biorefinery concept; the focus will be on the three main categories of biomass resources: carbohydrate-based feedstocks, lignin and triglycerides. We look at the structure and reactivity of these materials with special emphasis on catalytic methods and important platform chemicals. Finally, thermal methods such as pyrolysis and gasification are briefly explained.
An Introduction to Biocatalysis
Authors: Wever R. , Goss R. J. M. , Spence E. , Tong Xiaoxue , Hartog A. F.
Published: May 2023

This chapter provides the basis for understanding the parameters that determine the catalytic activity of enzymes. These kinetic parameters are discussed in some detail. The strategies that enzymes use to convert a substrate into a product are described and illustrated using specific examples. In addition, the origin of the unsurpassed chemo-, regio- and stereoselectivity of enzymes is discussed.
Homogeneous Catalysis
Authors: Vogt Dieter
Published: May 2023

The performance of homogeneous catalysts is largely controlled by the ligands bound to the central metal. This chapter presents the most common concepts in Homogeneous Catalysis to rationalize and predict typical ligand influences. Those concepts and their particular predictive power are demonstrated based on selected examples.
Organocatalysis
Authors: Stark Daniel G. , Smith Andrew D.
Published: May 2023

This chapter provides a guide to the use of organocatalysis as a general catalytic concept in synthetic chemistry and aims to demonstrate the fundamental ideas and reasoning that lie behind the most popular strategies in this area. The key to the rapid growth in this field within the least two decades lies in an improved understanding of the different modes of reactivity available through organocatalysis, which has allowed the field to develop in a systematic manner. The main emphasis of this chapter is not to give a comprehensive coverage of this research area, but to introduce the fundamental concepts of organocatalysis by broadly organising the most powerful methodologies for enantioselective organocatalysis under the categories of Brønsted acid, Brønsted base, Lewis acid and Lewis base catalysis.
Organocatalysts
Authors: Frost Aileen B. , Greenhalgh Mark D. , Smith Andrew D.
Published: May 2023

This chapter provides a guide to the most popular and reliable synthetic methods used to prepare selected organocatalysts. Some very simple guiding features are suggested that may allow the reader to assess the utility of these synthetic methods based on reliability, modularity and scalability. The main emphasis of this chapter is to give an overview of the synthetic methods available for the preparation of those catalysts most commonly used in enantioselective organocatalysis that are categorised according to the Brønsted acid, Brønsted base, Lewis acid or Lewis base characteristics of the catalyst.
Enzymes for Biocatalysis: Key Concepts, Engineering Principles and Case Studies
Authors: Sánchez-Carrón Guiomar , Campopiano Dominic J.
Published: May 2023

Enzymes are Nature’s remarkable catalysts found in every living organism. They are capable of catalysing a diverse range of chemical reactions being exquisitely selective, providing fast substrate conversion, water solubility, low operation temperature, and generating few by-products. All this makes enzymes an attractive, environmentally friendly alternative to conventional chemical catalysts. Consequently, the last two decades have seen continuously increasing applications of these ‘biocatalysts’ in a number of different industries. However, the use of enzymes generates some challenges such as their susceptibility to substrate and product inhibition, low stability in operating processes (high temperatures, non-neutral pHs), low solubility in organic solvents and low activity with unnatural substrates or enantiomers. A combination of advances in molecular biology, the availability of an increasing number of gene/genome sequences and high resolution enzyme structures has allowed the engineering of tailor-made enzymes able to meet the requirements of industrial processes. This chapter reviews the traditional and newer state-of-the-art techniques to engineer and evolve biocatalysts.
Bulk X-Ray Techniques
Authors: Lee Adam F. , Parlett Christopher M. A. , Wilson Karen
Published: May 2023

Methods to characterise the local and extended geometric structure of heterogeneous catalysts are also critical to their development and application. One of the most widely used techniques to assess the crystallinity of solids is Powder X-ray diffraction (XRD), which offers a powerful means to identify crystalline phases and their associated lattice strain and disorder, and the average crystallite size of powdered materials.
Operando Techniques
Authors: Bauer M. , Bentrup U. , Priebe J. B. , Brückner A.
Published: May 2023

Operando spectroscopic techniques are inevitable tools for deriving relevant relations between structure and performance of catalysts in a reaction as a basis for rational catalyst design. To ensure that the catalysts under study are indeed analyzed in their active working state, the spectroscopic cells must be connected to some kind of on-line product analysis for providing simultaneously data on conversion, selectivity, as well as spectroscopic data. This chapter provides an overview of the most common methods applicable in true operando mode with flowing reactants, at elevated temperatures and a total pressure of p ≥ 1 bar, including X-ray diffraction (XRD), absorption (XAS) and emission methods (XES), vibrational (FTIR and Raman) and electronic spectroscopy (UV-vis), as well as magnetic resonance techniques (NMR, EPR). For each technique, the basic principles, opportunities and limitations of the method are mentioned first, followed by a presentation of typical experimental setups and some instructive application examples from heterogeneous catalysis. The latter are described in more detail; however, application opportunities in homogeneous catalysis are also mentioned. At the end of this chapter, some ideas on future trends are put forward.
Multicomponent Hydrogels for Tissue Engineering Applications
Authors: Yang Boguang , Xu Jingwen , Zhang Kunyu
Published: May 2023

Tissue damage caused by disease, aging, or trauma has been a major concern for healthcare professionals. Tissue engineering, as an emerging field, offers the potential to restore damaged tissues. Given the high similarity to human tissues and tunable physical and biological properties, hydrogels are appealing biomaterials for applications in tissue engineering. However, owing to the distinct complex architecture as well as 3D organization and distribution of different components of the native extracellular matrix (ECM), it is still a significant challenge to precisely recapitulate the complexity of the ECM by artificial hydrogels. In recent years, rationally designed multicomponent hydrogels have opened new routes to mimic both composition and structural characteristics of the native ECM and provided a supportive environment for tissue regeneration. This chapter highlights the principles of multicomponent hydrogel designs and recent advances in their applications in various subfields of tissue engineering.