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When a heavy atomic nucleus splits (fission), the resulting fragments are observed to emerge spinning1; this phenomenon has been a mystery in nuclear physics for over 40 years2,3. The internal generation of typically six or seven units of angular momentum in each fragment is particularly puzzling for systems that start with zero, or almost zero, spin. There are currently no experimental observations that enable decisive discrimination between the many competing theories for the mechanism that generates the angular momentum4-12. Nevertheless, the consensus is that excitation of collective vibrational modes generates the intrinsic spin before the nucleus splits (pre-scission). Here we show that there is no significant correlation between the spins of the fragment partners, which leads us to conclude that angular momentum in fission is actually generated after the nucleus splits (post-scission). We present comprehensive data showing that the average spin is strongly mass-dependent, varying in saw-tooth distributions. We observe no notable dependence of fragment spin on the mass or charge of the partner nucleus, confirming the uncorrelated post-scission nature of the spin mechanism. To explain these observations, we propose that the collective motion of nucleons in the ruptured neck of the fissioning system generates two independent torques, analogous to the snapping of an elastic band. A parameterization based on occupation of angular momentum states according to statistical theory describes the full range of experimental data well. This insight into the role of spin in nuclear fission is not only important for the fundamental understanding and theoretical description of fission, but also has consequences for the γ-ray heating problem in nuclear reactors13,14, for the study of the structure of neutron-rich isotopes15,16, and for the synthesis and stability of super-heavy elements17,18.
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Bacteriophages typically have small genomes1 and depend on their bacterial hosts for replication2. Here we sequenced DNA from diverse ecosystems and found hundreds of phage genomes with lengths of more than 200 kilobases (kb), including a genome of 735 kb, which is-to our knowledge-the largest phage genome to be described to date. Thirty-five genomes were manually curated to completion (circular and no gaps). Expanded genetic repertoires include diverse and previously undescribed CRISPR-Cas systems, transfer RNAs (tRNAs), tRNA synthetases, tRNA-modification enzymes, translation-initiation and elongation factors, and ribosomal proteins. The CRISPR-Cas systems of phages have the capacity to silence host transcription factors and translational genes, potentially as part of a larger interaction network that intercepts translation to redirect biosynthesis to phage-encoded functions. In addition, some phages may repurpose bacterial CRISPR-Cas systems to eliminate competing phages. We phylogenetically define the major clades of huge phages from human and other animal microbiomes, as well as from oceans, lakes, sediments, soils and the built environment. We conclude that the large gene inventories of huge phages reflect a conserved biological strategy, and that the phages are distributed across a broad bacterial host range and across Earth's ecosystems.
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Bactérias/virologia , Bacteriófagos/classificação , Bacteriófagos/genética , Planeta Terra , Ecossistema , Genoma Viral/genética , Filogenia , Aminoacil-tRNA Sintetases/genética , Animais , Bactérias/genética , Bacteriófagos/isolamento & purificação , Bacteriófagos/metabolismo , Biodiversidade , Sistemas CRISPR-Cas/genética , Evolução Molecular , Regulação Bacteriana da Expressão Gênica , Regulação Viral da Expressão Gênica , Especificidade de Hospedeiro , Humanos , Lagos/virologia , Anotação de Sequência Molecular , Oceanos e Mares , Prófagos/genética , Biossíntese de Proteínas , RNA de Transferência/genética , Proteínas Ribossômicas/genética , Água do Mar/virologia , Microbiologia do Solo , Transcrição GênicaRESUMO
In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which has recently been implicated in the regulation of diverse molecular processes. However, because lncRNAs do not encode protein, there is uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements is challenging. The Developmental Genome Anatomy Project (DGAP) and similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes in order to annotate the human genome. We hypothesized that rearrangements disrupting lncRNAs could be the underlying genetic etiology for the phenotypes of a subset of these individuals. Thus, we assessed 279 cases with BCAs and selected 191 cases with simple BCAs (breakpoints at only two genomic locations) for further analysis of lncRNA disruptions. From these, we identified 66 cases in which the chromosomal rearrangements directly disrupt lncRNAs. In 30 cases, no genes of any other class aside from lncRNAs are directly disrupted, consistent with the hypothesis that lncRNA disruptions could underly the phenotypes of these individuals. Strikingly, the lncRNAs MEF2C-AS1 and ENSG00000257522 are each disrupted in two unrelated cases. Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription factors TBX2 and MEF2C, respectively. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of seven individuals with likely developmental etiologies due to lncRNA disruptions.
