Miracle-dz/UniFAR-FTUs huggingface dataset:
Identifying SARS-CoV-2 main protease inhibitors by applying the computer screening of a large database of molecules

ABSTRACT The outbreak of coronavirus disease 2019 (COVID-19) at the end of 2019 affected global health. Its infection agent was called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Wearing a mask, maintaining social distance, and vaccination are effective ways to prevent infection of SARS-CoV-2, but none of them help infected people. Targeting the enzymes of SARS-CoV-2 is an effective way to stop the replication of the virus in infected people and treat COVID-19 patients. SARS-CoV-2 main protease is a therapeutic target which the inhibition of its enzymatic activity prevents from the replication of SARS-CoV-2. A large database of molecules has been searched to identify new inhibitors for SARS-CoV-2 main protease enzyme. At the first step, ligand screening based on similarity search was used to select similar compounds to known SARS-CoV-2 main protease inhibitors. Then molecules with better predicted pharmacokinetic properties were selected. Structure-based virtual screening based on the application of molecular docking and molecular dynamics simulation methods was used to select more effective inhibitors among selected molecules in previous step. Finally two compounds were considered as SARS-CoV-2 main protease inhibitors.
Systemic allergic contact dermatitis caused by tea tree oil in a cream for treatment of molluscum contagiosum

Lack of response or worsening of psoriasis during topical treatment should cause suspicion of allergic contact dermatitis. For instance, cases of allergic contact dermatitis to calcipotriol have been reported. No cross-reactivity with other topical vitamin D analogues has been demonstrated. However, not only active, but also non-active ingredients of topical preparations should be considered. The culprit allergen in the presented case was cetylstearyl alcohol (also known as lanette O or cetearyl alcohol) which is commonly used as a stabilizer and emollient in topical drugs and cosmetics, including body depilatory creams and hair dyes, among others. It is obtained from a mixture of cetyl alcohol and stearyl alcohol. Patch test reactions should be interpreted with caution because of their high irritation potential, mainly related to cetyl alcohol. Cetylstearyl alcohol rarely causes allergic contact dermatitis. A few cases related to cetylstearyl alcohol in topical treatments have been reported, including cases caused by Thrombocid ointment (LACER, S.A.), Burnol-plus cream (Reckitt Benckiser [M] SDN. BHD), and Bepanthene Plus cream (Roche Polska). In summary, we present a new case of allergic contact dermatitis to cetylstearyl alcohol present as an excipient of Daivonex cream in a psoriasis patient. Patch testing with active and non-active ingredients is relevant for a correct diagnosis of allergic contact dermatitis in these patients with suspected allergic contact dermatitis to topical preparations.
Treatment of carbapenem-resistant Pseudomonas aeruginosa infections: a case for cefiderocol

ABSTRACT Introduction Carbapenem-resistant (CR) Pseudomonas aeruginosa infections constitute a serious clinical threat globally. Patients are often critically ill and/or immunocompromised. Antibiotic options are limited and are currently centered on beta-lactam–beta-lactamase inhibitor (BL–BLI) combinations and the siderophore cephalosporin cefiderocol. Areas covered This article reviews the mechanisms of P. aeruginosa resistance and their potential impact on the activity of current treatment options, along with evidence for the clinical efficacy of BL–BLI combinations in P. aeruginosa infections, some of which specifically target infections due to CR organisms. The preclinical and clinical evidence supporting cefiderocol as a treatment option for P. aeruginosa involving infections is also reviewed. Expert opinion Cefiderocol is active against most known P. aeruginosa mechanisms mediating carbapenem resistance. It is stable against different serine- and metallo-beta-lactamases, and, due to its iron channel-dependent uptake mechanism, is not impacted by porin channel loss. Furthermore, the periplasmic level of cefiderocol is not affected by upregulated efflux pumps. The potential for on-treatment resistance development currently appears to be low, although more clinical data are required. Information from surveillance programs, real-world compassionate use, and clinical studies demonstrate that cefiderocol is an important treatment option for CR P. aeruginosa infections.
Clear Cell Papillary Renal Cell Tumors: A Study of 42 Tumors with Emphasis on the Fibrous Capsule, Cystic Component, and GATA3 Immunohistochemistry

