Utilization of Additive Manufacturing Techniques for the Development of a Novel Scaffolds with Magnetic Properties for Potential Application in Enhanced Bone Regeneration.

This study focuses on designing and evaluating scaffolds with essential properties for bone regeneration, such as biocompatibility, macroporous geometry, mechanical strength, and magnetic responsiveness. The scaffolds are made using 3D printing with acrylic resin and iron oxides synthesized through solution combustion. Utilizing triply periodic minimal surfaces (TPMS) geometry and mask stereolithography (MSLA) printing, the scaffolds achieve precise geometrical features. The mechanical properties are enhanced through resin curing, and magnetite particles from synthesized nanoparticles and alluvial magnetite are added for magnetic properties. The scaffolds show a balance between stiffness, porosity, and magnetic responsiveness, with maximum compression strength between 4.8 and 9.2 MPa and Young's modulus between 58 and 174 MPa. Magnetic properties such as magnetic coercivity, remanence, and saturation are measured, with the best results from scaffolds containing synthetic iron oxides at 1% weight. The viscosity of the mixtures used for printing is between 350 and 380 mPas, and contact angles between 90° and 110° are achieved. Biocompatibility tests indicate the potential for clinical trials, though further research is needed to understand the impact of magnetic properties on cellular interactions and optimize scaffold design for specific applications. This integrated approach offers a promising avenue for the development of advanced materials capable of promoting enhanced bone regeneration.

A Better Understanding of Pediatric Autoimmune Pancreatitis: Over 13 Years of Experience.

OBJECTIVES: Pediatric autoimmune pancreatitis (P-AIP) is an uncommon disease whose diagnosis requires strong clinical suspicion. Late diagnosis increases morbidity. We aimed to compare the usefulness of the 2011 International Consensus Diagnostic Criteria (ICDC) for Autoimmune Pancreatitis with the 2018 INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE) criteria. METHODS: We retrospectively analyzed demographics and clinical, laboratory, radiological, and histological findings at diagnosis and during long-term follow-up in children diagnosed with AIP in 2 tertiary hospitals between 2008 and 2021. RESULTS: We included 11 patients [6 girls; median age at diagnosis, 12.5 (range 2.8-15.7) years]. The most common symptom was abdominal pain. Pancreatic enzymes were elevated in 10 patients, and serum immunoglobulin G4 was elevated in 1. Magnetic resonance imaging showed enlargement of the pancreatic head in 10 patients and general pancreatic enlargement in 1. Pancreatic and papilla tissue were obtained from 9 patients. All patients received corticosteroids (prednisolone), and 4 also received azathioprine. According to the ICDC, all patients were classified as probable or non-otherwise specified AIP. According to INSPPIRE criteria, all patients were classified as AIP. Using the INSPPIRE criteria would have avoided biopsies in 6 patients who responded well to corticosteroids. CONCLUSIONS: The INSPPIRE criteria are useful. Using the ICDC in pediatric patients can delay diagnosis and result in unnecessary invasive tests.

Identification of Active Compounds against Melanoma Growth by Virtual Screening for Non-Classical Human DHFR Inhibitors.

Antifolates such as methotrexate (MTX) have been largely known as anticancer agents because of their role in blocking nucleic acid synthesis and cell proliferation. Their mechanism of action lies in their ability to inhibit enzymes involved in the folic acid cycle, especially human dihydrofolate reductase (hDHFR). However, most of them have a classical structure that has proven ineffective against melanoma, and, therefore, inhibitors with a non-classical lipophilic structure are increasingly becoming an attractive alternative to circumvent this clinical resistance. In this study, we conducted a protocol combining virtual screening (VS) and cell-based assays to identify new potential non-classical hDHFR inhibitors. Among 173 hit compounds identified (average logP = 3.68; average MW = 378.34 Da), two-herein, called C1 and C2-exhibited activity against melanoma cell lines B16 and A375 by MTT and Trypan-Blue assays. C1 showed cell growth arrest (39% and 56%) and C2 showed potent cytotoxic activity (77% and 51%) in a dose-dependent manner. The effects of C2 on A375 cell viability were greater than MTX (98% vs 60%) at equivalent concentrations and times. Our results indicate that the integrated in silico/in vitro approach provided a benchmark to identify novel promising non-classical DHFR inhibitors showing activity against melanoma cells.

Inequities in diagnosis of Fragile X syndrome in Colombia.