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Fatores de Transcrição MEF2 , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Fatores de Transcrição MEF2/genética , Feminino , Aberrações Cromossômicas , Masculino , Genoma Humano , Fenótipo , Mutação em Linhagem GerminativaRESUMO
Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological condition. Initial treatment involves plasma exchange (PLEX), corticosteroids, caplacizumab and rituximab. In relapsed and refractory cases despite initial treatments, further immune-modulating therapy includes the proteasome inhibitor, bortezomib. Evidence for bortezomib in this setting is limited to case reports and case series. We report our experience and perform a systematic review of the literature. We identified 21 publications with 28 unique patients in addition to our cohort of eight patients treated with bortezomib. The median age of patients was 44 years (IQR: 27-53) and 69% female. They were usually in an initial, refractory presentation of iTTP where they had received PLEX, corticosteroids, rituximab and another line of therapy. After bortezomib administration, 72% of patients had a complete response, with 85% maintaining a durable response without relapse at the last follow-up.
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Púrpura Trombocitopênica Idiopática , Púrpura Trombocitopênica Trombótica , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Masculino , Bortezomib , Rituximab , Estudos Retrospectivos , Púrpura Trombocitopênica Idiopática/terapia , Corticosteroides , Troca Plasmática , Proteína ADAMTS13RESUMO
The cardiovascular and renovascular complications of metabolic deterioration are associated with localized adipose tissue dysfunction. We have previously demonstrated that metabolic impairment delineated the heightened vulnerability of both the perivascular (PVAT) and perirenal adipose tissue (PRAT) depots to hypoxia and inflammation, predisposing to cardioautonomic, vascular and renal deterioration. Interventions either addressing underlying metabolic disturbances or halting adipose tissue dysfunction rescued the observed pathological and functional manifestations. Several lines of evidence implicate adipose tissue thromboinflammation, which entails the activation of the proinflammatory properties of the blood clotting cascade, in the pathogenesis of metabolic and cardiovascular diseases. Despite offering valuable tools to interrupt the thromboinflammatory cycle, there exists a significant knowledge gap regarding the potential pleiotropic effects of anticoagulant drugs on adipose inflammation and cardiovascular function. As such, a systemic investigation of the consequences of PVAT and PRAT thromboinflammation and its interruption in the context of metabolic disease has not been attempted. Here, using an established prediabetic rat model, we demonstrate that metabolic disturbances are associated with PVAT and PRAT thromboinflammation in addition to cardioautonomic, vascular and renal functional decline. Administration of rivaroxaban, a FXa inhibitor, reduced PVAT and PRAT thromboinflammation and ameliorated the cardioautonomic, vascular and renal deterioration associated with prediabetes. Our present work outlines the involvement of PVAT and PRAT thromboinflammation during early metabolic derangement and offers novel perspectives into targeting adipose tissue thrombo-inflammatory pathways for the management its complications in future translational efforts.