Clear cell papillary renal cell tumor is a common and sometimes underdiagnosed renal cell neoplasm. Its proper recognition is important because its diagnosis implies a remarkably high probability of indolent behavior. This study aimed to evaluate the frequency of a fibrous capsule, a cystic component, and a GATA3 expression in clear cell papillary renal cell tumors. We assessed 419 renal cell neoplasms from three institutions located in northeastern Brazil and identified 42 clear cell papillary renal cell tumors (from 39 patients), which were the fourth most common renal cell neoplasm. These tumors commonly exhibited fibrous capsules (all showed complete or partial capsules) and cystic component (93%). Eighteen out of 42 tumors (43%) showed some expression of GATA3, and weak and focal staining was common among the positive tumors. Clear cell papillary renal cell tumor must always be included in the differential diagnosis of predominantly cystic renal cell neoplasms. As GATA3 is inconsistently expressed in clear cell papillary renal cell tumors, it is not useful in this diagnosis.
Epstein–Barr virus and malaria upregulate AID and APOBEC3 enzymes, but only AID seems to play a major mutagenic role in Burkitt lymphoma

Endemic Burkitt lymphoma (eBL) is characterized by an oncogenic IGH/c‐MYC translocation and Epstein–Barr virus (EBV) positivity, and is epidemiologically linked to Plasmodium falciparum malaria. Both EBV and malaria are thought to contribute to eBL by inducing the expression of activation‐induced cytidine deaminase (AID), an enzyme involved in the IGH/c‐MYC translocation. AID/apolipoprotein B mRNA editing catalytic polypeptide‐like (AID/APOBEC) family enzymes have recently emerged as potent mutagenic sources in a variety of cancers, but apart from AID, their involvement in eBL and their regulation by EBV and P. falciparum is unknown. Here, we show that upon inoculation with EBV, human B cells strongly upregulate the expression of enzymatically active APOBEC3B and APOBEC3G. In addition, we found significantly increased levels of APOBEC3A in B cells of malaria patients, which correlated with parasite load. Interestingly, despite the fact that APOBEC3A, APOBEC3B, and APOBEC3G caused c‐MYC mutations when overexpressed in HEK293T cells, a mutational enrichment in eBL tumors was only detected in AID motifs. This suggests that even though the EBV‐ and P. falciparum‐directed immune response triggers the expression and activity of several AID/APOBEC members, only the upregulation of AID has oncogenic consequences, while the induction of the APOBEC3 subfamily may primarily have immunoprotective functions.
Routine punctoplasty: isn’t it time we preserved the integrity of the punctum?

ABSTRACT Punctoplasty is a common procedure in the management of punctal stenosis and was first described by Sir William Bowman in 1853. Several types of punctoplasty are described, and include 1-snip, 2-snip, triangular 3-snip, rectangular 3-snip and 4-snip procedures. The understanding of the anatomy and physiology of the punctum has greatly improved in the last decade aided by electron microscopic and molecular techniques. The use of minimally invasive modalities for primary cases is on the rise with successful preservation of the physiological functions of the punctum and canaliculus. The paper reviews the current anatomical and physiological evidence to present an alternative perspective. Given our evolving understanding, it may be time to debate the practice of performing routine punctoplasty.
Image-Free Fast Ultrasound for Measurement of Local Pulse Wave Velocity: In Vitro Validation and In Vivo Feasibility