BACKGROUND: Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and autism spectrum disorder (ASD). In Colombia, there are no screening or testing protocols established for the diagnosis of FXS. In this study, we aimed to describe the diagnostic trends of FXS in Colombia. METHODS: Data were included on 1322 individuals obtained based on data from the only 2 databases available. Sociodemographic information and data related to the diagnostic process were obtained and included in this study. RESULTS: The average age at the time of diagnosis for individuals with the full mutation (FM) was of 26.9 ± 2.57 years and was strongly dependent on sex and socioeconomic status. Most individuals with a molecular diagnosis were from the main cities. CONCLUSION: The overall age of diagnosis of FXS is later in life than reports from other countries. Restricted access to molecular testing through the national health system might explain this discrepancy in Colombia.

A phased approach to implementing the Breast Imaging Reporting and Data System (BI-RADS) in low-income and middle-income countries.

BACKGROUND: Successful breast cancer detection programs rely on standardized reporting and interpreting systems, such as the Breast Imaging Reporting and Data System (BI-RADS), to improve system performance. In low-income and middle-income countries, evolving diagnostic programs have insufficient resources to either fully implement BI-RADS or to periodically evaluate the program's performance, which is a necessary component of BI-RADS. This leads to inconsistent breast ultrasound interpretation and a failure to improve performance. METHODS: The authors applied the Breast Health Global Initiative's phased implementation strategy to implement diagnostic ultrasound and BI-RADS within the context of a limited-resource setting. RESULTS: The authors recommended starting with triage ultrasound to distinguish suspicious masses from normal breast tissue and benign masses such as cysts because the majority of health workers performing ultrasounds at this level have minimal breast imaging experience. Transitioning to full diagnostic ultrasound with condensed or full BI-RADS should occur after performance and quality metrics have been met. CONCLUSIONS: Transitioning through these phases across facilities likely will occur at different times, particularly in rural versus urban settings.

Postoperative thrombocytopenia: why you should consider antiplatelet therapy?

PURPOSE OF REVIEW: This review addresses the role of platelets in perioperative ischemic complications involving the brain, kidneys, and gastrointestinal tract, and long-term survival in patients undergoing coronary artery bypass grafting surgery. Importantly, findings of several recent clinical studies will be discussed with emphasis on platelet activation and leukocyte inflammatory responses as important mediators of vascular microthrombosis and ischemic injury. RECENT FINDINGS: Our recent findings suggest that in some patients, the hemostatic balance during and after surgery may shift toward a hypercoagulable state and contribute to acute organ failure. SUMMARY: For over 6 decades, major postoperative complications after cardiac surgery have remained unchanged. The potential influence of microthrombosis involving platelets has been underappreciated and use of perioperative antiplatelet therapy remains very limited - primarily because of a culture of fear of bleeding.

Neural signatures of opioid-induced risk-taking behavior in the prelimbic prefrontal cortex.

Opioid use disorder occurs alongside impaired risk-related decision-making, but the underlying neural correlates are unclear. We developed a novel approach-avoidance conflict model using a modified conditioned place preference paradigm to study neural signals of risky opioid seeking in the prefrontal cortex, a region implicated in executive decision making. Upon establishment of morphine conditioned place preference, rats underwent a subsequent conflict test in which fear-inducing cat odor was introduced in the previously drug-paired side of the apparatus. While the saline control group avoided the cat odor side, the morphine group maintained preference for the paired side despite the presence of cat odor. K-means clustering identified two subsets of morphine-treated rats that exhibited either persistent drug seeking (Risk-Takers) or increased avoidance (Risk-Avoiders) during conflict. Single-unit recordings from the prelimbic cortex (PL) revealed decreased neuronal firing rates upon acute morphine exposure in both Risk-Takers and Risk-Avoiders, but this firing rate suppression was absent after repeated administration. Risk-Avoiders also displayed distinct post-morphine excitation in PL which persisted across conditioning. During the preference test, subpopulations of PL neurons in all groups were either excited or inhibited when rats entered the paired side. Interestingly, while this inhibitory signal was lost during the subsequent conflict test in both saline and Risk-Avoider groups, these inhibitory responses persisted in Risk-Takers. Our results suggest that loss of PL inhibition after opioid conditioning is associated with the formation of contextual reward memory. Furthermore, persistent PL inhibitory signaling in the drug-associated context during conflict may underlie increased risk taking following opioid exposure.