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Estado Pré-Diabético , Trombose , Doenças Vasculares , Ratos , Animais , Tromboinflamação , Inflamação/patologia , Trombose/metabolismo , Doenças Vasculares/metabolismo , Tecido Adiposo/metabolismoRESUMO
INTRODUCTION: This prospective cohort study aims to investigate the hearing dynamics and the changes in the central auditory pathways in infants with congenital cytomegalovirus (cCMV) infection. MATERIALS AND METHODS: cCMV-infected neonates aged ≤3 weeks old were recruited and underwent clinical and laboratory tests to detect viremia and symptomatic infection, hearing examinations at three and six months of age, and radiological imaging of brain auditory pathways using diffusion tensor imaging. RESULTS: From 26 eligible infants (52 ears), we detected symptomatic infection in nine (34.6%), viremia in 14 (14/25; 56.0%) and sensorineural hearing loss (SNHL) in 14 infants (53.8%). We observed 40 ears (76.9%) with unstable hearing thresholds, 17 (42.5%) of which fluctuated. Hearing fluctuation and progressivity were more common in symptomatic infection (66.7% vs. 14.7%, p<0.001; and 38.9% vs. 2.9%, p=0.002; respectively). A substantial proportion of ears had reduced fractional anisotropy (FA) in the medial geniculate body (59.1%), superior olivary nucleus (45.5%), trapezoid body (40.9%), auditory radiation (36.4%) and inferior colliculus (31.8%). Symptomatic infection was associated with an increased FA in the medial geniculate body (mean difference, MD: 0.12; 95% Confidence Intervals, 95%CI: 0.03, 0.22) and viremia in the inferior colliculus (MD: 0.09; 95%CI: 0.02, 0.16). An FA in the inferior colliculus of ≥0.404 had a sensitivity and specificity of 68.8% and 83.3% in predicting viremia (area under the curve 0.823; 95%CI: 0.633, 1.000, p=0.022). CONCLUSION: SNHL along with its fluctuation and progression are common in cCMV-infected infants. cCMV infection may induce structural changes in the central auditory pathway.
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Vias Auditivas , Infecções por Citomegalovirus , Humanos , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/diagnóstico por imagem , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/fisiopatologia , Estudos Prospectivos , Feminino , Masculino , Recém-Nascido , Vias Auditivas/diagnóstico por imagem , Vias Auditivas/fisiopatologia , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/virologia , Perda Auditiva Neurossensorial/fisiopatologia , Perda Auditiva Neurossensorial/diagnóstico por imagem , Lactente , Testes AuditivosRESUMO
The present study describes synthesizing a novel series of polyfunctionalized pyridine congeners 1-18 and assessed for cytotoxic efficacies versus HCT-116, MCF-7, and HepG-2 among one non-cancerous BJ-1 human normal cell. Most compounds were precisely potent anticancer candidate drugs. The molecular impact of the most active compounds 9, 10, 11, 13, 15, and 17 was evaluated after MCF-7 treatment. The gene expression of pro- and ant-apoptosis markers P53, Bax, Caspase-3 and Bcl-2 as well as VEGFR-2 and HER2 were determined. Compounds 13 and 15 induced upregulation of pro-apoptosis of P53, Bax, Caspase-3 and downregulation of anti-apoptosis Bcl-2 gene. However, compound 15 showed higher effect compared to 13 and respective control. Moreover, a slight reduction in HER2 gene expression was detected due to compound 15 treatment, while VEGFR-2 gene was upregulated. In agreement, the immunoblotting analysis showed higher accumulation of P53, Bax, Caspase-3 proteins and of decrease the Bcl-2 protein levels. Furthermore, docking studies united with molecular dynamic simulation exposed compounds 13 and 15 fitting in the middle of the active site at the interface linking the ATP binding site and the allosteric hydrophobic binding pocket. Finally, we performed Petra/Osiris/ Molinspiration (POM) analysis for the newly synthesized compounds. The evaluation of primary in silico parameters revealed significant differences among individual polyfunctionalized pyridine compounds, highlighting the most promising candidates. These preliminary results may help in coordinating and initiating other research projects focused on polyfunctionalized pyridine compounds, especially those with predicted bioactivity, low toxicity, optimal ADME parameters, and promising perspectives.
