Miracle-dz/UniFAR-FTUs huggingface dataset:
The numerical probability of carcinogenicity to humans of some pharmaceutical drugs: Alkylating agents, topoisomerase inhibitors or poisons, and DNA intercalators

The nonclinical branch of regulatory pharmacology has traditionally relied on the sensitivity and specificity of regulatorily recommended bioassays. Nonetheless, any predictive testing (eg, safety pharmacology) with less than 100% sensitivity or 100% specificity is prone to deliver false positive or negative results (namely, outcomes discordant to the clinical gold standard). It was recently suggested that the statistics‐based and regulatory pertinent “predictive values approach” (PVA) might help to reach a more predictive use of preclinical testing data. To resolve the associated probability of carcinogenicity to humans, the PVA was applied to 37 pharmaceuticals bearing inadequate epidemiological evidence of carcinogenicity, but identifiable as unequivocal mutagens. According to current knowledge, a 98.9% (or more) probability of carcinogenicity to humans was reckoned for those 37 genotoxic drugs. Accordingly, these pharmaceutical drugs might be either scientifically or regulatorily regarded as “carcinogenic to humans. ” In the USA, European Union, or Canada as examples, the great majority of these 37 pharmaceuticals are authorized for medical use in humans. From the results of the present appraisal, the following is suggested (1) for the pharmaceuticals listed in this report, to include significant carcinogenicity warnings in their prescribing information; (2) to conduct pharmacoepidemiology studies or risk‐benefit analyses (if warranted), and (3) based on the respective risk‐benefit analyses, to re‐evaluate the authorization of hydralazine and phenoxybenzamine as antihypertensives, oxcarbazepine as an anticonvulsant, and phenazopyridine as a urinary tract antimicrobial or analgesic. For the four latter drugs (eg, phenoxybenzamine), a 99.5% probability of carcinogenicity to humans was estimated.
Predicting Survival After Liver Transplantation: A Noble Pursuit or a Fool’s Errand?

Organ shortage continues to limit our ability to provide transplant to all in need of liver transplantation. The current urgency-based system is based on the laboratory MELD-Na score, which efficiently and effectively rank orders patients by their estimated risk for 90-day waitlist mortality, with a c-statistic of 0.88. 1 MELD-Na is agnostic to factors such as age, etiology of liver disease, and co-morbidity, as well as one's expected post-transplant survival. Transplant centers are entrusted, according to the Final Rule, to ensure that candidates meet a minimal threshold of utility where liver transplant would benefit the patient.
Atg4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system

The sequestration of damaged mitochondria within double-membrane structures termed autophagosomes is a key step of PINK1/Parkin mitophagy. The Atg4 family of proteases are thought to regulate autophagosome formation exclusively by processing the ubiquitin-like Atg8 family (LC3/GABARAPs). We make the unexpected discovery that human Atg4s can directly promote autophagosome formation independently of their protease activity and of Atg8 family processing. High resolution structures of phagophores generated with artificial intelligence-directed 3D electron microscopy reveal a role for the Atg4 family in promoting phagophore-ER contacts during the lipid-transfer phase of autophagosome formation. Atg4 proximity interaction networks stimulated by PINK1/Parkin mitophagy are consistent with roles for Atg4s in protein/vesicle transport and lipid modification. We also show that Atg8 removal during autophagosome maturation does not depend on Atg4 de-lipidation activity as previously thought. Instead, we find that Atg4s can disassemble Atg8-protein conjugates, revealing a role for Atg4s as deubiquitinating-like enzymes. These findings establish non-canonical roles of the Atg4 family beyond the Atg8 lipidation axis and provide an AI driven framework for high-throughput 3D electron microscopy.
QSAR Rationales for the Isoindolone Derivatives as 5-HT2C Receptor Antagonists.