Phosphorylation-induced flexibility of proto-oncogenic Bcl3 regulates transcriptional activation by NF-κB p52 homodimer.

B cell lymphoma 3 (Bcl3), a member of the IκB family proteins, modulates transcription by primarily associating with NF-κB p50 and p52 homodimers. Bcl3 undergoes extensive phosphorylation, though the functions of many of these modifications remain unclear. We previously described that phosphorylation at Ser33, Ser114 and Ser446 partially switches Bcl3 from acting as an IκB-like inhibitor to a transcription regulator by associating with the (p52:p52):DNA binary complex. Here, we identified another critical phosphorylation site, Ser366. Substituting at all four residues to phospho-mimetic glutamate further enhances Bcl3's transcriptional activity. Phospho-modifications retain Bcl3's ability to stably bind p52 but induces reciprocal structural changes as revealed by HDX-MS experiments; the N-terminal region stiffens, while the C-terminus becomes more flexible. The increased flexibility allowed the Bcl3:(p52p52) binary complex to better accommodate DNA. The removal of the C-terminal 28-residues transformed Bcl3 into a transcriptional activator independent of phosphorylation. Notably, most identified mutations in Bcl3 from various cancers map to its C-terminus, suggesting the functional relevance of Bcl3 C-terminal structural flexibility and enhanced interaction with (p52p52):DNA complex to transcriptional potential and disease. Overall, this study uncovers the mechanistic basis by which phosphorylation-driven structural changes convert Bcl3 from an inhibitor to a transcriptional cofactor of NF-κB, and how deregulation of its activity through altered phosphorylation or mutation can lead to cancer.

Non-Nucleoside Lycorine-Based Analogs as Potential DENV/ZIKV NS5 Dual Inhibitors: Structure-Based Virtual Screening and Chemoinformatic Analysis.

Dengue (DENV) and Zika (ZIKV) virus continue to pose significant challenges globally due to their widespread prevalence and severe health implications. Given the absence of effective vaccines and specific therapeutics, targeting the highly conserved NS5 RNA-dependent RNA polymerase (RdRp) domain has emerged as a promising strategy. However, limited efforts have been made to develop inhibitors for this crucial target. In this study, we employed an integrated in silico approach utilizing combinatorial chemistry, docking, molecular dynamics simulations, MM/GBSA, and ADMET studies to target the allosteric N-pocket of DENV3-RdRp and ZIKV-RdRp. Using this methodology, we designed lycorine analogs with natural S-enantiomers (LYCS) and R-enantiomers (LYCR) as potential inhibitors of non-structural protein 5 (NS5) in DENV3 and ZIKV. Notably, 12 lycorine analogs displayed a robust binding free energy (<-9.00 kcal/mol), surpassing that of RdRp-ribavirin (<-7.00 kcal/mol) along with promising ADMET score predictions (<4.00), of which (LYCR728-210, LYCS728-210, LYCR728-212, LYCS505-214) displayed binding properties to both DENV3 and ZIKV targets. Our research highlights the potential of non-nucleoside lycorine-based analogs with different enantiomers that may present different or even completely opposite metabolic, toxicological, and pharmacological profiles as promising candidates for inhibiting NS5-RdRp in ZIKV and DENV3, paving the way for further exploration for the development of effective antiviral agents.

Lumbar vertebral pattern variation in the common opossum (Didelphis marsupialis Linnaeus, 1758): implication on lumbar nerve distribution.

The lumbar nerve distribution can differ depending on vertebral count variations among individuals of the same species. The variation in the lumbar vertebra formula and the lumbar nerve distribution in twenty adult common opossums (eight female and twelve males) was studied. Radiographs were taken to confirm vertebral identification and count. Two vertebral patterns were recognized: three specimens presented five lumbar vertebrae (5VP) and seventeen individuals presented six lumbar vertebrae (6VP). All the 6VP specimens had the same innervation pattern; however, the 5PV had three different innervation patterns (5PVa, 5VPB, and 5PVc). 5VPa and 6VP differed only in the origin of the lateral femoral cutaneous nerve (L2-L3 and L3, respectively). The differences among 5PVa, 5PVb, and 5VPc were seen in the iliohypogastric nerve, which was formed by L1 in 5VPa and 5VPb, and T13 in 5VPc. The ilioinguinal nerve was formed by L1-L2 in 5VPa and 5VPb, while it was formed by T13-L1 in 5VPc. The genitofemoral nerve was formed by L2-L3 in 5VPa, L2 in 5VPb, and L1-L2 in 5VPc. The cutaneous femoris lateralis was formed by L2-L3 in 5VPa and 5VPc, while it is formed only by L2 in 5VPb. The femoral and obturator nerves were formed by L3-L4 in 5VPa, and L2-L3 in 5VPb and 5VPc. The lumbosacral trunk originated from L4-L5-S1 in 5VP and L5-L6-S1 in 6VP. The data provided in this study may help understand the relationship between the spine and lumbosacral plexus variations and may find application in veterinary spine surgery.