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Antineoplásicos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Caspase 3/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Antineoplásicos/farmacologia , Antineoplásicos/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Simulação de Dinâmica Molecular , Piridinas/farmacologia , Simulação de Acoplamento Molecular , Proliferação de Células , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Inhibiting the CDK2/cyclin A2 enzyme has been validated in multiple clinical manifestations related to multiple types of cancer. Herein, novel series of pyrolo[2,3-c]pyrazole, pyrolo[2,3-c]isoaxazole and pyrolo[2,3-d]pyrimidine, pyrolo[3,2-c]pyridine & indole based analogs were designed, synthesized and biologically evaluated for their in vitro antiproliferative activity where the obtained results revealed that most of the newly synthesized compounds showed significant cytotoxic activity towards MCF-7 (breast cancer cell lines) and HepG-2 (hepatocellular carcinoma) with IC50 ranging from 3.20 µM to 10.05 µM & from 2.18 µM to 13.49 µM, respectively, compared to that of Sorafenib (IC50 9.76 & 13.19 µM, respectively). The in vitro inhibitory profile of the most promising compounds (9, 11, 14, 15, 16, 17 and 20) towards CDK2/CyclinA2 was evaluated. Compounds 14 & 15 exhibited potent inhibitory profile against CDK2 with (IC50 0.11 and 0.262 µM, respectively comparable to Sorafenib IC50 0.184 µM. Western blotting of 14 & 15 at MCF-7 cell line confirmed the diminishing activity on CDK2. Furthermore, both compounds exserted a significant cell cycle arrest and apoptosis. Moreover, the normal cell line cytotoxicity for both compounds revealed low cytotoxic results in normal cells rather than cancer cells. Molecular docking and dynamic simulation validated the potentiality of the newly synthesized compounds to have high binding affinity within CDK2 binding pocket. 3DQSAR pharmacophore, in-silico ADME/TOPKAT studies and drug-likeness showed proper pharmacokinetic properties and helped in structure requirements prediction. The obtained model and pattern of substitution could be used for further development of CDK2 inhibitors.
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Antineoplásicos , Simulação de Dinâmica Molecular , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Sorafenibe/farmacologia , Simulação de Acoplamento Molecular , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/química , Pirimidinas/química , Pirazóis/química , Inibidores de Proteínas Quinases , Linhagem Celular Tumoral , Quinase 2 Dependente de CiclinaRESUMO
BACKGROUND: Hyperhemolysis syndrome (HHS) is an uncommon transfusion reaction described in several hematologic disorders, including sickle cell disease (SCD). HHS is characterized by a decline in hemoglobin (Hb) values below pre-transfusion levels following transfusion of red blood cells (RBCs), coupled with laboratory markers consistent with hemolysis. The proposed pathophysiologic mechanisms underlying HHS include increased phosphatidylserine expression, macrophage activation, and complement dysregulation. Many pathophysiologic mechanisms thought to contribute to HHS have been similarly described in cases of severe COVID-19. CASE REPORT: A 28-year-old male with a history of HbSS presented with shortness of breath, right-sided chest pain, and a two-day history of fever. Polymerase chain reaction (PCR) detected SARS-CoV-2 infection with the omicron variant. The patient required an RBC transfusion (pre-transfusion hemoglobin [Hb]5.8 g/dL) with an immediate post-transfusion Hb of 6.3 g/dL. However, Hb rapidly declined to 1.7 g/dL, and lactate dehydrogenase (LDH) rose to 8701 u/L. The absolute reticulocyte count of 538 × 109/L correspondingly fell to 29 × 109/L. Despite additional RBC transfusions and initiation of immunosuppressive therapy, he expired on Day 9(D9). CONCLUSION: Given the similarities in their proposed pathophysiology, patients with SCD and concomitant SARS-CoV-2 infection may be predisposed to developing HHS.
