bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of Small‐Molecules as Potential GSK‐3β Inhibitors for the Treatment of Alzheimer's Disease Using Pharmacophore‐Based Virtual Screening
Authors: Jangid Kailash , Devi Bharti , Rani Pooja , Kumar Naveen , Kumar Vinay , Kumar Vinod 
Published: April 2024

AbstractGlycogen synthase kinase‐3β (GSK‐3β) plays pivotal role in regulating diverse range of cellular functions. It plays negative role in cellular signaling pathways and believed to involved in the pathologies of various diseases like neurological disorders, type II diabetes, inflammation, cardiac hypertrophy, cancer and bipolar disorders. GSK‐3β is proposed as a promising target for drug discovery in treating these disease conditions. A number of structurally different chemical scaffolds including pyrimidinone derivatives have been identified as potential GSK‐3β inhibitors. In the current study, PHASE module of Schrödinger 3D QSAR was used on about 157 pyrimidinone derivatives for the development of statistically significant PLS model. Consecutively, the best pharmacophore hypothesis with features like three hydrogen bond acceptors (A1‐3), two hydrophobic regions (H1 and H2), and one aromatic ring (R1), was selected to screen ZINC and PUBCHEM databases. Molecules with matching pharmacophoric features and ROF were subjected to structure‐based virtual screening (HTVS→SP→XP) and MMGBSA. Two hits from each library were selected for MD simulation studies that showed good pharmacokinetic properties, binding score (−6.8–−8.8 kcal/mol) and ▵GMMGBSA (−55.80–−58.1 kcal/mol) as compared to the reference molecule, NP‐12. Similarly, MD simulation, and MMPBSA identified three compounds i. e. ZINC67743231, ZINC01582756, and PUBCHEM11553018 displaying stability in the binding pocket and demonstrated better binding affinity of −22.07, −27.33, and −30.61 kcal/mol, respectively, within the active site of GSK‐3β. DFT studies also demonstrated the stability of these three lead compounds with a high energy gap between HOMO and LUMO ranging between 0.14546 and 0.1718 eV.
Green Fluorescent Diamino‐Terephthalonitriles with Reactive Terminal Groups Towards Synthesis of Value‐Added Fluorophores
Authors: Raghava Tanya , Banerjee Subhadeep 
Published: April 2024

AbstractWe report synthesis of a library of diamino‐terephthalonitrile based single‐benzene fluorophores (SBFs). These SBFs contain a reactive terminal linker group. They open up the possibility of marrying their excellent fluorescent property with various biogenic units, leading to value‐added SBFs. The solvatofluorochromism behavior of these newly synthesized SBFs was also studied. The emission enhances and blue‐shifts in case of non‐polar solvents and vice versa in the polar solvents, implying the environmental sensitivity of these fluorophores. Photostability test was also done to test for the stability of the emission of these fluorophores with time and the fluorophores were found to be stable. We also observed time‐dependent fluorescence enhancement of one of our SBFs in presence of reactive biogenic amines. Overall, the generation of these novel molecules opens up new opportunities towards bioconjugated fluorophores.
Double‐digest restriction‐associated DNA sequencing‐based genotyping and its applications in sesame germplasm management
Authors: Ruperao Pradeep , Bajaj Prasad , Yadav Rashmi , Angamuthu Mahalingam , Subramani Rajkumar , Rai Vandana , Tiwari Kapil , Rathore Abhishek , Singh Kuldeep , Singh Gyanendra Pratap , Angadi Ulavappa B. , Mayes Sean , Rangan Parimalan 
Published: April 2024