P-wave Sommerfeld enhancement near threshold: a simplified approach.

The calculation of P-wave Sommerfeld enhancement in processes with unstable particles in the final state is known to be divergent. In a complete description, where resonant (on-shell unstable particles) and non-resonant contributions are included, it has been shown that results are finite. For most beyond the Standard Model applications, these complete calculations are not readily available. In this work, we are interested in the near-threshold region and we consider only the resonant contribution. In this case, we provide a simplified prescription to compute the P-wave Sommerfeld enhancement in the narrow-width approximation of the unstable particle that directly eliminates divergences. We show that we can define a finite resonant contribution without the inclusion of the non-resonant processes in a way similar to the usual S-wave Sommerfeld enhancement.

Radiological features of nephrocalcinosis, a common but forgotten entity.

Nephrocalcinosis refers to calcium deposition in the form of calcium oxalate or calcium phosphate in the renal parenchyma and tubules. After diagnosis, the cause of nephrocalcinosis must be established to carry out a comprehensive approach to this entity. Although this is a common finding, it can be underdiagnosed due to the lack of knowledge of the different presentation patterns that exist. Many causes have been described related to this disease.A pictorial review about the most common features of cortical and medullary nephrocalcinosis both in ultrasound and CT is presented in the present work as well as a review of its main causes and graphics to easily recognize each pattern.

Clinical perspective in relation to age in patients treated with thrombectomy for anterior circulation stroke in a stroke center in Colombia.

BACKGROUND AND AIMS: Endovascular treatment for cerebrovascular disease is accepted as a first-line option with level I evidence in patients with an early and late time of window of onset symptoms, and an additional option in patients who do not respond or with contraindications to systemic thrombolysis; nevertheless the efficacy and outcomes of some groups were not clear, one of them are patients aged 80 years and older, because they were excluded of the trials, so the evidence is controversial with significant heterogeneity, for that reason in our study, we decided to analyze the age in the patients treated in our stroke center, as a predictor of prognosis, and to provide a baseline for the establishment of personalized treatment plans. METHODS: Observational, retrospective study of patients that received endovascular treatment for cerebrovascular disease in a Colombian stroke center between 2016 and 2020, continuous and categorical variables were compared using the Student's t test and Chi-Square. To determine cut-off points in the variable against death and Rankin score variable on 90th day. RESULTS: In total, 108 patients were recruited, 35 of them were of 80 or more years, and the mean age was 72.7 years, we found age as a significant variable to predict the risk in the population over 80 years of age [RR 3.37 CI (95% 1.14-103) p = 0.029]. CONCLUSIONS: Age younger than 80 is a significant predictor for results and long-term outcomes in patients suffering from stroke, and in patients older than 80 years old a Thrombolysis in Cerebral Infarction score 2b-3 is a predictor of good outcomes. Further studies are needed to evaluate the relationship between intrahospital complications and long-term outcomes.

Classical MD and metadynamics simulations on back-pocket binders of CDK2 and VEGFR2: a guidepost to design novel small-molecule dual inhibitors.

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.

Complications associated with the use of temporary pacemaker in patients waiting for definitive device implantation.

OBJECTIVE: To determine the rate of complications associated with the use of temporary pacemakers in patients in the waiting list for the definitive pacemaker implantation in a public hospital located in São Paulo, SP, Brazil. METHODS: Retrospective observational study based on data extracted from medical records of patients admitted to Hospital Municipal Dr. Moyses Deutsch, Hospital Israelita Albert Einstein from January 2014 to December 2018. Patients aged 18 years or older, diagnosed with high degree atrioventricular block upon admission and with indications for definitive pacemaker implantation were included. All-cause mortality, clinical and surgical complications and length of hospital stay while waiting for the procedure were defined as primary outcomes. RESULTS: The sample comprised 66 patient allocated to one of two groups: with and without the need of temporary pacemaker while in hospital (n=45 and n=21, respectively). The rate of complications was higher in patients who used a temporary pacemaker (p<0.001). These included primarily pneumonia (p=0.048) and length of hospital stay (p=0.029). CONCLUSION: Patients who required a temporary pacemaker stayed longer in hospital. Longer hospital stay is associated with higher rates of general complications and all-cause mortality.