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Anemia Falciforme , COVID-19 , Masculino , Humanos , Adulto , COVID-19/complicações , SARS-CoV-2 , Anemia Falciforme/complicações , Anemia Falciforme/terapia , Hemólise , Síndrome , HemoglobinasRESUMO
This in vivo study aimed to investigate local and systemic immune responses induced by sperm in cows after artificial insemination (AI). Initially, 12 multiparous Japanese Black cows were subjected to intrauterine AI (AI group, n = 6) or saline infusion (control group, n = 6). The uterine body and horn ipsilateral to the ovulatory follicle were mini-flushed with 2 ml of RPMI-1640 medium at different time points (0, 1, 6, 10, 24, 48 h, and 7 days after AI), centrifuged, and the sediments were examined under a light microscope. Vaginal smears were prepared at 0, 1, 6, and 10 h after AI to investigate the sperm backflow. Subsequently, another experiment was conducted by assigning cows to three groups: intrauterine AI (AI group, n = 5), heat-inactivated AI (Heat-AI group, n = 5), or saline infusion (control group, n = 5). Blood samples were collected, and polymorphonuclear neutrophils (PMNs) and peripheral blood mononuclear cells (PBMCs) were separated and analyzed for gene expression using real-time PCR. The results showed that most sperm were rapidly transported either forward into the uterine horn or backward into the vagina within 1 h after AI. The PMNs migrated into the uterine lumen 6 hours after AI. Only active sperm-induced proinflammatory responses in PMNs and PBMCs via upregulation of TNFa, IL8, IL1B, and PGES and downregulation of IL10 at 6 h after AI. These data provide evidence that sperm generate transient proinflammatory responses locally in the uterus and systemically in the peripheral immune cells, which may be prerequisites for uterine clearance, embryo receptivity, and implantation in cows.
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Leucócitos Mononucleares , Sêmen , Feminino , Bovinos , Masculino , Animais , Útero/fisiologia , Espermatozoides/metabolismo , Inseminação Artificial/veterinária , Inseminação Artificial/métodosRESUMO
OBJECTIVE: To determine the indications and optimal surgical treatment of aberrant subclavian artery. MATERIAL AND METHODS: There were 3 patients with aberrant subclavian artery with clinical manifestations such as dysphagia, shortness of breath, weight loss, cough and chest pain between 2005 and 2020. Right-and left-sided aberrant artery was observed in 2 and 1 case, respectively. Supraclavicular unilateral or bilateral access depended on the side of aberrant artery. Carotid-subclavian anastomosis was performed. RESULTS: All patients were discharged without any symptoms. CONCLUSION: Close location of aberrant subclavian artery to common carotid artery can disturb circulation in brain and upper limb. Abnormal discharge of subclavian artery can cause compression of nearby organs (esophagus, trachea). Abnormal vascular discharge does not always have clinical manifestations that do not require surgical correction. Only symptomatic patients are subjects to surgical correction of aberrant subclavian artery. Knowledge of variant anatomy of supra-aortic vessels can minimize the risk of complications.
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Anormalidades Cardiovasculares , Artéria Subclávia , Humanos , Artéria Subclávia/diagnóstico por imagem , Artéria Subclávia/cirurgia , Anormalidades Cardiovasculares/cirurgia , Esôfago , Artérias Carótidas , Aorta TorácicaRESUMO
The phylum "Candidatus Patescibacteria" (or Candidate Phyla Radiation [CPR]) accounts for roughly one-quarter of microbial diversity on Earth, but the presence and diversity of these bacteria in marine sediments have been rarely charted. Here, we investigate the abundance, diversity, and metabolic capacities of CPR bacteria in three sediment sites (Mohns Ridge, North Pond, and Costa Rica Margin) with samples covering a wide range of redox zones formed during the early diagenesis of organic matter. Through metagenome sequencing, we found that all investigated sediment horizons contain "Ca. Patescibacteria" (0.4 to 28% of the total communities), which are affiliated with the classes "Ca. Paceibacteria," "Ca. Gracilibacteria," "Ca. Microgenomatia," "Ca. Saccharimonadia," "Ca. ABY1," and "Ca. WWE3." However, only a subset of the diversity of marine sediment "Ca. Patescibacteria," especially the classes "Ca. Paceibacteria" and "Ca. Gracilibacteria," can be captured by 16S rRNA gene amplicon sequencing with commonly used universal primers. We recovered 11 metagenome-assembled genomes (MAGs) of CPR from these sediments, most of which are novel at the family or genus level in the "Ca. Paceibacteria" class and are missed by the amplicon sequencing. While individual MAGs are confined to specific anoxic