AbstractSesame (Sesamum indicum L.) is an ancient oilseed crop belonging to the family Pedaliaceae and a globally cultivated crop for its use as oil and food. In this study, 2496 sesame accessions, being conserved at the National Genebank of ICAR‐National Bureau of Plant Genetic Resources (NBPGR), were genotyped using genomics‐assisted double‐digest restriction‐associated DNA sequencing (ddRAD‐seq) approach. A total of 64,910 filtered single‐nucleotide polymorphisms (SNPs) were utilized to assess the genome‐scale diversity. Applications of this genome‐scale information (reduced representation using restriction enzymes) are demonstrated through the development of a molecular core collection (CC) representing maximal SNP diversity. This information is also applied in developing a mid‐density panel (MDP) comprising 2515 hyper‐variable SNPs, representing almost equally the genic and non‐genic regions. The sesame CC comprising 384 accessions, a representative set of accessions with maximal diversity, was identified using multiple criteria such as k‐mer (subsequence of length “k” in a sequence read) diversity, observed heterozygosity, CoreHunter3, GenoCore, and genetic differentiation. The coreset constituted around 15% of the total accessions studied, and this small subset had captured >60% SNP diversity of the entire population. In the coreset, the admixture analysis shows reduced genetic complexity, increased nucleotide diversity (π), and is geographically distributed without any repetitiveness in the CC germplasm. Within the CC, India‐originated accessions exhibit higher diversity (as expected based on the center of diversity concept), than those accessions that were procured from various other countries. The identified CC set and the MDP will be a valuable resource for genomics‐assisted accelerated sesame improvement program.
Maternal prepregnancy weight as an independent risk factor for congenital heart defect: systematic review and meta‐analysis stratified by subtype and severity of defect
Authors: Salmeri N. , Seidenari A. , Cavoretto P. I. , Papale M. , Candiani M. , Farina A. 
Published: April 2024

ABSTRACTObjectiveTo assess the association between increased maternal prepregnancy body mass index (BMI) and the risk of congenital heart defect (CHD) in offspring.MethodsThis systematic review and meta‐analysis searched PubMed/MEDLINE, Web of Science and Scopus from inception to 20 April 2023. Risk estimates were abstracted or calculated for increased BMI categories (overweight, obesity, moderate obesity and severe obesity) compared with normal weight (reference). Fixed‐effects or random‐effects models were used to combine individual study risk estimates based on the degree of heterogeneity. Sensitivity analyses were conducted to weight pooled estimates for relevant moderators, particularly diabetes before and during pregnancy. Subgroup analyses for specific CHD subtypes were conducted if there were at least two studies with available data. Findings were presented for groups of defects, categorized using severity and topographic–functional criteria, and for individual defects. The certainty of the evidence for each effect estimate was evaluated according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines.ResultsOverall, 31 studies comprising 4 861 693 patients and 86 136 CHD cases were included. The risk of CHD increased progressively from moderate to severe obesity (pooled odds ratio (OR), 1.15 (95% CI, 1.11–1.20) and 1.39 (95% CI, 1.27–1.53), respectively). Sensitivity analysis indicated that this effect persisted independently of maternal diabetes status before or during pregnancy. In the subgroup analysis, obesity was associated with up to a 1.5‐fold increase in the risk of severe CHD (pooled OR, 1.48 (95% CI, 1.03–2.13)). Severe obesity was associated with an even higher risk, with 1.8‐times higher odds compared with the reference group for specific CHD subtypes, including tetralogy of Fallot (pooled OR, 1.72 (95% CI, 1.38–2.16)), pulmonary valve stenosis (pooled OR, 1.79 (95% CI, 1.39–2.30)) and atrial septal defect (pooled OR, 1.71 (95% CI, 1.48–1.97)).ConclusionsMaternal weight is a crucial modifiable risk factor for CHD, particularly for severe forms of defect. Further research is needed to investigate whether weight management before pregnancy might serve as a preventive measure against CHD. In pregnant women with obesity, fetal echocardiography should be a routine diagnostic procedure. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Recent developments in the use of nanocrystals to improve bioavailability of APIs
Authors: Ding Yidan , Zhao Tongyi , Fang Jianing , Song Jiexin , Dong Haobo , Liu Jiarui , Li Sijin , Zhao Min 
Published: April 2024

AbstractNanocrystals refer to materials with at least one dimension smaller than 100 nm, composing of atoms arranged in single crystals or polycrystals. Nanocrystals have significant research value as they offer unique advantages over conventional pharmaceutical formulations, such as high bioavailability, enhanced targeting selectivity and controlled release ability and are therefore suitable for the delivery of a wide range of drugs such as insoluble drugs, antitumor drugs and genetic drugs with broad application prospects. In recent years, research on nanocrystals has been progressively refined and new products have been launched or entered the clinical phase of studies. However, issues such as safety and stability still stand that need to be addressed for further development of nanocrystal formulations, and significant gaps do exist in research in various fields in this pharmaceutical arena. This paper presents a systematic overview of the advanced development of nanocrystals, ranging from the preparation approaches of nanocrystals with which the bioavailability of poorly water‐soluble drugs is improved, critical properties of nanocrystals and associated characterization techniques, the recent development of nanocrystals with different administration routes, the advantages and associated limitations of nanocrystal formulations, the mechanisms of physical instability, and the enhanced dissolution performance, to the future perspectives, with a final view to shed more light on the future development of nanocrystals as a means of optimizing the bioavailability of drug candidates.This article is categorized under:
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Permanent Counterrevolution, Technocracy, and World War III
Authors: Hughes David A. 
Published: April 2024