The 5-HT2C receptor binding affinities of the isoindolone derivatives have been quantitatively analyzed in terms of Dragon descriptors. The derived QSAR models have provided rationales to explain the binding affinity of titled compounds. The associations of atomic mass to the highest eigenvalue n.2 and lowest eigenvalue n.5 of the Burden matrix (BEHm2 and BELm5, respectively), atomic van der Waals volume to path length 2 and 8 of the Moran autocorrelations (MATS2v and MATS8v) and path length 2 of Geary autocorrelation (GATS2v), polarizability to the highest eigenvalue n.1 and n.6 of the Burden matrix (BEHp1 and BEHp6) and Sanderson electronegativity to path length 4 of Geary autocorrelation (GATS4e) have shown the prevalence of atomic properties to explain the binding affinity. Absence of R--CR--R type structural fragment (C-025) in a molecular structure and a lower values of path/walk 4 - Randic shape index (PW4) and Balaban Y index (Yindex) are favorable to the activity. The derived models and participating descriptors in them have suggested that the substituents of isoindolone moiety have sufficient scope for further modification.
Structural parameters of palindromic repeats determine the specificity of nuclease attack of secondary structures

Abstract Palindromic sequences are a potent source of chromosomal instability in many organisms and are implicated in the pathogenesis of human diseases. In this study, we investigate which nucleases are responsible for cleavage of the hairpin and cruciform structures and generation of double-strand breaks at inverted repeats in Saccharomyces cerevisiae. We demonstrate that the involvement of structure-specific nucleases in palindrome fragility depends on the distance between inverted repeats and their transcriptional status. The attack by the Mre11 complex is constrained to hairpins with loops <9 nucleotides. This restriction is alleviated upon RPA depletion, indicating that RPA controls the stability and/or formation of secondary structures otherwise responsible for replication fork stalling and DSB formation. Mus81-Mms4 cleavage of cruciforms occurs at divergently but not convergently transcribed or nontranscribed repeats. Our study also reveals the third pathway for fragility at perfect and quasi-palindromes, which involves cruciform resolution during the G2 phase of the cell cycle.
An immunologically friendly classification of non-peptidic ligands

Abstract The Immune Epitope Database (IEDB) freely provides experimental data regarding immune epitopes to the scientific public. The main users of the IEDB are immunologists who can easily use our web interface to search for peptidic epitopes via their simple single-letter codes. For example, ‘A’ stands for ‘alanine’. Similarly, users can easily navigate the IEDB’s simplified NCBI taxonomy hierarchy to locate proteins from specific organisms. However, some epitopes are non-peptidic, such as carbohydrates, lipids, chemicals and drugs, and it is more challenging to consistently name them and search upon, making access to their data more problematic for immunologists. Therefore, we set out to improve access to non-peptidic epitope data in the IEDB through the simplification of the non-peptidic hierarchy used in our search interfaces. Here, we present these efforts and their outcomes. Database URL: http://www.iedb. org/
ZEAL: protein structure alignment based on shape similarity

Abstract Motivation Most protein-structure superimposition tools consider only Cartesian coordinates. Yet, much of biology happens on the surface of proteins, which is why proteins with shared ancestry and similar function often have comparable surface shapes. Superposition of proteins based on surface shape can enable comparison of highly divergent proteins, identify convergent evolution and enable detailed comparison of surface features and binding sites. Results We present ZEAL, an interactive tool to superpose global and local protein structures based on their shape resemblance using 3D (Zernike-Canterakis) functions to represent the molecular surface. In a benchmark study of structures with the same fold, we show that ZEAL outperforms two other methods for shape-based superposition. In addition, alignments from ZEAL were of comparable quality to the coordinate-based superpositions provided by TM-align. For comparisons of proteins with limited sequence and backbone-fold similarity, where coordinate-based methods typically fail, ZEAL can often find alignments with substantial surface-shape correspondence. In combination with shape-based matching, ZEAL can be used as a general tool to study relationships between shape and protein function. We identify several categories of protein functions where global shape similarity is significantly more likely than expected by random chance, when comparing proteins with little similarity on the fold level. In particular, we find that global surface shape similarity is particular common among DNA binding proteins. Availability and implementation ZEAL can be used online at https://andrelab.org/zeal or as a standalone program with command line or graphical user interface. Source files and installers are available at https://github.com/Andre-lab/ZEAL. Supplementary information Supplementary data are available at Bioinformatics online.
Topographic distribution of the EEG ad hoc broad bands during sleep and wakefulness in the spider monkey (Ateles Geoffroyi)

