N-Benzyl-N-(2-meth­oxy­phen­yl)benzene­sulfonamide

In the title mol­ecule, C20H19NO3S, the dihedral angle between the phenyl rings is 48.93 (18)°, and they make dihedral angles of 38.37 (17) and 86.50 (19)° with the benzene ring. A weak intra­molecular C—H⋯O inter­action might stabilize the mol­ecular conformation. In the crystal, weak π–π stacking inter­actions between the benzene rings [centroid–centroid distance = 3.774 (2) Å] may help to establish the packing

Alzheimer-related decrease in CYFIP2 links amyloid production to tau hyperphosphorylation and memory loss

Characteristic features of Alzheimer's disease are memory loss, plaques resulting from abnormal processing of amyloid precursor protein (APP), and presence of neurofibrillary tangles and dystrophic neurites containing hyperphosphorylated tau. Currently, it is not known what links these abnormalities together. Cytoplasmic FMR1 interacting protein 2 (CYFIP2) has been suggested to regulate mRNA translation at synapses and this may include local synthesis of APP and alpha-calcium/calmodulin-dependent kinase II, a kinase that can phosphorylate tau. Further, CYFIP2 is part of the Wiskott-Aldrich syndrome protein-family verprolin-homologous protein complex, which has been implicated in actin polymerization at synapses, a process thought to be required for memory formation. Our previous studies on p25 dysregulation put forward the hypothesis that CYFIP2 expression is reduced in Alzheimer's disease and that this contributes to memory impairment, abnormal APP processing and tau hyperphosphorylation. Here, we tested this hypothesis. First, in post-mortem tissue CYFIP2 expression was reduced by ∼50% in severe Alzheimer's hippocampus and superior temporal gyrus when normalized to expression of a neuronal or synaptic marker protein. Interestingly, there was also a trend for decreased expression in mild Alzheimer's disease hippocampus. Second, CYFIP2 expression was reduced in old but not in young Tg2576 mice, a model of familial Alzheimer's disease. Finally, we tested the direct impact of reduced CYFIP2 expression in heterozygous null mutant mice. We found that in hippocampus this reduced expression causes an increase in APP and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) protein, but not mRNA expression, and elevates production of amyloid-β42 Reduced CYFIP2 expression also increases alpha-calcium/calmodulin-dependent kinase II protein expression, and this is associated with hyperphosphorylation of tau at serine-214. The reduced expression also impairs spine maturity without affecting spine density in apical dendrites of CA1 pyramidal neurons. Furthermore, the reduced expression prevents retention of spatial memory in the water maze. Taken together, our findings indicate that reduced CYFIP2 expression triggers a cascade of change towards Alzheimer's disease, including amyloid production, tau hyperphosphorylation and memory loss. We therefore suggest that CYFIP2 could be a potential hub for targeting treatment of the disease

Multi-input synapses, but not LTP-strengthened synapses, correlate with hippocampal memory storage in aged mice

Long-lasting changes at synapses enable memory storage in the brain. Although aging is associated with impaired memory formation, it is not known whether the synaptic underpinnings of memory storage differ with age. Using a training schedule that results in the same behavioral memory formation in young and aged mice, we examined synapse ultrastructure and molecular signaling in hippocampus after contextual fear conditioning. Only in young, but not old mice contextual fear memory formation was associated with synaptic changes that characterize well-known long-term potentiation,a strengthening of existing synapses with one input. Instead old age memory was correlated with generation of multi-innervated dendritic spines (MIS), which are predominantly two-input synapses formed by the attraction of an additional excitatory, presynaptic terminal onto an existing synapse. Accordingly, a blocker used to inhibit MIS generation impaired contextual fear memory only in old mice. Our results reveal how the synaptic basis of hippocampal memory storage changes with age and they suggest that these distinct memory-storing mechanisms may explain impaired updating in old age

Synaptic dysfunction by mutations in GRIN2B: influence of triheteromeric NMDA receptors on gain-of-function and loss-of-function mutant classification