AbstractAn undeclared global class war was initiated in 2020, whose aim is the controlled demolition of liberal democracy and the institution of global technocracy—a novel, biodigital form of totalitarianism that threatens to lead to the irreversible enslavement of humanity. World War III looks nothing like its two predecessors and is waged by the transnational deep state against populations using the novel methods of Omniwar, i.e. war waged in every domain, but clandestinely, so that the public does not recognise it as such. The opening campaign of World War III involved the largest psychological warfare operation in history, which I refer to as the “‘Covid-19’ operation.” This was intended to demoralise, disorientate, and debilitate the public, thus weakening its resistance to the intended transition to technocracy. Historically, psychological warfare has served as the prelude to physical war, raising the alarm concerning what is to come.
Cognitive Attack
Authors: Hughes David A. 
Published: April 2024

AbstractMenticide attacks the cognitive faculties of victims to break down their mental integrity and render them susceptible to indoctrination. During “Covid-19,” confusion was weaponised in various ways, including a proliferation of nonsensical and ever-changing “rules,” last-minute U-turns on key Government decisions, unpredictability of restrictions easing or tightening, and a fundamental irrationality in Government behaviour. Verbal confusion was deployed against the public through constant mixed messaging. A strategy of continuous questioning by the media caused bewilderment. Words and phrases were twisted to mean their opposites, or were used in an esoteric fashion. The public was made to question its own sanity via means used to make social reality seem surreal. The past was rewritten to deny events that actually took place. The public was gaslighted to think that anything but the “vaccines” were to blame for injuries/deaths to young people. A Soviet-style abuse of psychiatry was used to pathologise dissent.
Legal Design and Visual Law: The Roadmap
Authors: Parola Giulia , Poto Margherita Paola 
Published: April 2024

AbstractThis chapter focuses on illustrating the steps of Legal Design (LD) and Visual Law (VL). Before delving into the process of comic book co-creation, the chapter provides an overview of LD and VL, emphasizing their relative unfamiliarity, even among legal scholars. LD, originating from an initiative at Stanford Law School, aims to simplify legal language by evaluating and designing legal business in a simple, functional, attractive, and usable way. It centers on people’s needs, shifting focus from professionals to recipients, such as citizens, organizations, and communities. LD emphasizes ongoing interactions and feedback from recipients throughout the project, fostering empathy and active listening. While LD focuses on effective communication for the benefit of legal beneficiaries, VL serves as its visual manifestation. VL utilizes various visual elements, such as images, illustrations, videos, infographics, comics, and more, making legal documents more explanatory. LD and VL, initially tools for law firms to aid law firm clients understanding, have evolved for broader applications in legal education, research dissemination, empowering society to advocate for their rights, and supporting the decolonization of legal mindsets. The chapter discusses the interchangeable use of LD and VL in legal research, legal education, and as strategic tools for societal empowerment. Importantly, it highlights their potential role in decolonizing legal mindsets by involving participants outside the dominant Western legal doctrine and supporting knowledge co-creation. The chapter underscores the importance of LD and VL in contributing to the re-emergence of Indigenous perspectives and cosmovisions, ultimately facilitating effective participation in environmental matters.
Toward a Spanish Version of the Escazú Agreement in Comics: Needs, Research Background, and Methodological Steps
Authors: Parola Giulia , Poto Margherita Paola , Porrone Arianna , Koessl Natasha 
Published: April 2024