niches, the lack of capacities to utilize the prevailing terminal electron acceptors indicates that they may not be directly selected by the local redox conditions. These CPR bacteria lack essential biosynthesis pathways and may use a truncated glycolysis pathway to conserve energy as fermentative organotrophs. Our findings suggest that marine sediments harbor some novel yet widespread CPR bacteria during the early diagenesis of organic matter, which needs to be considered in population dynamics assessments in this vast environment. IMPORTANCE Ultrasmall-celled "Ca. Patescibacteria" have been estimated to account for one-quarter of the total microbial diversity on Earth, the parasitic lifestyle of which may exert a profound control on the overall microbial population size of the local ecosystems. However, their diversity and metabolic functions in marine sediments, one of the largest yet understudied ecosystems on Earth, remain virtually uncharacterized. By applying cultivation-independent approaches to a range of sediment redox zones, we reveal that "Ca. Patescibacteria" members are rare but widespread regardless of the prevailing geochemical conditions. These bacteria are affiliated with novel branches of "Ca. Patescibacteria" and have been largely missed in marker gene-based surveys. They do not have respiration capacity but may conserve energy by fermenting organic compounds from their episymbiotic hosts. Our findings suggest that these novel "Ca. Patescibacteria" are among the previously overlooked microbes in diverse marine sediments.
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Bactérias , Ecossistema , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo , Filogenia , Metagenoma , Sedimentos Geológicos/microbiologiaRESUMO
Acquired von Willebrand syndrome (AVWS) is a rare hematologic disorder characterized by quantitative or qualitative defects of von Willebrand factor (vWF), a protein crucial for normal hemostasis. AVWS has been described in association with several pathologic entities with varied mechanisms. Among these, lymphoproliferative disorders are the most common, with monoclonal gammopathy of undetermined significance (MGUS) being the most frequently reported. AVWS in this setting is commonly associated with the development of bleeding that is clinically challenging to manage due to accelerated clearance of vWF, limiting the utility of many conventional treatment modalities such as DDAVP or vWF/FVIII. We report a case of a 43-year-old male who was sent to our institution for new-onset easy bruising and laboratories concerning for von Willebrand disease (vWD). Further diagnostic workup revealed evidence of an IgG monoclonal gammopathy and findings suggestive of vWF inhibition. Ultimately, he was found to have monoclonal gammopathy of clinical significance (MGCS)-associated AVWS refractory to conventional treatment but responsive to lenalidomide and dexamethasone. This case suggests that lenalidomide may be suitable for patients with AVWS secondary to MGCS.
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Gamopatia Monoclonal de Significância Indeterminada , Paraproteinemias , Doenças de von Willebrand , Masculino , Humanos , Adulto , Doenças de von Willebrand/complicações , Doenças de von Willebrand/tratamento farmacológico , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/tratamento farmacológico , Fator de von Willebrand/metabolismo , Lenalidomida/uso terapêutico , Paraproteinemias/complicações , Paraproteinemias/tratamento farmacológico , Paraproteinemias/diagnósticoRESUMO
Despite tangible advances in machine learning (ML) over the last few decades, many of the ML techniques still suffer from fundamental issues like overfitting and lack of explainability. These issues mandate requirements for mathematical rigor to ensure robust learning from observed data. In this context, topological invariants in data manifolds provide a rich representation of the underlying dynamical system, which can be utilized for developing a mathematically rigorous ML tool to characterize the dynamical behaviour and operational phases of the underlying process. This paper aims to investigate spectral invariants of symbolic systems for detecting changes in topological characteristics of data manifolds. A novel ML approach is proposed, where commutator norms are used on sequences of endomorphisms to symbolically describe dynamical systems on probability spaces with ergodic measures. The objective here is to detect topological invariants of data manifolds that can be used for signal processing, pattern recognition, and anomaly detection. The proposed ML approach is validated on models of selected chaotic dynamical systems for prompt detection of phase transitions. This article is part of the theme issue 'Data-driven prediction in dynamical systems'.
