We apply a matched‐filter‐technique to augment the detected events in the time window between the two mainshocks of the 2012 Emilia seismic sequence (Italy), 20 (Mw 6.1) and 29 (Mw 6.0) May. Using ...well‐located templates, we increase the number of detections from 1,727 to 7,616. This greater detail allows evidencing migrations of seismic events from the nucleation point of the first shock to the second. Repeating earthquakes are also found between the two mainshocks. The seismicity pattern suggests a transient slip acting immediately after the shallow first event, weakening and loading the volume around the deep nucleation point of the 29 May Mw 6.0 earthquake. We interpret migrations and repeaters as the fingerprint of an early afterslip triggered by the first mainshock. By taking into account the earliest repeater we estimate a cumulative slip of approximately 27 cm (Mw 5.7). This value could represent the lower bound of the total released afterslip.
Plain Language Summary
To improve our understanding of interactions between subsequent mainshocks, we investigated the spatiotemporal evolution of the seismicity for the 2012 Emilia seismic sequence (Italy) in the time window from 20 to 29 May 2012. We use a technique based on waveform matching to augment the detected earthquakes. From the new catalog, we observe along‐strike and at depth seismic migrations consistent with a phase of rapid postseismic slip concentrated near the base of the seismogenic zone immediately after the first main shock. We suggest that the afterslip contributed to loading the fault rupture area of the 29 May Mw 6.0 earthquake.
Key Points
Newly detected early aftershocks suggest a fast migration at depth moving from the 20 May hypocenter to the 29 May nucleation point
Repeating earthquakes have been identified between the two mainshocks
Migration and repeaters suggest an afterslip that could have contributed to loading the 29 May focal volume
Loss of neurotrophic support in the striatum caused by reduced brain-derived neurotrophic factor (BDNF) levels plays a critical role in Huntington's disease (HD) pathogenesis. BDNF acts via TrkB and ...p75 neurotrophin receptors (NTR), and restoring its signaling is a prime target for HD therapeutics. Here we sought to determine whether a small molecule ligand, LM22A-4, specific for TrkB and without effects on p75(NTR), could alleviate HD-related pathology in R6/2 and BACHD mouse models of HD. LM22A-4 was administered to R6/2 mice once daily (5-6 d/week) from 4 to 11 weeks of age via intraperitoneal and intranasal routes simultaneously to maximize brain levels. The ligand reached levels in the R6/2 forebrain greater than the maximal neuroprotective dose in vitro and corrected deficits in activation of striatal TrkB and its key signaling intermediates AKT, PLCγ, and CREB. Ligand-induced TrkB activation was associated with a reduction in HD pathologies in the striatum including decreased DARPP-32 levels, neurite degeneration of parvalbumin-containing interneurons, inflammation, and intranuclear huntingtin aggregates. Aggregates were also reduced in the cortex. Notably, LM22A-4 prevented deficits in dendritic spine density of medium spiny neurons. Moreover, R6/2 mice given LM22A-4 demonstrated improved downward climbing and grip strength compared with those given vehicle, though these groups had comparable rotarod performances and survival times. In BACHD mice, long-term LM22A-4 treatment (6 months) produced similar ameliorative effects. These results support the hypothesis that targeted activation of TrkB inhibits HD-related degenerative mechanisms, including spine loss, and may provide a disease mechanism-directed therapy for HD and other neurodegenerative conditions.
Abstract
Background
The relevance of tobacco smoking for infectious respiratory diseases (IRD) is uncertain. We investigated the associations of cigarette smoking with severe IRD resulting in ...hospitalization or death in UK adults.
Methods
We conducted a prospective study of cigarette smoking and risk of severe IRD in UK Biobank. The outcomes included pneumonia, other acute lower respiratory tract infections (OA-LRTI) and influenza. Multivariable Cox regression analyses were used to estimate hazard ratios (HRs) of severe IRD associated with smoking habits after adjusting for confounding factors.
