Notes

Wave-particle connection effects from the Vehicle Allen devices.
Epcoritamab (DuoBody-CD3xCD20, GEN3013) is a novel bispecific IgG1 antibody redirecting T-cells toward CD20+ tumor cells. Selleck FTY720 Here, we assessed the preclinical efficacy of epcoritamab against primary tumor cells present in the lymph node biopsies from newly diagnosed (ND) and relapsed/refractory (RR) B-NHL patients. In the presence of T-cells from a healthy donor, epcoritamab demonstrated potent activity against primary tumor cells, irrespective of prior treatments, including CD20 mAbs. Median lysis of 65, 74, and 84% were achieved in diffuse large B-cell lymphoma (n = 16), follicular lymphoma (n = 15), and mantle cell lymphoma (n = 8), respectively. Furthermore, in this allogeneic setting, we discovered that the capacity of B-cell tumors to activate T-cells was heterogeneous and showed an inverse association with their surface expression levels of the immune checkpoint molecule Herpesvirus Entry Mediator (HVEM). In the autologous setting, when lymph node (LN)-residing T-cells were the only source of effector cells, the epcoritamab-dependent cytotoxicity strongly correlated with local effector cell-to-target cell ratios. Further analyses revealed that LN-residing-derived or peripheral blood-derived T-cells of B-NHL patients, as well as heathy donor T-cells equally mediated epcoritamab-dependent cytotoxicity. These results show the promise of epcoritamab for treatment of newly-diagnosed or relapsed/refractory B-NHL patients, including those who became refractory to previous CD20-directed therapies.Transcription activation of bacteriophage T4 late genes is accomplished by a transcription activation complex containing RNA polymerase (RNAP), the promoter specificity factor gp55, the coactivator gp33, and a universal component of cellular DNA replication, the sliding clamp gp45. Although genetic and biochemical studies have elucidated many aspects of T4 late gene transcription, no precise structure of the transcription machinery in the process is available. Here, we report the cryo-EM structures of a gp55-dependent RNAP-promoter open complex and an intact gp45-dependent transcription activation complex. The structures reveal the interactions between gp55 and the promoter DNA that mediate the recognition of T4 late promoters. In addition to the σR2 homology domain, gp55 has a helix-loop-helix motif that chaperons the template-strand single-stranded DNA of the transcription bubble. Gp33 contacts both RNAP and the upstream double-stranded DNA. Gp45 encircles the DNA and tethers RNAP to it, supporting the idea that gp45 switches the promoter search from three-dimensional diffusion mode to one-dimensional scanning mode.Genetic and epidemiological evidence has suggested that genetic factors are important in schizophrenia, although its pathophysiology is poorly understood. This study used whole-exome sequencing to investigate potential novel schizophrenia-causing genes in a Japanese family containing several members affected by severe or treatment-resistant schizophrenia. A missense variant, chr12132064747C>T (rs200626129, P2805L), in the E1A-binding protein P400 (EP400) gene completely segregated with schizophrenia in this family. Furthermore, numerous other EP400 mutations were identified in the targeted sequencing of a schizophrenia patient cohort. We also created two lines of Ep400 gene-edited mice, which had anxiety-like behaviours and reduced axon diameters. Our findings suggest that rs200626129 in EP400 is likely to cause schizophrenia in this Japanese family, and may lead to a better understanding and treatment of schizophrenia.As a portable media device that enables ubiquitous access to friends and entertainment, smartphones are inextricably linked with our lives. Although there is growing concern about the detrimental effect of problematic smartphone use on attentional control, the underlying neural mechanisms of impaired attentional control in problematic smartphone users (PSU) has yet to be investigated. Using a modified cognitive conflict task, we examined behavioral performance in the presence of distracting words during functional magnetic resonance imaging in 33 PSU and 33 control participants (CON). Compared with the CON group, the PSU group demonstrated impaired performance that was accompanied by constantly enhanced but not differentiated activation in the frontoparietal regions across all conditions, regardless of distractor saliency. The inferior parietal lobule (IPL) activation in the PSU group, in particular, showed an association with performance deficits in the distractor conditions. Furthermore, the PSU group exhibited decreased functional connectivity of the right IPL with the right superior temporal gyrus of the ventral attention system in the attention-demanding condition relative to the easiest condition, which was associated with the severe dependence on smartphone use. Our findings suggest that greater distractibility in the PSU group during the attentional control task may be associated with inefficient recruitment of the ventral attention network involved in bottom-up attentional processing, as indicated by hyperactivation but less coherence within the network. The present study provides evidence for understanding the neural mechanisms underlying the impaired ability to keep attention from being oriented to task-irrelevant stimuli observed in PSU.The pervasive and frequently devastating nature of aggressive behavior calls for a collective effort to understand its psychosocial and neurobiological underpinnings. Regarding the latter, diverse brain areas, neural networks, neurotransmitters, hormones, and candidate genes have been associated with antisocial and aggressive behavior in humans and animals. This review focuses on the role of monoamine oxidases (MAOs) and the genes coding for them, in the modulation of aggression. During the past 20 years, a substantial number of studies using both pharmacological and genetic approaches have linked the MAO system with aggressive and impulsive behaviors in healthy and clinical populations, including the recent discovery of MAALIN, a long noncoding RNA (lncRNA) regulating the MAO-A gene in the human brain. Here, we first provide an overview of the MAOs and their physiological functions, we then summarize recent key findings linking MAO-related enzymatic and gene activity and aggressive behavior, and, finally, we offer novel insights into the mechanisms underlying this association.
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