Local pulse wave velocity (PWV), a metric of the target artery’s stiffness, has been emerging in its clinical value and adoption. State-of-the-art ultrasound technologies used to evaluate local PWV based on pulse waves’ features are sophisticated, non-real-time, and are not amenable for field and resource-constrained settings. In this work, we present an image-free ultrasound system to measure local PWV in real-time by employing a pair of ultrasound transducer elements. An <italic>in vitro</italic> study was performed on the arterial phantom to: 1) characterize the design aspects of the system and 2) validate its accuracy against beat-by-beat (invasive) local PWV measured by a reference dual-element catheter. Furthermore, a repeatability and reproducibility study on 33 subjects (21–52 years) investigated the in vivo measurement feasibility from the carotid artery. With the experimentally deduced optimal design (frame-rate <inline-formula> <tex-math notation="LaTeX">$=500$ </tex-math></inline-formula> Hz, RF sampling rate <inline-formula> <tex-math notation="LaTeX">$=125$ </tex-math></inline-formula> MHz, LPF cutoff <inline-formula> <tex-math notation="LaTeX">$=14$ </tex-math></inline-formula> Hz, and order <inline-formula> <tex-math notation="LaTeX">$=4$ </tex-math></inline-formula>), the system yielded repeatable beat-to-beat measurements (variability <inline-formula> <tex-math notation="LaTeX">$=1.9$ </tex-math></inline-formula>% and over 15 cycles) and achieved a high accuracy (root-mean-square-error <inline-formula> <tex-math notation="LaTeX">$=0.19$ </tex-math></inline-formula> m/s and absolute-percentage-error <inline-formula> <tex-math notation="LaTeX">$=2.4$ </tex-math></inline-formula>%) over a wide range of PWVs (2.7–11.4 m/s) from the phantom. Subsequently, on human subjects, the intra- and inter-operator PWV measurements were highly repeatable (intraclass correlation coefficient <inline-formula> <tex-math notation="LaTeX">$>0.92$ </tex-math></inline-formula>). The system does not impose a demand for special processors with high-computational power while offering real-time feedback on acquisition and measurement quality and provides local PWV online. Future large population and animal studies are required to establish the device’s clinical usability.
Genome-Wide Knockout Screen Identifies Human Sialomucin CD164 as an Essential Entry Factor for Lymphocytic Choriomeningitis Virus

Lymphocytic choriomeningitis virus (LCMV) is a human-pathogenic mammarenavirus that can be fatal in congenital infections. Although frequently used in the study of persistent infections in the field of immunology, aspects of this virus’s life cycle remain incomplete. ABSTRACT Lymphocytic choriomeningitis virus (LCMV) is a well-studied mammarenavirus that can be fatal in congenital infections. However, our understanding of LCMV and its interactions with human host factors remains incomplete. Here, host determinants affecting LCMV infection were investigated through a genome-wide CRISPR knockout screen in A549 cells, a human lung adenocarcinoma line. We identified and validated a variety of novel host factors that play a functional role in LCMV infection. Among these, knockout of the sialomucin CD164, a heavily glycosylated transmembrane protein, was found to ablate infection with multiple LCMV strains but not other hemorrhagic mammarenaviruses in several cell types. Further characterization revealed a dependency of LCMV entry on the cysteine-rich domain of CD164, including an N-linked glycosylation site at residue 104 in that region. Given the documented role of LCMV with respect to transplacental human infections, CD164 expression was investigated in human placental tissue and placental cell lines. CD164 was found to be highly expressed in the cytotrophoblast cells, an initial contact site for pathogens within the placenta, and LCMV infection in placental cells was effectively blocked using a monoclonal antibody specific to the cysteine-rich domain of CD164. Together, this study identifies novel factors associated with LCMV infection of human tissues and highlights the importance of CD164, a sialomucin that previously had not been associated with viral infection. IMPORTANCE Lymphocytic choriomeningitis virus (LCMV) is a human-pathogenic mammarenavirus that can be fatal in congenital infections. Although frequently used in the study of persistent infections in the field of immunology, aspects of this virus’s life cycle remain incomplete. For example, while viral entry has been shown to depend on a cell adhesion molecule, DAG1, genetic knockout of this gene allows for residual viral infection, implying that additional receptors can mediate cell entry. The significance of our study is the identification of host factors important for successful infection, including the sialomucin CD164, which had not been previously associated with viral infection. We demonstrated that CD164 is essential for LCMV entry into human cells and can serve as a possible therapeutic target for treatment of congenital infection.
Slipped Capital Femoral Epiphysis Associated With Athletic Activity

