A cannabinoid anticancer para-quinone, HU-331, which was synthesized by our group five decades ago, was shown to have very high efficacy against human cancer cell lines in-vitro and against in-vivo grafts of human tumors in nude mice. The main mechanism was topoisomerase IIα catalytic inhibition. Later, several groups synthesized related compounds. In the present presentation, we review the publications on compounds synthesized on the basis of HU-331, summarize their published activities and mechanisms of action and report the synthesis and action of novel quinones, thus expanding the structure-activity relationship in these series.
BACKGROUND: Endocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5-21 years) with ASD. METHODS: We tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and $Δ$9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and $Δ$9-tetrahydrocannabinol at the same ratio. Participants (N = 150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability. Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI). RESULTS: Changes in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract (n = 45) versus 21% on placebo (n = 47; p = 0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract (n = 34) versus 3.6 points after placebo (n = 36); p = 0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively (n = 95); 23% and 21% on pure-cannabinoids (n = 93), and 8% and 15% on placebo (n = 94). Limitations Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results. CONCLUSIONS: This interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended. Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226.
BACKGROUND: Endocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5-21 years) with ASD. METHODS: We tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and $Δ$9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and $Δ$9-tetrahydrocannabinol at the same ratio. Participants (N = 150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability. Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI). RESULTS: Changes in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract (n = 45) versus 21% on placebo (n = 47; p = 0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract (n = 34) versus 3.6 points after placebo (n = 36); p = 0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively (n = 95); 23% and 21% on pure-cannabinoids (n = 93), and 8% and 15% on placebo (n = 94). Limitations Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results. CONCLUSIONS: This interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended. Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226.
The developmental fates of offspring have the potential to be influenced by the identity of their care-givers and by the nature of the care that they receive. In animals that exhibit both parental and alloparental care, such as the annually eusocial insects, the influence of care-giver identity can be directly assessed to yield mechanistic and evolutionary insights into the origins and elaboration of brood care. Here, we performed a comparative investigation of maternal and worker brood care in bumble bees, a pollinator group where mothers (queens) rear the first offspring in the nest, and then daughters (workers) assume this role upon their emergence. Specifically, we compared the effects of queen and worker brood care on offspring development and also offspring performance, for a set of traits related to sensory biology, learning, and stress resistance.
OBJECTIVES: To investigate the association of psychiatric disorders with (1) caries experience, (2) periodontal status, and (3) metabolic syndrome (MetS) components.
METHOD AND MATERIALS: This 7-year cross-sectional study retrospectively analyzed the medical records of 504 individuals aged 18 to 90 years who attended the student dental clinic. Collected data included: demographics, smoking habits, systolic and diastolic blood pressures, pulse, waist circumference, full-mouth plaque score (FMPS), full-mouth bleeding score (FMBS), maximal pocket probing depth (PPD), average and maximal radiographic bone loss (RBL), the sum of the number of decayed (D), missing (M), and filled (F) teeth (DMFT score), and presence of MetS components, consequences and related conditions including diabetes, hypertension, hyperlipidemia, ischemic heart disease, heart failure, s/p stroke, and cancer.
RESULTS: 68 (13.5%) had psychiatric disorders with an average age of 53.42 ± 15.71 years. Psychiatric disorders were positively associated with smoking (P = .008), smoking pack-years (P = .004), DMFT score (P = .005), and negatively associated with hypertension (P = .046). Psychiatric disorders had no statistically significant associations with all periodontal indices studied and with other components of MetS. Following multivariate analysis, psychiatric disorders retained a statistically significant positive association with smoking (odds ratio [OR] and 95% confidence interval [CI] = 2.24 [1.28 to 3.92]) and with DMFT (OR and 95% CI = 1.08 [1.02 to 1.14]), and a statistically significant negative association with hypertension (OR and 95% CI = 0.46 [0.25 to 0.84]).
CONCLUSIONS: Psychiatric disorders were positively associated with smoking and caries experience but not with periodontal status and metabolic morbidity. Communication between dental and medical professionals is needed to address the higher smoking consumption and caries morbidity in psychiatric patients. (Quintessence Int 2021;52:516-526; doi: 10.3290/j.qi.b1044091).
Atrazine (ATZ) is an extensively used herbicide and ubiquitous environmental contaminant. ATZ and its metabolite, diaminochlorotriazine (DACT), cause several cellular and functional alterations in spermatozoa. We aimed to examine the effect of ATZ/DACT on spermatozoon DNA integrity, fertilization competence, embryonic development, and transcriptome profile of in vitro-produced embryos derived from fertilization with pre-exposed sperm. Bovine spermatozoa exposed to ATZ (0.1 or 1 mu M) or DACT (1 or 10 mu M) during in vitro capacitation were used for in vitro fertilization of untreated oocytes. Cleavage and blastocyst-formation rates were evaluated 42 h and 7 days postfertilization, respectively. The association between DNA fragmentation and apoptosis (annexin V kit) was determined. Fertilization competence of annexin-positive (AV+) and annexin-negative (AV-) spermatozoa was examined. Microarray analysis was performed for 7-day blastocysts. Intracytoplasmic sperm injection was performed with control (AV+, AV-) and DACT (AV+, AV-) spermatozoa. Cleavage rates did not differ between groups and blastocyst formation tended to be higher for AV- vs. AV+ in both control and DACT groups, suggesting that acrosome reaction, rather than DNA fragmentation, underlies the reduced cleavage. Transcriptomic analysis revealed 139 and 230 differentially expressed genes in blastocysts derived from ATZ- and DACT-exposed spermatozoa, respectively, relative to controls. Proteomic analysis shown differential expression of proteins in ATZ- or DACT-treated spermatozoa, in particular proteins related to cellular processes and biological pathways. Therefore, we assume that factors delivered by the spermatozoa, regardless of DNA fragmentation, are also involved. Overall, the current study reveals a deleterious carryover effect of ATZ/DACT from the spermatozoa to the developing embryo. Summary sentence Summary sentence: Atrazine and its metabolite, diaminochlorotriazine, induce multifactorial damage in sperm, which is carried over to the embryo's transcriptome.