AbstractThis chapter delves into the project’s evolution after the successful publication of books on the Escazú Agreement in English and Portuguese. The initiative shifted focus towards disseminating the knowledge contained in these works to the Chiquitano communities in Mato Grosso and sharing project results in academic fora and international conferences. The reception of these books was enthusiastic among both indigenous and scientific communities, garnering positive feedback. One notable suggestion emerged prominently: the urgent need to develop a Spanish version. This recommendation was driven by the widespread prevalence of Spanish as a major language in Latin American and Caribbean countries, including Bolivia, where the majority of Chiquitano communities reside. Therefore, this chapter explores the process of expanding the initiative to include a Spanish version, emphasizing its significance and implications for promoting indigenous rights and environmental protection. Adapting the project to this crucial language aims to ensure broader and more effective access to information about the Escazú Agreement, thereby strengthening indigenous community participation and fostering environmental protection in the region.
Dark showers from Z-dark Z′ mixing
Authors: Cheng Hsin-Chia , Jiang Xu-Hui , Li Lingfeng , Salvioni Ennio 
Published: April 2024

Abstract
We discuss dark shower signals at the LHC from a dark QCD sector, containing GeV-scale dark pions. The portal with the Standard Model is given by the mixing of the Z boson with a dark Z′ coupled to the dark quarks. Both mass and kinetic mixings are included, but the mass mixing is the essential ingredient, as it is the one mediating visible decays of the long-lived dark pions. We focus especially on the possibility that the dark Z′ is lighter than the Z. Indirect constraints are dominated by electroweak precision tests, which we thoroughly discuss, showing that both Z-pole and low-energy observables are important. We then recast CMS and LHCb searches for displaced dimuon resonances to dark shower signals initiated by the production of on-shell Z or Z′, where the visible signature is left by a dark pion decaying to μ+μ−. We demonstrate how dark shower topologies have already tested new parameter space in Run 2, reaching better sensitivity on a light dark Z′ compared to the flavor-changing decays of B mesons, which can produce a single dark pion at a time, and the electroweak precision tests.
RUNX transcription factors are essential in maintaining epididymal epithelial differentiation
Authors: Toriseva Mervi , Björkgren Ida , Junnila Arttu , Mehmood Arfa , Mattsson Jesse , Raimoranta Inka , Kim Bongki , Laiho Asta , Nees Matthias , Elo Laura , Poutanen Matti , Breton Sylvie , Sipilä Petra 
Published: April 2024

AbstractApart from the androgen receptor, transcription factors (TFs) that are required for the development and formation of the different segments of the epididymis have remained unknown. We identified TF families expressed in the developing epididymides, of which many showed segment specificity. From these TFs, down-regulation of runt related transcription factors (RUNXs) 1 and 2 expression coincides with epithelial regression in Dicer1 cKO mice. Concomitant deletion of both Runx1 and Runx2 in a mouse epididymal epithelial cell line affected cell morphology, adhesion and mobility in vitro. Furthermore, lack of functional RUNXs severely disturbed the formation of 3D epididymal organoid-like structures. Transcriptomic analysis of the epididymal cell organoid-like structures indicated that RUNX1 and RUNX2 are involved in the regulation of MAPK signaling, NOTCH pathway activity, and EMT-related gene expression. This suggests that RUNXs are master regulators of several essential signaling pathways, and necessary for the maintenance of proper differentiation of the epididymal epithelium.
When DNA-damage responses meet innate and adaptive immunity
Authors: Tong Jie , Song Jiangwei , Zhang Wuchao , Zhai Jingbo , Guan Qingli , Wang Huiqing , Liu Gentao , Zheng Chunfu 
Published: April 2024

AbstractWhen cells proliferate, stress on DNA replication or exposure to endogenous or external insults frequently results in DNA damage. DNA-Damage Response (DDR) networks are complex signaling pathways used by multicellular organisms to prevent DNA damage. Depending on the type of broken DNA, the various pathways, Base-Excision Repair (BER), Nucleotide Excision Repair (NER), Mismatch Repair (MMR), Homologous Recombination (HR), Non-Homologous End-Joining (NHEJ), Interstrand Crosslink (ICL) repair, and other direct repair pathways, can be activated separately or in combination to repair DNA damage. To preserve homeostasis, innate and adaptive immune responses are effective defenses against endogenous mutation or invasion by external pathogens. It is interesting to note that new research keeps showing how closely DDR components and the immune system are related. DDR and immunological response are linked by immune effectors such as the cyclic GMP-AMP synthase (cGAS)–Stimulator of Interferon Genes (STING) pathway. These effectors act as sensors of DNA damage-caused immune response. Furthermore, DDR components themselves function in immune responses to trigger the generation of inflammatory cytokines in a cascade or even trigger programmed cell death. Defective DDR components are known to disrupt genomic stability and compromise immunological responses, aggravating immune imbalance and leading to serious diseases such as cancer and autoimmune disorders. This study examines the most recent developments in the interaction between DDR elements and immunological responses. The DDR network’s immune modulators’ dual roles may offer new perspectives on treating infectious disorders linked to DNA damage, including cancer, and on the development of target immunotherapy.
Ritueller sexueller Missbrauch
Authors: Fegert Jörg M. , Urbaniok Frank 
Published: April 2024