Background: Little data exist regarding the association of slipped capital femoral epiphysis (SCFE) and sporting activities. Hypothesis: There is no association between SCFE and sporting activities. Study Design: Retrospective review of all SCFE cases at our institution from 2010 through March 2021. Level of Evidence: Level 3. Methods: All patients with idiopathic SCFE were reviewed looking for the presence/absence of sporting activities and symptom onset. Also collected were the age, symptom duration, and weight/height of the patient, sex, race, and stable/unstable nature of the SCFE. The severity of the SCFE was measured using the lateral epiphyseal-shaft angle. Results: There were 193 children (110 boys, 83 girls) with idiopathic SCFEs. The SCFE was stable in 147, unstable in 45, and unknown in 1. The average age was 12.1 ± 1.8 years, average SCFE angle 38° ± 20° and symptom duration 4.0 ± 5.1 months. An association with a sporting activity was present in 64 (33%). The sporting activity was basketball (18), football (11), baseball/softball (10), and others (23). Football, basketball, and soccer predominated in boys, baseball and running sports were equal between boys and girls, and cheerleading/gymnastics/dancing predominated in girls. Differences showed that those involved in sports had a slightly lower body mass index (BMI) (88th percentile vs 95th percentile, P = 0.00). There were no differences between those involved and those not those involved in sporting activities for symptom duration, SCFE severity, sex, race, or stable/unstable SCFE type. Conclusion: Sporting activities are associated with the onset of symptoms in 1 of 3 of patients with SCFE, refuting the null hypothesis. Clinical Relevance: A high level of suspicion for SCFE should be given when any peripubertal athlete presents with hip or knee pain regardless of BMI/obesity status, and appropriate imaging performed.
Screening of Organophosphate Flame Retardants with Placentation-Disrupting Effects in Human Trophoblast Organoid Model and Characterization of Adverse Pregnancy Outcomes in Mice

Background: Abnormal placental development may result in adverse pregnancy outcomes and metabolic diseases in adulthood; however, it remains unknown whether and how xenobiotics affect human placentation. Objectives: This study aimed to screen and identify placentation-disrupting chemicals in commonly used organophosphate flame retardants (OPFRs) and, if identified, to investigate potential adverse effects on placentation in relation to adverse pregnancy outcomes and metabolic disorder in offspring in mice. Methods: We devised a high-throughput immunofluorescence screening assay based on human trophoblast organoids and used it to screen OPFRs that inhibit the proliferation of organoids. One identified chemical was assessed for its effects on placentation by evaluating villous cytotrophoblasts, syncytiotrophoblasts, and extravillous trophoblasts using immunofluorescence and a mitochondrial stress test after 2 d of exposure. A 10-d exposure study was further performed to observe the dynamic effect of the OPFR on the structure of the organoids. RNA-sequencing and western blotting experiments were performed to explore the associated pathways, and a potential binding protein was identified by immunoprecipitation and in vitro kinase activity assays. Animal studies were performed to determine whether the findings in organoids could be replicated in mice and to observe adverse pregnancy outcomes. Results: The proliferation of organoids exposed to three aryl-OPFRs was significantly lower than the proliferation of control organoids. Further analysis demonstrated that one such chemical, 2-ethylhexyl-diphenyl phosphate (EHDPP), disrupted placentation in organoids. Mechanistically, EHDPP interfered with insulin-like growth factor 1 receptor (IGF1R) to inhibit aerobic respiration. Mice exposed to EHDPP at a physiological human concentrations exhibited immature and mature placental disorders, which correlated with fetal growth restriction, implantation failure, stillbirth, and impaired glucose tolerance. Conclusions: The human trophoblast organoid model showed that the commonly used OPFRs disrupted placentation via IGF1R, indicating that its use may contribute to adverse pregnancy outcomes and metabolic disorders in offspring. https://doi.org/10.1289/EHP10273
A Structural View of Alkyl-Coenzyme M Reductases, the First Step of Alkane Anaerobic Oxidation Catalyzed by Archaea

Microbial anaerobic oxidation of alkanes intrigues the scientific community by way of its impact on the global carbon cycle, and its biotechnological applications. Archaea are proposed to degrade short- and long-chain alkanes to CO2 by reversing methanogenesis, a theoretically reversible process. The pathway would start with alkane activation, an endergonic step catalyzed by methyl-coenzyme M reductase (MCR) homologues that would generate alkyl-thiols carried by coenzyme M. While the methane-generating MCR found in methanogens has been well characterized, the enzymatic activity of the putative alkane-fixing counterparts has not been validated so far. Such an absence of biochemical investigations contrasts with the current explosion of metagenomics data, which draws new potential alkane-oxidizing pathways in various archaeal phyla. Therefore, validating the physiological function of these putative alkane-fixing machines and investigating how their structures, catalytic mechanisms, and cofactors vary depending on the targeted alkane have become urgent needs. The first structural insights into the methane- and ethane-capturing MCRs highlighted unsuspected differences and proposed some explanations for their substrate specificity. This Perspective reviews the current physiological, biochemical, and structural knowledge of alkyl-CoM reductases and offers fresh ideas about the expected mechanistic and chemical differences among members of this broad family. We conclude with the challenges of the investigation of these particular enzymes, which might one day generate biofuels for our modern society.
Effects of doxorubicin and apigenin on chronic myeloid leukemia cells (K562) in vitro: anti-proliferative and apoptosis induction assessments