GRIN2B mutations are rare but often associated with patients having severe neurodevel-opmental disorders with varying range of symptoms such as intellectual disability, developmental delay and epilepsy. Patient symptoms likely arise from mutations disturbing the role that the en-coded NMDA receptor subunit, GluN2B, plays at neuronal connections in the developing nervous system. In this study, we investigated the cell-autonomous effects of putative gain-(GoF) and loss-of-function (LoF) missense GRIN2B mutations on excitatory synapses onto CA1 pyramidal neurons in organotypic hippocampal slices. In the absence of both native GluN2A and GluN2B subunits, functional incorporation into synaptic NMDA receptors was attenuated for GoF mutants, or almost eliminated for LoF GluN2B mutants. NMDA-receptor-mediated excitatory postsynaptic currents (NMDA-EPSCs) from synaptic GoF GluN1/2B receptors had prolonged decays consistent with their functional classification. Nonetheless, in the presence of native GluN2A, molecular replacement of native GluN2B with GoF and LoF GluN2B mutants all led to similar functional incorporation into synaptic receptors, more rapidly decaying NMDA-EPSCs and greater inhibition by TCN-201, a selective antagonist for GluN2A-containing NMDA receptors. Mechanistic insight was gained from experiments in HEK293T cells, which revealed that GluN2B GoF mutants slowed deactivation in diheteromeric GluN1/2B, but not triheteromeric GluN1/2A/2B receptors. We also show that a dis-ease-associated missense mutation, which severely affects surface expression, causes opposing effects on NMDA-EPSC decay and charge transfer when introduced into GluN2A or GluN2B. Finally, we show that having a single null Grin2b allele has only a modest effect on NMDA-EPSC decay kinetics. Our results demonstrate that functional incorporation of GoF and LoF GluN2B mutants into synaptic receptors and the effects on EPSC decay times are highly dependent on the presence of triheteromeric GluN1/2A/2B NMDA receptors, thereby influencing the functional classification of NMDA receptor variants as GoF or LoF mutations. These findings highlight the complexity of interpreting effects of disease-causing NMDA receptor missense mutations in the context of neuronal function

Generation of multi-innervated dendritic spines as a novel mechanism of long-term memory formation

NMDA receptor-dependent long-term potentiation (LTP) at hippocampal CA1 synapses is a well-accepted mechanism underlying long-term memory (LTM) formation. However, studies with mice that lack threonine-286 autophosphorylation of αCaMKII have shown that hippocampal LTM can be formed despite absence of NMDA receptor-dependent CA1 LTP. After multiple training trials, LTM formation in these mutants is linked to the generation of multi-innervated dendritic spines (MIS), a spine that receives typically two presynaptic inputs. PSD-95 overexpression is sufficient for MIS generation and depends on mTOR signaling. LTM that involves MIS generation appears less modifiable upon retrieval in comparison to LTM without MIS generation. Taken together, MIS generation appears to be a novel LTM mechanism after multiple training trials, which may occur in diseases with impaired LTP or conditions affecting negative feedback CaMKII signaling at the synapse

Age-dependent changes in autophosphorylation of alpha calcium/calmodulin dependent kinase II in hippocampus and amygdala after contextual fear conditioning

The hippocampus and amygdala are essential brain regions responsible for contextual fear conditioning (CFC). The autophosphorylation of alpha calciumcalmodulin kinase II (αCaMKII) at threonine-286 (T286) is a critical step 3 implicated in long-term potentiation (LTP), learning and memory. However, the changes in αCaMKII levels with aging and training in associated brain regions are not fully understood. Here, we studied how aging and training affect the levels of phosphorylated (T286) and proportion of phosphorylated:total αCaMKII in the hippocampus and amygdala. Young and aged mice, naïve (untrained) and trained in CFC, were analysed by immunohistochemistry for the levels of total and phosphorylated αCaMKII in the hippocampus and amygdala. We found that two hours after CFC training, young mice exhibited a higher level of phosphorylated and increased ratio of phosphorylated:total αCaMKII in hippocampal CA3 stratum radiatum. Furthermore, aged untrained mice showed a higher ratio of phosphorylated:total αCaMKII in the CA3 region of the hippocampus when compared to the young untrained group. No effect of training or aging were seen in the central, lateral and basolateral amygdala regions, for both phosphorylated and ratio of phosphorylated:total αCaMKII. These results show that aging impairs the training-induced upregulation of autophosphorylated (T286) αCaMKII in the CA3 stratum radiatum of the hippocampus. This indicates that distinct age-related mechanisms underlie CFC that may rely more heavily on NMDA receptor-dependent plasticity in young age

Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A

Dominant mutations in the human gene GRIN2A, encoding NMDA receptor (NMDAR) subunit GluN2A, make a significant and growing contribution to the catalogue of published single-gene epilepsies. Understanding the disease mechanism in these epilepsy patients is complicated by the surprising diversity of effects that the mutations have on NMDARs. Here we have examined the cell-autonomous effect of five GluN2A mutations, 3 loss-of-function and 2 gain-of-function, on evoked NMDAR-mediated synaptic currents (NMDA-EPSCs) in CA1 pyramidal neurons in cultured hippocampal slices. Despite the mutants differing in their functional incorporation at synapses, prolonged NMDA-EPSC current decays (with only marginal changes in charge transfer) were a common effect for both gain- and loss-of-function mutants. Modelling NMDA-EPSCs with mutant properties in a CA1 neuron revealed that the effect of GRIN2A mutations can lead to abnormal temporal integration and spine calcium dynamics during trains of concerted synaptic activity. Investigations beyond establishing the molecular defects of GluN2A mutants are much needed to understand their impact on synaptic transmission

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Temporal patterns of training determines distinct kinetics of structural plasticity, memory formation and decay

During learning, memories are formed in the selective population of the neuronal circuits which are then consolidated in order to persist. These memory processes are supported by distinct sub cellular events such as reversible functional modifications of synaptic transmission and persistent structural modifications in size or number of synaptic connections. However, how these synaptic modifications relate to the dynamics of formation and decay of memory in behaving animals remain elusive. Memory formation and its persistence are also known to be sensitive to the temporal features of the stimulus presentation, highlighted in the well-known “spacing effect” observed in a variety of explicit and implicit memory tasks. Training trials with resting intervals between them (spaced training) produce stronger and longer-lasting memory than the same number of trials with no interval (massed training). Despite numerous behavioral and molecular studies of the spacing effect, no conjoint study has demonstrated the underpinning synaptic plasticity in the expression of spacing effect during physiological learning. In invertebrate models, the different phases of memory are well dissected based on the temporal patterns of training. In Drosophila, implicit memory for odor avoidance task formed by massed training decayed over 3 days whereas by spaced training the memory retention was seen at least for a week. Studies using Aplysia model has shown that spaced training produced sensitization of gill withdrawal reflex lasting more than 24 h while massed training failed to induce long-term memory. However, there is no study showing the time course of memory formation and its decay following massed or spaced training in the mammalian brain. Here, we set out to study the temporal evolution and decay of memory and its correlation with synaptic modifications in learning with distinct temporal patterns of training.Adaptation of horizontal optokinetic response (HOKR) is a simple model of cerebellar motor learning to stabilize the visual image of moving surround. A phylogenetically preserved cerebellar lobule, flocculus (Fl) is known to be involved in the control of horizontal eye movement and the adaptation of HOKR. Previously, we have shown that short-term adaptation (STA, within a day) of HOKR in mice is accompanied with a transient reduction in number of AMPA receptors in parallel fiber to Purkinje cell (PF-PC) synapses which is recovered after 24 h. Long-term adaptation (LTA) of HOKR (days to weeks) with repeated 1 h massed training for five days was accompanied with long-lasting reduction of PF-PC synapses in the flocculus (Fl). Thus, HOKR serves as an ideal tool to study the effect of distributed and continues motor practice on kinetics of the memory and its relationship to the modifications in PF-PC synapses.In the present study; I examined adaptation of horizontal optokinetic response by massed or spaced training with varying intervals in mice. Despite similar acquisition of HOKR gain at the end of all training protocols, the retention of HOKR examined at 24 h was significantly resting-interval dependent. Massed training showed significant reduction of gain at 24 h. Also, the shorter intervals of 10 and 20 min produced poor retention of HOKR gain where as 1hour spacing interval showed the highest memory retention at 24 h. These results showed that optimum spacing is critical for efficient memory retention.Further, time course study revealed the distinct kinetics of long-lasting memory. Spaced training with optimum interval of 1 h not only developed the long-lasting memory quickly but also maintained it for about a month. This distinct kinetics of long-lasting memory by spaced training also strongly correlated with reduction of floccular parallel fiber-Purkinje cell (PC) synapses. Shrinkage in PF-PC synapses and PC spine together with reduction in density of AMPA receptors were already detected just at the end of spaced training. These structural changes were completed within 4 h after spaced training accompanied with 50% reduction of PF-PC synapses and PC spines and maintained for at least 2 weeks. Surprisingly, massed training also showed long-lasting memory with corresponding synapse reduction that developed slowly reaching the peak of 50% by 5th day. However, the memory lasted for a week with recovery of PF-PC synapses. Thus, I for the first time revealed a distinct form of long-lasting memory by massed training which is slow to remember and quick to forget as compared to spaced training. Moreover, the distinct memory kinetics was tightly correlated with structural modifications at the synapse. Taken together, the unique temporal profiles of synaptic plasticity may serve as a structural basis for distinct memory processes in learning with and without intervals