There is evidence that research on sleep among New World monkeys may provide important knowledge related to the evolution of sleep more broadly in the primate order. Digital electroencephalographic (EEG) analyses provide essential knowledge on sleep in the spider monkey. Recently, specific EEG bands related to sleep in these animals have been obtained using principal component analysis, but the exact spatio‐temporal distribution of these EEG bands in this species has not yet been analyzed. This study determined the topographic distribution of the EEG spectral power of ad hoc broad bands during rapid eye movement sleep, nonrapid eye movement sleep, and wakefulness. Superficial EEG activity was obtained from the occipital, frontal, and central areas of six young adult male monkeys housed in a laboratory. During wakefulness, occipital areas showed high absolute power in the 1–3, 3–12, and 11–30 Hz ranges, while during nonrapid eye movement 1 sleep the highest absolute power was in the 13–30 Hz range. During nonrapid eye movement 3 sleep, frontal and central areas showed a high absolute power in the 18–19 Hz range. Finally, the right central area showed a high absolute power in the 20–30 Hz range during rapid eye movement sleep. This topographic distribution of EEG bands could represent the brain organization required for arousal and mnemonic processing during sleep in the spider monkey.
When rice gets the chills: Comparative transcriptome profiling at germination shows WRKY transcription factors responses.

Rice is vital for food security. Due to its tropical origin, rice suffers from cold that affects the entire plant lifecycle. Key genes have been identified involved in cold tolerance. WRKY transcription factors have been reported downstream of cold signaling cascade and regulate cold responsive genes. WRKYs generally are downstream of MAPK cascade and can act together with VQ proteins to regulate stress-responsive genes. Chilling treatment was applied at germination in two rice genotypes (tolerant and sensitive). Shoots at S3 stage were collected for RNA-seq to identify OsWRKY, OsMAPKs and OsVQs expression. Relationships among MAPKs, WRKYs and VQs were predicted through correlation analysis. OsWRKY transcriptional regulation was predicted by in silico analysis of cis-regulatory elements. 39 OsWRKYs were differentially expressed. OsWRKY21, OsWRK24 and OsWRKY69 are potential positive while OsWRKY10, OsWRK47, OsWRKY62, OsWRKY72 and OsWRKY77 are potential negative regulators of chilling tolerance. 12 OsMAPKs were differentially expressed. OsMAPKs were downregulated and negatively correlated with the upregulated OsWRKYs in the tolerant genotype. 19 OsVQs were differentially expressed, 3 and 6 OsVQs were positively correlated with OsWRKYs in the tolerant and sensitive genotype, respectively. Seven differentially expressed OsWRKYs presented cold responsive elements in its promoters and five upregulated OsWRKYs in the tolerant genotype showed W-box motif. Chilling causes changes in OsWRKY, OsMAPK and OsVQ gene expression at germination. OsWRKYs may not act downstream of MAPK cascade to coordinate chilling tolerance. OsWRKYs may act with VQs to regulate chilling tolerance. Candidate OsWRKY are correlated and present W-box in its promoter suggesting an auto-regulation mechanism.
Managerial Communication and Frontline Workers’ Willingness to Abide by Rules: Evidence From Local Security Agencies in China

