Miracle-dz/UniFAR-FTUs huggingface dataset:
Classical MD and metadynamics simulations on back-pocket binders of CDK2 and VEGFR2: a guidepost to design novel small-molecule dual inhibitors

Abstract Cyclin-Dependent Kinase 2 (CDK2) and Vascular-Endothelial Growth Factor Receptor 2 (VEGFR2) are promising targets for the design of novel inhibitors in anticancer therapeutics. In a recent work, our group designed a set of potential dual inhibitors predicted to occupy an allosteric back pocket near the active site of both enzymes, but their dynamic and unbinding behavior was unclear. Here, we used molecular dynamics (MD) and metadynamics (meta-D) simulations to study two of these virtual candidates (herein called IQ2 and IQ3). Their binding mode was predicted to be similar to that observed in LQ5 and BAX, well-known back-pocket binders of CDK2 and VEGFR2, respectively, including H-bonding with critical residues such as Leu83/Cys113 and Asp145/Asp190 (but excepting H-bonding with Glu51/Glu111) in CDK2/VEGFR2, correspondingly. Likewise, while LQ5 and BAX unbound through the allosteric channel as expected for type-IIA inhibitors, IQ2 and IQ3 unbound via the ATP channel (except for CDK2-IQ2) as expected for type-I½A inhibitors. Interestingly, a C-C single/double bond difference between IQ2/IQ3, respectively, resulted associated with differences in the AS/T loop flexibility observed for CDK2. These insights will help developing scaffold modifications during an optimization stage, serving as a starting point to develop dual kinase inhibitors in challenging biological targets with a promising anticancer potential. Communicated by Ramaswamy H. Sarma
Academic Journal Retractions and the COVID-19 Pandemic

The 2020 COVID-19 pandemic has produced an unprecedented amount of scientific research, with over 100,000 articles on the SARS-COV2 virus or the associated pandemic published within the first year. To effectively disseminate such a large volume of research, some academic journal publishers altered their review criteria, and many articles were made available before undergoing a traditional review process. However, with this rapid influx of information, multiple COVID-19 articles have been retracted or withdrawn. Some researchers have expressed concern that these retractions call into question the validity of an expedited review process and the overall quality of the larger body of COVID-19 research. We examined 68 removed articles and determined that many of the articles were removed for unknown reasons (n = 22) or as duplications (n = 12); 24 papers were retracted for more significant reasons (data integrity, plagiarism, reporting or analysis, and IRB or privacy issues). The majority of removed papers were from the USA (n = 23) and China (n = 19).
Peer involvement in service provision: how US human service nonprofit organisations include sex workers as organisational staff

Abstract Human service non-profit organisations (HSNPs) looking to improve the representation of clients in the work of their organisation may decide to hire people with lived experience as peer providers. This paper looks at how HSNPs that provide services to sex workers make decisions about hiring those with lived experience of sex work as staff. To address the issue, the following questions were asked: 1) how do HSNPs make the decision to hire sex workers as staff members; and 2) if hired, how are individuals actually involved in the organisation? The study aimed to answer these questions using open-ended interviews with 64 staff in HSNPs in the US Midwest that indirectly or directly provide services to sex workers. Findings indicate that while many organisations hire individuals with lived experience in sex work, the expectations placed on these individuals vary considerably depending on the perceptions other HSNP staff have about sex work. When HSNPs hire individuals with lived experience to further their organisational agendas with respect to sex work, they should include sex workers in a substantive and inclusive way to minimise organisational bias and ensure sex worker views are accurately represented.
PLIP 2021: expanding the scope of the protein–ligand interaction profiler to DNA and RNA

Abstract With the growth of protein structure data, the analysis of molecular interactions between ligands and their target molecules is gaining importance. PLIP, the protein–ligand interaction profiler, detects and visualises these interactions and provides data in formats suitable for further processing. PLIP has proven very successful in applications ranging from the characterisation of docking experiments to the assessment of novel ligand–protein complexes. Besides ligand–protein interactions, interactions with DNA and RNA play a vital role in many applications, such as drugs targeting DNA or RNA-binding proteins. To date, over 7% of all 3D structures in the Protein Data Bank include DNA or RNA. Therefore, we extended PLIP to encompass these important molecules. We demonstrate the power of this extension with examples of a cancer drug binding to a DNA target, and an RNA–protein complex central to a neurological disease. PLIP is available online at https://plip-tool.biotec. tu-dresden.de and as open source code. So far, the engine has served over a million queries and the source code has been downloaded several thousand times.
Global trends in research output by zoos and aquariums