Novel covalent and non-covalent complex-based pharmacophore models of SARS-CoV-2 main protease (Mpro) elucidated by microsecond MD simulations.

As the world enters its second year of the pandemic caused by SARS-CoV-2, intense efforts have been directed to develop an effective diagnosis, prevention, and treatment strategies. One promising drug target to design COVID-19 treatments is the SARS-CoV-2 Mpro. To date, a comparative understanding of Mpro dynamic stereoelectronic interactions with either covalent or non-covalent inhibitors (depending on their interaction with a pocket called S1' or oxyanion hole) has not been still achieved. In this study, we seek to fill this knowledge gap using a cascade in silico protocol of docking, molecular dynamics simulations, and MM/PBSA in order to elucidate pharmacophore models for both types of inhibitors. After docking and MD analysis, a set of complex-based pharmacophore models was elucidated for covalent and non-covalent categories making use of the residue bonding point feature. The highest ranked models exhibited ROC-AUC values of 0.93 and 0.73, respectively for each category. Interestingly, we observed that the active site region of Mpro protein-ligand complex undergoes large conformational changes, especially within the S2 and S4 subsites. The results reported in this article may be helpful in virtual screening (VS) campaigns to guide the design and discovery of novel small-molecule therapeutic agents against SARS-CoV-2 Mpro protein.

Clinical and CT patterns to predict EGFR mutation in patients with non-small cell lung cancer: A systematic literature review and meta-analysis.

PURPOSE: This study aims to determine if the presence of specific clinical and computed tomography (CT) patterns are associated with epidermal growth factor receptor (EGFR) mutation in patients with non-small cell lung cancer. METHODS: A systematic literature review and meta-analysis was carried out in 6 databases between January 2002 and July 2021. The relationship between clinical and CT patterns to detect EGFR mutation was measured and pooled using odds ratios (OR). These results were used to build several mathematical models to predict EGFR mutation. RESULTS: 34 retrospective diagnostic accuracy studies met the inclusion and exclusion criteria. The results showed that ground-glass opacities (GGO) have an OR of 1.86 (95%CI 1.34 -2.57), air bronchogram OR 1.60 (95%CI 1.38 - 1.85), vascular convergence OR 1.39 (95%CI 1.12 - 1.74), pleural retraction OR 1.99 (95%CI 1.72 - 2.31), spiculation OR 1.42 (95%CI 1.19 - 1.70), cavitation OR 0.70 (95%CI 0.57 - 0.86), early disease stage OR 1.58 (95%CI 1.14 - 2.18), non-smoker status OR 2.79 (95%CI 2.34 - 3.31), female gender OR 2.33 (95%CI 1.97 - 2.75). A mathematical model was built, including all clinical and CT patterns assessed, showing an area under the curve (AUC) of 0.81. CONCLUSIONS: GGO, air bronchogram, vascular convergence, pleural retraction, spiculated margins, early disease stage, female gender, and non-smoking status are significant risk factors for EGFR mutation. At the same time, cavitation is a protective factor for EGFR mutation. The mathematical model built acts as a good predictor for EGFR mutation in patients with lung adenocarcinoma.

Non-Extensive Fragmentation of Natural Products and Pharmacophore-Based Virtual Screening as a Practical Approach to Identify Novel Promising Chemical Scaffolds.