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MatemáticaRESUMO
Alzheimer's disease (AD) is known as one of the most devastating neurodegenerative disease diagnosed for the old-aged people and cholinesterase inhibitors (ChEI) can be used as an effective palliative treatment for AD. A range of novel monomeric and dimeric indole based thiosemicarbazone derivatives 17-28 was synthesized in order to target cholinesterases (ChE). Biological importance of the targeted compounds 17-28 was investigated by employing the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes along with three different antioxidant property determination assays, namely DPPH free radical scavenging, ABTS cationic radical decolarization, and CUPRAC cupric reducing antioxidant capacity. The compounds 18 and 19 displayed the best inhibitor activity against BChE with IC50 values of 7.42 and 1.95 µM, respectively. The antioxidant potentials were found to be moderate for DPPH and ABTS assays and the compounds 28 and 18 were the most potent candidates for both antioxidant assays. Cupric reducing capacity was the most promising assay and the compounds 25, 26 and 28 provided better inhibition values than all the standards. Further binding mode and affinity studies performed by molecular docking and molecular dynamics simulations. Accordingly, the compound 19 is the most plausible candidate that can compete with galantamine (GNT), a common pharmaceutics targeting both cholinesterase enzymes.
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Doença de Alzheimer , Doenças Neurodegenerativas , Tiossemicarbazonas , Acetilcolinesterase/metabolismo , Idoso , Antioxidantes/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Humanos , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Tiossemicarbazonas/farmacologiaRESUMO
BACKGROUND: Acquired Hemophilia A (AHA) is a rare autoimmune disorder associated with the development of autoantibodies against factor VIII (FVIII). Although obtaining hemostatic control through the use of recombinant factor VIIa, activated prothrombin complex concentrate and recombinant porcine FVIII are cornerstones in the clinical management of AHA, these therapies have several disadvantages, including a higher risk for the development of thromboembolic events, unpredictable efficacy and short half-lives. While emicizumab has been FDA licensed for use in bleeding prophylaxis for patients with Congenital Hemophilia A (CHA) with and without inhibitors, it has not been approved for use in AHA, with only a few reports describing its use in this context. CASE REPORT: We report our experience with the use of emicizumab in an 83-year old male with AHA, complicated by the onset of atrial fibrillation following admission, drug-induced thrombocytopenia, infectious complications, and the identification of a low-grade lymphoproliferative disorder, in which emicizumab prophylaxis was used for bleeding prophylaxis in the context of persistently elevated inhibitor titers without evidence of thrombotic events or thrombotic microangiopathy.
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Anticorpos Biespecíficos , Hemofilia A , Hemostáticos , Masculino , Suínos , Animais , Hemofilia A/tratamento farmacológico , Fator VIII/uso terapêutico , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Hemorragia/tratamento farmacológico , Hemorragia/prevenção & controle , Hemostáticos/uso terapêuticoRESUMO
Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (4-15) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8, 14, and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC50 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.
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Antineoplásicos , Inibidores de Proteínas Quinases , Antineoplásicos/química , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
In this paper, we presented a novel electrostatic Roll/Pitch MEMS gyroscope with in-plane drive mode and out-of-plane sense mode. The proposed structure is developed based on a tuning fork gyroscope with decoupled sense mass on each tine that control the sense out-of-plane frequency. A multi-height deep reactive ion etching (DRIE) fabrication process was utilized to achieve and enhance decoupling between the drive and sense modes. We presented our design methodology followed by an analytical and finite element (FEM) model. Our experimental results showed a good match between the analytical model and those obtained experimentally, from the drive and sense oscillation frequencies. Our characterization setup used a custom made application specific integrated circuit (ASIC) for characterization and was able to achieve ARW of 0.2 deg/rt-h, a bias instability 5.5 deg/h, and scale factor non-linearity (SFNL) 156 ppm FS.