Zusammenfassung
Hintergrund
Hintergrund des Beitrags bildet die polarisierte mediale Debatte um rituelle sexuelle Gewalt gegen Kinder. Es haben sich zwei Lager gebildet, die sich gegenüberstehen und denen ein sachlicher Austausch miteinander nicht möglich ist.

Ziel
Der Artikel verfolgt daher das Ziel, einen klinischen Beitrag zur Überbrückung der Differenzen zu leisten und argumentiert vor allem im Sinne des Wohls von Patient:innen dafür, sich auf eine Evidenzbasierung sowohl in der Krankenbehandlung als auch im wissenschaftlichen Diskurs zu besinnen.

Material und Methoden
Der Beitrag basiert auf der kritischen Auseinandersetzung mit exemplarischer Fachliteratur, öffentlichen Untersuchungsberichten zu Fehlbehandlungen vor allem in der Schweiz sowie auf die Medienberichterstattung.

Ergebnisse
In bestimmten psychotraumatologischen Kreisen sowie in den Medien (gerade auch in sozialen Medien auf Plattformen wie Telegram) ist ein Verschwörungsnarrativ über ein großes Täter:innennetzwerk, welches im rituellen Kontext Kindern schwerste Gewalt antue, präsent. Ein unkritischer Glaube z. B. an Konzepte wie „mind control“ (Vorstellung eines absichtlichen und planvollen Herbeiführens einer dissoziativen Identitätsstörung) hat zu Fehlbehandlungen von Patient:innen sowie im Gegenzug zu einem grundlegenden Misstrauen gegenüber deren Aussagen geführt. Dadurch droht diesen ohnehin vulnerablen Patient:innen weiterer Schaden, was den basalen Prinzipien medizinischer Ethik widerspricht.
A 3D atlas of the human developing pancreas to explore progenitor proliferation and differentiation
Authors: Villalba Adrian , Gitton Yorick , Inoue Megumi , Aiello Virginie , Blain Raphaël , Toupin Maryne , Mazaud-Guittot Séverine , Rachdi Latif , Semb Henrik , Chédotal Alain , Scharfmann Raphaël 
Published: April 2024

Abstract
Aims/hypothesis
Rodent pancreas development has been described in great detail. On the other hand, there are still gaps in our understanding of the developmental trajectories of pancreatic cells during human ontogenesis. Here, our aim was to map the spatial and chronological dynamics of human pancreatic cell differentiation and proliferation by using 3D imaging of cleared human embryonic and fetal pancreases.

Methods
We combined tissue clearing with light-sheet fluorescence imaging in human embryonic and fetal pancreases during the first trimester of pregnancy. In addition, we validated an explant culture system enabling in vitro proliferation of pancreatic progenitors to determine the mitogenic effect of candidate molecules.

Results
We detected the first insulin-positive cells as early as five post-conceptional weeks, two weeks earlier than previously observed. We observed few insulin-positive clusters at five post-conceptional weeks (mean ± SD 9.25±5.65) with a sharp increase to 11 post-conceptional weeks (4307±152.34). We identified a central niche as the location of onset of the earliest insulin cell production and detected extra-pancreatic loci within the adjacent developing gut. Conversely, proliferating pancreatic progenitors were located in the periphery of the epithelium, suggesting the existence of two separated pancreatic niches for differentiation and proliferation. Additionally, we observed that the proliferation ratio of progenitors ranged between 20% and 30%, while for insulin-positive cells it was 1%. We next unveiled a mitogenic effect of the platelet-derived growth factor AA isoform (PDGFAA) in progenitors acting through the pancreatic mesenchyme by increasing threefold the number of proliferating progenitors.

Conclusions/interpretation
This work presents a first 3D atlas of the human developing pancreas, charting both endocrine and proliferating cells across early development.

Graphical Abstract