Abstract In this study, we aimed to investigate the effect of the co-treatment with apigenin and doxorubicin (DOX) on K562 cells. Our results show that apigenin (0, 40, 60, 80 ,100 µM) and DOX (0–10 µM) as single therapy, could decrease K562 cell viability (after 24 h of treatment) in a dose-dependent manner. Additionally, the co-treatment with apigenin (60, 80 µM) and 10 µM of DOX led to a greater reduction in cell growth (CI: 0.92 and 0.97) after 24 h of treatment compared to the single DOX treatment (p < 0.05). Consequently, apigenin and DOX, either as single or as co-treatment (24 h of treatment), were indicated to induce apoptosis in K562 cells through morphological studies, RT-qPCR, and western-blot analysis. Eventually, the expressions of Caspase 3, 6, 7, and 9 genes in the single treatment with DOX had higher alteration compared to the co-treatment with DOX and apigenin (p < 0.05). Graphical Abstract
Multichannel Synthetic Preictal EEG Signals to Enhance the Prediction of Epileptic Seizures

Epilepsy is a chronic neurological disorder affecting 1% of people worldwide, deep learning (DL) algorithms-based electroencephalograph (EEG) analysis provides the possibility for accurate epileptic seizure (ES) prediction, thereby benefiting patients suffering from epilepsy. To identify the preictal region that precedes the onset of seizure, a large number of annotated EEG signals are required to train DL algorithms. However, the scarcity of seizure onsets leads to significant insufficiency of data for training the DL algorithms. To overcome this data insufficiency, in this paper, we propose a preictal artificial signal synthesis algorithm based on a generative adversarial network to generate synthetic multichannel EEG preictal samples. A high-quality single-channel architecture, determined by visual and statistical evaluations, is used to train the generators of multichannel samples. The effectiveness of the synthetic samples is evaluated by comparing the ES prediction performances without and with synthetic preictal sample augmentation. The leave-one-seizure-out cross validation ES prediction accuracy and corresponding area under the receiver operating characteristic curve evaluation improve from 73.0% and 0.676 to 78.0% and 0.704 by 10× synthetic sample augmentation, respectively. The obtained results indicate that synthetic preictal samples are effective for enhancing ES prediction performance.
Karyotype Evolution of Talking Thorny Catfishes Anadoras (Doradidae, Astrodoradinae): A Process Mediated by Structural Rearrangements and Intense Reorganization of Repetitive DNAs

Anadoras is a thorny catfish genus widespread through the Amazon and Paraguay river basins. It includes 2 nominal species, A. grypus and A. weddellii, plus Anadoras sp. “araguaia,” an undescribed species only recognized morphologically. Since Anadoras occupies a basal position within the Astrodoradinae phylogeny, it is crucial to identify its cytogenetic features to comprehend the mechanisms involved in the chromosomal diversification of this subfamily. Therefore, we performed a comparative cytogenetic analysis including all species of Anadoras. Furthermore, we applied a species delimitation analysis based on 600 bp of the mitochondrial cytochrome oxidase subunit 1 (CO1) gene to investigate the taxonomic status of the species. Cytogenetic markers revealed a high degree of similarity among Anadoras weddellii and Anadoras sp. “araguaia,” both have 2n = 56 chromosomes (24m + 10sm + 22st/a), single NOR sites on acrocentric pair 28, and 5S rDNA sites on submetacentric pair 15. A. grypus has the most divergent chromosomal characteristics because, even though it also has 2n = 56 chromosomes, it exhibits several differences in the chromosome formula, heterochromatin distribution, and number/position of the rDNA sites. In sum, we believe that the chromosome diversification of Anadoras is due to 4 mechanisms: centric fusion, pericentric/paracentric inversions, nonreciprocal translocations, and activity of transposable elements. Additionally, our phylogenetic tree revealed well-supported clades and, by barcode species delimitation analysis, confirmed the existence of 3 molecular operational taxonomic units, including the putative new species Anadoras sp. “araguaia. ”