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BACKGROUND: Laparoscopic surgery for colorectal cancer is mostly performed in university hospitals or experienced centers. This study aimed at determining the learning curve of laparoscopic surgery for colorectal cancer at a new regional state hospital. PATIENTS AND METHODS: Clinico-pathological data of 106 consecutive patients who underwent laparoscopic surgery for colorectal cancer at a new regional state hospital between August 2018 and September 2021 were prospectively recorded and analyzed. All surgeries were performed by a single inexperienced surgeon without supervision. The primary outcome of the study was the operative time, which was used for a Cumulative Sum (CUSUM) analysis of the learning curve. The secondary outcomes included a comparison of preoperative, intraoperative, and postoperative outcomes during the learning curve period. RESULTS: According to the CUSUM analysis, the learning curve consisted of three unique phases: phase 1 [the initial learning period (cases 1-53)], phase 2 [the consolidation period (cases 54-68)], and phase 3 [the experienced period (cases 69-106)]. Of the intraoperative outcomes, operative time and estimated blood loss were significantly reduced from phase 1 to phase 3 (p<0.001). Of the postoperative outcomes, time to pass stool (p<0.05), time to oral feeding (p=0.001), drain removal time (p<0.001), and length of hospital stay (p=0.042) were shorter in phase 3 compared to phases 1 and 2. Of the histopathological results, the specimen length and the number of harvested lymph nodes increased with experience (p=0.001). CONCLUSIONS: The present results suggest that a surgeon at a new regional state hospital must experience 53-68 cases to achieve competence in laparoscopic colorectal cancer surgery.
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Cardiac and hepatotoxicities are major concerns in the development of new drugs. Better alternatives to other treatments are being sought to protect these vital organs from the toxicities of these pharmaceuticals. In this regard, a preclinical study is designed to investigate the histopathological effects of a new succinimide derivative (Comp-1) on myocardial and liver tissues, and the biochemical effects on selected cardiac biomarkers, hepatic enzymes, and lipid profiles. For this, an initially lethal/toxic dose was determined, followed by a grouping of selected albino rats into five groups (each group had n = 6). The control group received daily oral saline for 8 days. The 5-FU (5-Fluorouracil) group received oral saline daily for 8 days, added with the administration of a single dose of 5-FU (150 mg/kg I.P.) on day 5 of the study. The atenolol group received oral atenolol (20 mg/kg) for 8 days and 5-FU (150 mg/kg I.P.) on day 5 of the protocol. Similarly, two groups of rats treated with test compound (Comp-1) were administered with 5 mg/kg I.P. and 10 mg/kg I.P. for 8 days, followed by 5-FU (150 mg/kg I.P.) on day 5. Toxicity induced by 5-FU was manifested by increases in the serum creatinine kinase myocardial band (CK-MB), troponin I (cTnI) and lactate dehydrogenase (LDH), lipid profile, and selected liver enzymes, including ALP (alkaline phosphatase), ALT (alanine transaminase), AST (aspartate aminotransferase), BT (bilirubin total), and BD (direct bilirubin). These biomarkers were highly significantly decreased after the administration of the mentioned doses of the test compound (5 mg/kg and 10 mg/kg). Similarly, histological examination revealed cardiac and hepatic tissue toxicity by 5-FU. However, those toxic effects were also significantly recovered/improved after the administration of Comp-1 at the said doses. This derivative showed dose-dependent effects and was most effective at a dose of 10 mg/kg body weight. Binding energy data computed via docking simulations revealed that our compound interacts toward the human beta2-adrenergic G protein-coupled receptor (S = -7.89 kcal/mol) with a slight stronger affinity than the calcium channel T-type (S = -7.07 kcal/mol). In conclusion, the histological and biochemical results showed that the test compound (Comp-1) had prominent cardioprotective, hepatoprotective, and lipolytic effects against 5-FU-induced toxicity in the subjected animal model.