Previous research has studied both rule- and individual-level determinants of rule abidance of frontline workers, but the effect of managerial communication has not been adequately explored. Based on extant literature on street-level bureaucracy, managerial communication, and behavioral public administration, this study develops a novel framework to theorize the relationship between managerial communication and frontline workers’ willingness to abide by frontline rules. The framework highlights that managerial communication could improve frontline workers’ willingness to abide by rules by directly monitoring their behaviors or indirectly increasing their perceived rule clarity and risk of punishment. Moreover, as organizational size increases, the effect of managerial communication on frontline workers’ willingness to abide by rules decreases. The study uses unique data from a 2018–2019 survey covering 94 frontline managers and 717 frontline workers in local security agencies in mainland China to empirically test the hypotheses.
Aging Without Children: The Link between Parental Status and Tangible Support

Having children is a potential resource for care and support in later life. However, whether and, if so, under what conditions, childless older individuals risk insufficient support remains unclear. Using the Danish Longitudinal Study of Ageing (2017), restricted to respondents aged 67 years to 97 years (n = 5,006), our study analyzes the link between availability of tangible support and parental status in a Nordic welfare state. Our results confirm a negative link between childlessness and support mainly among unpartnered individuals. This combined disadvantage is stronger among men than among women, and the support gap intensifies with increased health needs. Taken together, although childlessness in itself is no major disadvantage for support in late life, childless men living alone risk insufficient support, particularly when in poor health. Our findings have important policy implications for future cohorts of older individuals, who will have less access to support from either a spouse or children.
A model for fostering creativity in the product development process

ABSTRACT The present paper illustrates a pilot experiment in which a new model for fostering creativity in the product development process is tested with novice engineers. After introducing creativity in the field of product development, the current author presents the new standard. The theoretical background that embodies the new model is presented, based on relevant literature. Making use of the new model, a methodology for testing it, using novice engineers is then proposed. It relies on the comparison between novices that were trained in the model in comparison to other novices that were not trained in the model. Higher results for creativity achieved by novice engineers that have employed the model show the advantages of its application during product development activities.
Transcriptome Profiling of the Ovarian Cells at the Single-Cell Resolution in Adult Asian Seabass

Single-cell RNA sequencing (scRNA-seq) is widely adopted for identifying the signature molecular markers or regulators in cells, as this would benefit defining or isolating various types of cells. Likewise, the signature transcriptome profile analysis at the single cell level would well illustrate the key regulators or networks involved in gametogenesis and gonad development in animals; however, there is limited scRNA-seq analysis on gonadal cells in lower vertebrates, especially in the sexual reversal fish species. In this study, we analyzed the molecular signature of several distinct cell populations of Asian seabass adult ovaries through scRNA-seq. We identified five cell types and also successfully validated some specific genes of germ cells and granulosa cells. Likewise, we found some key pathways involved in ovarian development that may concert germline-somatic interactions. Moreover, we compared the transcriptomic profiles across fruit fly, mammals, and fish, and thus uncovered the conservation and divergence in molecular mechanisms that might drive ovarian development. Our results provide a basis for studying the crucial features of germ cells and somatic cells, which will benefit the understandings of the molecular mechanisms behind gametogenesis and gonad development in fish.
Case Report: Could Hennebert's Sign Be Evoked Despite Global Vestibular Impairment on Video Head Impulse Test? Considerations Upon Pathomechanisms Underlying Pressure-Induced Nystagmus due to Labyrinthine Fistula