Fragment-based drug design (FBDD) and pharmacophore modeling have proven to be efficient tools to discover novel drugs. However, these approaches may become limited if the collection of fragments is highly repetitive, poorly diverse, or excessively simple. In this article, combining pharmacophore modeling and a non-classical type of fragmentation (herein called non-extensive) to screen a natural product (NP) library may provide fragments predicted as potent, diverse, and developable. Initially, we applied retrosynthetic combinatorial analysis procedure (RECAP) rules in two versions, extensive and non-extensive, in order to deconstruct a virtual library of NPs formed by the databases Traditional Chinese Medicine (TCM), AfroDb (African Medicinal Plants database), NuBBE (Nuclei of Bioassays, Biosynthesis, and Ecophysiology of Natural Products), and UEFS (Universidade Estadual de Feira de Santana). We then developed a virtual screening (VS) using two groups of natural-product-derived fragments (extensive and non-extensive NPDFs) and two overlapping pharmacophore models for each of 20 different proteins of therapeutic interest. Molecular weight, lipophilicity, and molecular complexity were estimated and compared for both types of NPDFs (and their original NPs) before and after the VS proceedings. As a result, we found that non-extensive NPDFs exhibited a much higher number of chemical entities compared to extensive NPDFs (45,355 vs. 11,525 compounds), accounting for the larger part of the hits recovered and being far less repetitive than extensive NPDFs. The structural diversity of both types of NPDFs and the NPs was shown to diminish slightly after VS procedures. Finally, and most interestingly, the pharmacophore fit score of the non-extensive NPDFs proved to be not only higher, on average, than extensive NPDFs (56% of cases) but also higher than their original NPs (69% of cases) when all of them were also recognized as hits after the VS. The findings obtained in this study indicated that the proposed cascade approach was useful to enhance the probability of identifying innovative chemical scaffolds, which deserve further development to become drug-sized candidate compounds. We consider that the knowledge about the deconstruction degree required to produce NPDFs of interest represents a good starting point for eventual synthesis, characterization, and biological activity studies.

Discovery of new potential CDK2/VEGFR2 type II inhibitors by fragmentation and virtual screening of natural products.

Cyclin-Dependent Kinase 2 (CDK2) and Vascular Endothelial Growth Factor Receptor (VEGFR2) have largely been considered as attractive targets for developing anticancer agents. However, there is no dual inhibitor commercially available in the market that interacts simultaneously with the allosteric back pocket of these enzymes. We applied a combined computational strategy that started with the generation of two overlapping pharmacophore models of both kinases at 'inactive' conformation. Next, several virtual libraries of natural products, including the databases TCM (Traditional Chinese Medicine), UEFS (Universidade Estadual de Feira de Santana), NuBBE (Nuclei of Bioassays, Biosynthesis, and Ecophysiology of Natural Products) and AfroDb (African Medicinal Plants Database) were deconstructed using a non-extensive version of the approach RECAP (retrosynthetic combinatorial analysis procedure). These natural-product-derived fragments (NPDFs) were screened and merged into drug-sized compounds, which were filtered by Lipinski's Rule-of-five (Ro5) and docking. As a result, two pharmacophore models, namely Hypo1 and Hypo2, were developed with an accuracy of 0.94 and 0.84, respectively. Deconstruction of natural products produced a set of 16655 unique non-extensive NPDFs that were screened against both pharmacophore models. Finally, after merging, Ro5-filtering and docking, we obtained a set of 20 hit compounds predicted to be diverse, developable, synthesizable and potent. The computational strategy proved successful to find virtual candidates of kinase inhibitors and therefore contributes to the identification of innovative multi-target compounds with potential anticancer activity. Communicated by Ramaswamy H. Sarma.

The Clinics of Work: An Alternative Vision of Occupational Health.

This theoretical paper depicts the clinics of work as a subdisciplinary and interdisciplinary field of the social psychology of work and organizations, interested in analyzing and intervening from a critical-clinical perspective in the subjectivity-work-context relationship, in the context of discomfort, suffering, and pleasure, and thus, in the mental health within this field. Consequently, it separates from traditional occupational health, which ignores subjective singularities. The subdiscipline of CW develops the determinants of pleasure, discomfort, and suffering at work, standing out in the process as a possible alternative of occupational health, based on research practice and intervention from a critical perspective.

Este artículo teórico presenta las clínicas del trabajo como campo subdisciplinar e interdisciplinar de la psicología social de las organizaciones y del trabajo, interesado en analizar e intervenir desde una perspectiva clínico-crítica sobre las relaciones subjetividad-trabajo-contexto, en clave de malestar, sufrimiento y placer, y, por ende, en la salud mental en este campo, deslindado de la salud ocupacional tradicional que se aleja de la singularidad subjetiva. Se desarrollan los determinantes del placer, el malestar y el sufrimiento en el trabajo y subraya desde la perspectiva crítica cómo puede ser una alternativa posible a la salud ocupacional como práctica investigativa y de intervención.