Mitosis detection is one of the challenging steps in biomedical imaging research, which can be used to observe the cell behavior. Most of the already existing methods that are applied in detecting mitosis usually contain many nonmitotic events (normal cell and background) in the result (false positives, FPs). In order to address such a problem, in this study, we propose to apply 2.5-dimensional (2.5D) networks called CasDetNet\_CLSTM, which can accurately detect mitotic events in 4D microscopic images. This CasDetNet\_CLSTM involves a 2.5D faster region-based convolutional neural network (Faster R-CNN) as the first network, and a convolutional long short-term memory (CLSTM) network as the second network. The first network is used to select candidate cells using the information from nearby slices, whereas the second network uses temporal information to eliminate FPs and refine the result of the first network. Our experiment shows that the precision and recall of our networks yield better results than those of other state-of-the-art methods.
The reconnection of two interacting vortex tubes is a fundamental process in fluid mechanics, which, at very high Reynolds numbers, is associated with the formation of intense velocity gradients. Reconnection is usually studied using two antiparallel tubes which are destabilized via the long-wavelength Crow instability, leading to a very symmetric configuration and to a strong flattening of the cores into thin sheets. Here, we consider the interaction of two initially straight tubes at an angle of β and show that by relaxing some symmetries of the problem, a rich phenomenology appears. When the angle between the two tubes is close to β=90∘, their interaction leads to pairing of small portions of antiparallel tubes, followed by the formation of thin and localized vortex sheets as a precursor of reconnection. The subsequent breakdown of these sheets involves a twisting of the paired sheets, followed by the appearance of a localized cloud of small-scale vortex structures. By decreasing β, we show that reconnection involves increasingly larger portions of tubes, whose cores are subsequently destabilizing, leaving behind more small-scale vortices. At the smallest values of the angle β studied, the two vortices break down through a mechanism, which leads to a cascadelike process of energy conveyance across length scales similar to what was found for previous studies of antiparallel vortex tubes (β=0) which imposed no symmetries. While, in all cases, the interaction of two vortices depends on the initial condition, the rapid formation of fine-scale vortex structures appears to be a robust feature, possibly universal at very high Reynolds numbers.
This paper introduces the Special Issue on Cascading Effects in Disaster Risk Management. It reviews the contributions and highlights their multi-disciplinary interpretations of cascades. It proceeds to discuss whether the on-going unfolding of the COVID-19 pandemic illustrates the cascades metaphor.
A proliferation inducing ligand (APRIL) mediates a key role in the generation and survival of antibody-inducing plasmocytes. Based on this, APRIL has been targeted in autoimmune diseases including multiple sclerosis (MS) and optic neuritis (ON). In MS lesions, APRIL has a new cellular target, the reactive astrocyte and mediates an immunosuppressive activity. Here, we analyzed APRIL expression in a case of neuromyelitis optica (NMO), another autoimmune neurodegenerative disease, showing selective aquaporin-4 depletion in the spinal cord, complement deposition and infiltration of polymorphonuclear cells. We analyzed by immunohistochemistry the presence of APRIL-producing cells, plasmocytes, astrocytes and the localization of secreted APRIL in a lesion from NMO. Plasmocytes were present close to APRIL-producing cells in meninges. However, our main observation was that APRIL targets reactive astrocytes in this lesion of NMO similarly to MS.
Causal Selection is a widely discussed topic in philosophy and the cognitive sciences, concerned with characterizing the choice of “the cause” among the many individually necessary and jointly sufficient conditions on which any effect depends on. In this paper, we argue for an additional selection process underlying causal state-ments: Causative-Construction Selection, which pertains to the choice of linguistic constructions used to express causal relations. By exploring this phenomenon, we aim to answer the following question: given that a speaker wishes to describe the relation between one of the conditions and the effect, which linguistic constructions are avail-able? We take CC-selection to be more crucial than causal selection, since the latter is in fact restricted by the linguistic options resulting from the former. Based on a series of experiments, we demonstrate that factors taken previously as contributing to causal selection should, in fact, be considered as the parameters that license the various lin-guistic constructions under given circumstances, based on previous knowledge about the causal structure of the world (the causal model). These factors are therefore part of the meaning of the causative expressions.
The osteological study of eight well-dated horse skeletons from Xinjiang (350 BCE) is reported as an important discovery: the earliest direct evidence for horseback riding in China. However, the sites are located roughly 2,000 km from the centers of Chinese civilization, where evidence for domesticated horses predates these skeletons by some 1,000 years, and artistic depictions of horseback riding appear some 400 years earlier than these skeletons. Horses in China were extensively used for charioteering: The duke of Qi’s tomb complex in Shandong (490 BCE) included several hundred sacrificial horses. Why, then, is this discovery so important?
Its importance, we argue, lies elsewhere: the beginning of cavalry warfare, a phenomenon that changed the geopolitical makeup of this region for the next two millennia. The occurrence rate of vertebral abnormalities suggests extensive exploitation, which is commonly attributed to excessive horseback riding, and their dating correlates with the onset of cavalry warfare on China’s northern frontiers.