We describe a case series of labyrinthine fistula, characterized by Hennebert's sign (HS) elicited by tragal compression despite global hypofunction of semicircular canals (SCs) on a video-head impulse test (vHIT), and review the relevant literature. All three patients presented with different amounts of cochleo-vestibular loss, consistent with labyrinthitis likely induced by labyrinthine fistula due to different temporal bone pathologies (squamous cell carcinoma involving the external auditory canal in one case and middle ear cholesteatoma in two cases). Despite global hypofunction on vHIT proving impaired function for each SC for high accelerations, all patients developed pressure-induced nystagmus, presumably through spared and/or recovered activity for low-velocity canal afferents. In particular, two patients with isolated horizontal SC fistula developed HS with ipsilesional horizontal nystagmus due to resulting excitatory ampullopetal endolymphatic flows within horizontal canals. Conversely, the last patient with bony erosion involving all SCs developed mainly torsional nystagmus directed contralaterally due to additional inhibitory ampullopetal flows within vertical canals. Moreover, despite impaired measurements on vHIT, we found simultaneous direction-changing positional nystagmus likely due to a buoyancy mechanism within the affected horizontal canal in a case and benign paroxysmal positional vertigo involving the dehiscent posterior canal in another case. Based on our findings, we might suggest a functional dissociation between high (impaired) and low (spared/recovered) accelerations for SCs. Therefore, it could be hypothesized that HS in labyrinthine fistula might be due to the activation of regular ampullary fibers encoding low-velocity inputs, as pressure-induced nystagmus is perfectly aligned with the planes of dehiscent SCs in accordance with Ewald's laws, despite global vestibular impairment on vHIT. Moreover, we showed how pressure-induced nystagmus could present in a rare case of labyrinthine fistulas involving all canals simultaneously. Nevertheless, definite conclusions on the genesis of pressure-induced nystagmus in our patients are prevented due to the lack of objective measurements of both low-acceleration canal responses and otolith function.
The CRISPR-Cas System Is Involved in OmpR Genetic Regulation for Outer Membrane Protein Synthesis in Salmonella Typhi

The CRISPR-Cas cluster is found in many prokaryotic genomes including those of the Enterobacteriaceae family. Salmonella enterica serovar Typhi (S. Typhi) harbors a Type I-E CRISPR-Cas locus composed of cas3, cse1, cse2, cas7, cas5, cas6e, cas1, cas2, and a CRISPR1 array. In this work, it was determined that, in the absence of cas5 or cas2, the amount of the OmpC porin decreased substantially, whereas in individual cse2, cas6e, cas1, or cas3 null mutants, the OmpF porin was not observed in an electrophoretic profile of outer membrane proteins. Furthermore, the LysR-type transcriptional regulator LeuO was unable to positively regulate the expression of the quiescent OmpS2 porin, in individual S. Typhi cse2, cas5, cas6e, cas1, cas2, and cas3 mutants. Remarkably, the expression of the master porin regulator OmpR was dependent on the Cse2, Cas5, Cas6e, Cas1, Cas2, and Cas3 proteins. Therefore, the data suggest that the CRISPR-Cas system acts hierarchically on OmpR to control the synthesis of outer membrane proteins in S. Typhi.
Glycolysis and Fatty Acid Oxidation Inhibition Improves Survival in Glioblastoma

Glioblastoma (GBM) is the most aggressive adult glioma with a median survival of 14 months. While standard treatments (safe maximal resection, radiation, and temozolomide chemotherapy) have increased the median survival in favorable O(6)-methylguanine-DNA methyltransferase (MGMT)-methylated GBM (~21 months), a large proportion of patients experience a highly debilitating and rapidly fatal disease. This study examined GBM cellular energetic pathways and blockade using repurposed drugs: the glycolytic inhibitor, namely dicholoroacetate (DCA), and the partial fatty acid oxidation (FAO) inhibitor, namely ranolazine (Rano). Gene expression data show that GBM subtypes have similar glucose and FAO pathways, and GBM tumors have significant upregulation of enzymes in both pathways, compared to normal brain tissue (p < 0.01). DCA and the DCA/Rano combination showed reduced colony-forming activity of GBM and increased oxidative stress, DNA damage, autophagy, and apoptosis in vitro. In the orthotopic Gl261 and CT2A syngeneic murine models of GBM, DCA, Rano, and DCA/Rano increased median survival and induced focal tumor necrosis and hemorrhage. In conclusion, dual targeting of glycolytic and FAO metabolic pathways provides a viable treatment that warrants further investigation concurrently or as an adjuvant to standard chemoradiation for GBM.