Zoos and aquaria, often regarded as preservation‐cum‐entertainment enterprises, are also actors in the effort to curb the biodiversity crisis: raising awareness, supporting conservation, and conducting research. We assessed trends in zoo and aquaria research topics and study organisms over time worldwide. For the zoos and aquaria registered in the Species360's Zoological Information Management System and the World Association of Zoos and Aquariums, we compiled metadata on their research published in the peer‐reviewed literature indexed in Scopus and carried out a keyword frequency analysis. The production of scientific papers by zoos increased at a much faster rate than the average accrual of scientific papers in the literature. Evolution of research themes ran parallel to that of biological sciences (e.g., development of molecular genetics or increased awareness about conservation). The focus of 48.5% of zoo‐led research was on vertebrates, of which mammal research was 33.7%. Whether zoos are effectively contributing to conservation may still be debatable, but our results highlight their institutional efforts to increase knowledge about the species in their care.
A Novel Bone Substitute Based on Recombinant Type I Collagen for Reconstruction of Alveolar Cleft

This study aimed to examine the optimal cross-link density of recombinant peptide (RCP) particles, based on human collagen type I, for bone reconstruction in human alveolar cleft. Low- (group 1), medium- (group 2), and high- (group 3) cross-linked RCP particles were prepared by altering the duration of the heat-dependent dehydration reaction. Rat palatine fissures (n = 45), analogous to human congenital bone defects, were examined to evaluate the potential of bone formation by the three different RCP particles. Microcomputed tomography images were obtained to measure bone volume and bone mineral density at 4, 8, 12, and 16 weeks post grafting. Specimens were obtained for histological analysis at 16 weeks after grafting. Additionally, alkaline phosphatase and tartrate acid phosphatase staining were performed to visualize the presence of osteoblasts and osteoclasts. At 16 weeks, bone volume, bone mineral density, and new bone area measurements in group 2 were significantly higher than in any other group. In addition, the number of osteoblasts and osteoclasts on the new bone surface in group 2 was significantly higher than in any other group. Our results demonstrated that medium cross-linking was more suitable for bone formation—and could be useful in human alveolar cleft repairs as well.
Detoxification and Excretion of Trichothecenes in Transgenic Arabidopsis thaliana Expressing Fusarium graminearum Trichothecene 3-O-acetyltransferase

Fusarium graminearum, the causal agent of Fusarium head blight (FHB), produces trichothecenes including deoxynivalenol (DON), nivalenol (NIV), and 3,7,15-trihydroxy-12,13-epoxytrichothec-9-ene (NX-3). These toxins contaminate grains and cause profound health problems in humans and animals. To explore exploiting a fungal self-protection mechanism in plants, we examined the ability of F. graminearum trichothecene 3-O-acetyltransferase (FgTri101) to detoxify several key trichothecenes produced by F. graminearum: DON, 15-ADON, NX-3, and NIV. FgTri101 was cloned from F. graminearum and expressed in Arabidopsis plants. We compared the phytotoxic effects of purified DON, NIV, and NX-3 on the root growth of transgenic Arabidopsis expressing FgTri101. Compared to wild type and GUS controls, FgTri101 transgenic Arabidopsis plants displayed significantly longer root length on media containing DON and NX-3. Furthermore, we confirmed that the FgTri101 transgenic plants acetylated DON to 3-ADON, 15-ADON to 3,15-diADON, and NX-3 to NX-2, but did not acetylate NIV. Approximately 90% of the converted toxins were excreted into the media. Our study indicates that transgenic Arabidopsis expressing FgTri101 can provide plant protection by detoxifying trichothecenes and excreting the acetylated toxins out of plant cells. Characterization of plant transporters involved in trichothecene efflux will provide novel targets to reduce FHB and mycotoxin contamination in economically important plant crops.
The MYB family transcription factor TuODORANT1 from Triticum urartu and the homolog TaODORANT1 from Triticum aestivum inhibit seed storage protein synthesis in wheat

Summary Seed storage proteins (SSPs) are determinants of wheat end‐product quality. SSP synthesis is mainly regulated at the transcriptional level. Few transcriptional regulators of SSP synthesis have been identified in wheat and this study aims to identify novel SSP gene regulators. Here, the R2R3 MYB transcription factor TuODORANT1 from Triticum urartu was found to be preferentially expressed in the developing endosperm during grain filling. In common wheat (Triticum aestivum) overexpressing TuODORANT1, the transcription levels of all the SSP genes tested by RNA‐Seq analysis were reduced by 49.71% throughout grain filling, which contributed to 13.38%–35.60% declines in the total SSP levels of mature grains. In in vitro assays, TuODORANT1 inhibited both the promoter activities and the transcription of SSP genes by 1‐ to 13‐fold. The electrophoretic mobility shift assay (EMSA) and ChIP‐qPCR analysis demonstrated that TuODORANT1 bound to the cis‐elements 5′‐T/CAACCA‐3′ and 5′‐T/CAACT/AG‐3′ in SSP gene promoters both in vitro and in vivo. Similarly, the homolog TaODORANT1 in common wheat hindered both the promoter activities and the transcription of SSP genes by 1‐ to 112‐fold in vitro. Knockdown of TaODORANT1 in common wheat led to 14.73%–232.78% increases in the transcription of the tested SSP genes, which contributed to 11.43%–19.35% elevation in the total SSP levels. Our data show that both TuODORANT1 and TaODORANT1 are repressors of SSP synthesis.
Development and validation of a set of novel and robust 4-lncRNA-based nomogram predicting prostate cancer survival by bioinformatics analysis

Background and objective Accumulating evidence shows that long noncoding RNAs (lncRNAs) possess great potential in the diagnosis and prognosis of prostate cancer (PCa). Therefore, this study aimed to construct an lncRNA-based signature to more accurately predict the prognosis of different PCa patients, so as to improve patient management and prognosis. Methods Through univariate and multivariate Cox regression analysis, this study constructed a 4 lncRNAs-based prognosis nomogram for the classification and prediction of survival risk in patients with PCa based on TCGA data. Then we used the data of TCGA and ICGC to verify the performance of our prediction model. The receiver operating characteristic curve was plotted for detecting and validating our prediction model sensitivity and specificity. In addition, Cox regression analysis was conducted to examine whether the signature’s prediction ability was independent of additional clinicopathological variables. Possible biological functions for those prognostic lncRNAs were predicted on those 4 protein-coding genes (PCGs) related to lncRNAs. Results Four lncRNAs (HOXB-AS3, YEATS2-AS1, LINC01679, PRRT3-AS1) were extracted after COX regression analysis for classifying patients into high and low-risk groups by different OS rates. As suggested by ROC analysis, our proposed model showed high sensitivity and specificity. Independent prognostic capability of the model from other clinicopathological factors was indicated through further analysis. Based on functional enrichment, those action sites for prognostic lncRNAs were mostly located in the extracellular matrix and cell membrane, and their functions are mainly associated with the adhesion, activation and transport of the components across the extracellular matrix or cell membrane. Conclusion Our current study successfully identifies a novel candidate, which can provide more convincing evidence for prognosis in addition to the traditional clinicopathological indicators to predict the PCa survival, and laying the foundation for offering potentially novel therapeutic treatment. Additionally, this study sheds more lights on the PCa-related molecular mechanisms.
Hamstring and gluteal activation during high-speed overground running: Impact of prior strain injury

ABSTRACT This study examined the spatial patterns of hamstring and gluteal muscle activation during high-speed overground running in limbs with and without aprior hamstring strain injury. Ten active males with arecent (<18 month) unilateral biceps femoris long head (BFLH) strain injury underwent functional magnetic resonance imaging before and immediately after arepeat-sprint running protocol. Transverse relaxation (T2) time, an index of muscle activation, of the BFLH and short head (BFSH), semitendinosus (ST), semimembranosus (SM), gluteus maximus (GMAX) and medius (GMED) was assessed pre-post exercise. No significant between-limb differences in running-induced mean T2 changes were observed (p = 0.949), however, decision tree induction revealed that previously injured limbs were characterised by highly variable intramuscular activation of the ST (SD5.3). T2 times increased more for GMAX than all other muscles (all p< 0.001, d= 0.5–2.5). Further, T2 changes were greater for ST than BFSH, SM, GMED, and BFLH (all p≤ 0.001, d= 0.5–2.9); and were greater for BFLH than BFSH, SM, and GMED (all p< 0.001, d= 1.2–1.6). Athletes display heterogenous patterns of posterior thigh activation when sprinting (GMAX>ST>BFLH>GMED>SM>BFSH) and may exhibit altered intramuscular hamstring activation after returning to sport from BFLH strain injury.
Disruption of entire Cables2 locus leads to embryonic lethality by diminished Rps21 gene expression and enhanced p53 pathway

In vivo function of CDK5 and Abl enzyme substrate 2 (Cables2), belonging to the Cables protein family, is unknown. Here, we found that targeted disruption of the entire Cables2 locus (Cables2d) caused growth retardation and enhanced apoptosis at the gastrulation stage and then induced embryonic lethality in mice. Comparative transcriptome analysis revealed disruption of Cables2, 50% down-regulation of Rps21 abutting on the Cables2 locus, and up-regulation of p53-target genes in Cables2d gastrulas. We further revealed the lethality phenotype in Rps21-deleted mice and unexpectedly, the exon 1-deleted Cables2 mice survived. Interestingly, chimeric mice derived from Cables2d ESCs carrying exogenous Cables2 and tetraploid wild-type embryo overcame gastrulation. These results suggest that the diminished expression of Rps21 and the completed lack of Cables2 expression are intricately involved in the embryonic lethality via the p53 pathway. This study sheds light on the importance of Cables2 locus in mouse embryonic development.
Hormonal Responses to Susceptible, Intermediate, and Resistant Interactions in the Brassica napus–Leptosphaeria maculans Pathosystem

Hormone signaling plays a pivotal role in plant–microbe interactions. There are three major phytohormones in plant defense: salicylic acid (SA), jasmonic acid (JA), and ethylene (ET). The activation and trade-off of signaling between these three hormones likely determines the strength of plant defense in response to pathogens. Here, we describe the allocation of hormonal signaling in Brassica napus against the fungal pathogen Leptosphaeria maculans. Three B. napus genotypes (Westar, Surpass400, and 01-23-2-1) were inoculated with two L. maculans isolates (H75 8-1 and H77 7-2), subsequently exhibiting three levels of resistance: susceptible, intermediate, and resistant. Quantitative analyses suggest that the early activation of some SA-responsive genes, including WRKY70 and NPR1, contribute to an effective defense against L. maculans. The co-expression among factors responding to SA/ET/JA was also observed in the late stage of infection. The results of conjugated SA measurement also support that early SA activation plays a crucial role in durable resistance. Our results demonstrate the relationship between the onset patterns of certain hormone regulators and the effectiveness of the defense of B. napus against L. maculans.
Association of Iron Supplementation Programs with Iron-Deficiency Anemia Outcomes among Children in Brazil

Anemia remains a condition with high prevalence in populations worldwide, and the prevalence of anemia among children under five years old in Brazil is approximately 40%, being higher in communities marked by social inequities. Diverse government programs during recent decades targeted iron-deficiency anemia, considering its impacts throughout the lifetime. The objective of this study was to investigate the effects of two government iron supplementation programs on health outcomes related to iron-deficiency anemia among children up to 4 years old in Brazilian municipalities. A longitudinal panel encompassing data from 5570 municipalities from 1998 to 2019 was investigated using a difference-in-differences framework with multiple interventions and distinct times of adhesion, and fixed-effects models were estimated to control for invariant municipal characteristics throughout the period in order to ensure comparability. The results indicate significant effects of the federal programs in reducing hospitalizations and lengths of stay due to iron-deficiency anemia, especially in non-poor municipalities. There was complementarity in the effects of the programs; however, neither of the programs influenced mortality rates. Thus, it is important to consider possible improvements in the operationalization of the programs, in order to achieve better results in the reduction of severe iron-deficiency anemia among children up to 4 years old.
Anthocyanins Recovered from Agri-Food By-Products Using Innovative Processes: Trends, Challenges, and Perspectives for Their Application in Food Systems

Anthocyanins are naturally occurring phytochemicals that have attracted growing interest from consumers and the food industry due to their multiple biological properties and technological applications. Nevertheless, conventional extraction techniques based on thermal technologies can compromise both the recovery and stability of anthocyanins, reducing their global yield and/or limiting their application in food systems. The current review provides an overview of the main innovative processes (e.g., pulsed electric field, microwave, and ultrasound) used to recover anthocyanins from agri-food waste/by-products and the mechanisms involved in anthocyanin extraction and their impacts on the stability of these compounds. Moreover, trends and perspectives of anthocyanins’ applications in food systems, such as antioxidants, natural colorants, preservatives, and active and smart packaging components, are addressed. Challenges behind anthocyanin implementation in food systems are displayed and potential solutions to overcome these drawbacks are proposed.
Juvenile hormone regulates the reproductive diapause through Methoprene‐tolerant gene in Galeruca daurica

Juvenile hormone (JH) signalling plays an important role in regulation of reproductive diapause in insects. However, its underlying molecular mechanism has been unclear. Methoprene‐tolerant (Met), as a universal JH receptor, is involved in JH action. To gain some insight into its function in the reproductive diapause of Galeruca daurica, a serious pest on the Inner Mongolia grasslands undergoing obligatory summer diapause at the adult stage, we cloned the complete open‐reading frame (ORF) sequences of Met and other 7 JH signalling‐related genes, including JH acid methyltransferase (JHAMT), JH esterase (JHE), JH epoxide hydrolase (JHEH), Krüppel homologue 1 (Kr‐h1), vitellogenin (Vg), forkhead box O (FOXO) and fatty acid synthase 2 (FAS2), from this species. GdMet encoded a putative protein, which contained three domains typical of the bHLH‐PAS family. Expression patterns of these eight genes were developmentally regulated during adult development. Topical application of JH analogue (JHA) methoprene into the 3‐day‐old and 5‐day‐old adults induced the expression of GdMet. Silencing GdMet by RNAi inhibited the expression of JHBP, JHE, Kr‐h1 and Vg, whereas promoted the FAS2 expression, which enhanced lipid accumulation and fat body development, and finally induced the adults into diapause ahead. Combining with our previous results, we conclude that JH may regulate reproductive diapause through a conserved Met‐dependent pathway in G. daurica.