Results
Among 341 352 participants with no prior history of major chronic diseases, there were 12 384 incident cases with pneumonia, 7054 with OA-LRTI and 795 with influenza during a 12-year follow-up. Compared with non-smokers, current smoking was associated with ⁓2-fold higher rates of severe IRD (HR 2.40 2.27–2.53 for pneumonia, 1.99 1.84–2.14 for OA-LRTI and 1.82 95% confidence interval: 1.47–2.24 for influenza). Incidence of all severe IRDs were positively associated with amount of cigarettes smoked. The HRs for each IRD (except influenza) also declined with increasing duration since quitting.
Conclusions
Current cigarette smoking was positively associated with higher rates of IRD and the findings extend indications for tobacco control measures and vaccination of current smokers for prevention of severe IRD.
Longitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling ...networks regulated by the p75 neurotrophin receptor (p75
) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75
will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aβ-induced injury. In neurons exposed to oligomeric Aβ in vitro and APP mutant mouse models, modulation of p75
signaling using the small-molecule LM11A-31 was found to inhibit Aβ-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75
signaling inhibits a broad spectrum of Aβ-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.
Degeneration of basal forebrain cholinergic neurons (BFCNs) in the nucleus basalis of Meynert (NBM) and vertical diagonal band (VDB) along with their connections is a key pathological event leading ...to memory impairment in Alzheimer's disease (AD). Aberrant neurotrophin signaling via Trks and the p75 neurotrophin receptor (p75NTR) contributes importantly to BFCN dystrophy. While NGF/TrkA signaling has received the most attention in this regard, TrkB and TrkC signaling also provide trophic support to BFCNs and these receptors may be well located to preserve BFCN connectivity. We previously identified a small molecule TrkB/TrkC ligand, LM22B-10, that promotes cell survival and neurite outgrowth in vitro and activates TrkB/TrkC signaling in the hippocampus of aged mice when given intranasally, but shows poor oral bioavailability. An LM22B-10 derivative, PTX-BD10–2, with improved oral bioavailability has been developed and this study examined its effects on BFCN atrophy in the hAPPLond/Swe (APPL/S) AD mouse model. Oral delivery of PTX-BD10–2 was started after appreciable amyloid and cholinergic pathology was present to parallel the clinical context, as most AD patients start treatment at advanced pathological stages. PTX-BD10–2 restored cholinergic neurite integrity in the NBM and VDB, and reduced NBM neuronal atrophy in symptomatic APPL/S mice. Dystrophy of cholinergic neurites in BF target regions, including the cortex, hippocampus, and amygdala, was also reduced with treatment. Finally, PTX-BD10–2 reduced NBM tau pathology and improved the survival of cholinergic neurons derived from human induced pluripotent stem cells (iPSCs) after amyloid-β exposure. These data provide evidence that targeting TrkB and TrkC signaling with PTX-BD10–2 may be an effective disease-modifying strategy for combating cholinergic dysfunction in AD. The potential for clinical translation is further supported by the compound's reduction of AD-related degenerative processes that have progressed beyond early stages and its neuroprotective effects in human iPSC-derived cholinergic neurons.
•PTX-BD10–2, a TrkB/C modulator, prevented & reversed BFCN degeneration in APPL/S mice.•Targeting TrkB/C preserved BFCN target innervation and reduced BF tau pathology.•PTX-BD10–2 is neuroprotective for Aβ-exposed human iPSC-derived cholinergic neurons.•Targeting TrkB/C may reduce AD-related pathology that has moved beyond early stages.
The current review summarizes the pathobiology of nerve growth factor (NGF) and its cognate receptors during the progression of Alzheimer's disease (AD). Both transcript and protein data indicate ...that cholinotrophic neuronal dysfunction is related to an imbalance between TrkA-mediated survival signaling and the NGF precursor (proNGF)/p75
-mediated pro-apoptotic signaling, which may be related to alteration in the metabolism of NGF. Data indicate a spatiotemporal pattern of degeneration related to the evolution of tau pathology within cholinotrophic neuronal subgroups located within the nucleus basalis of Meynert (nbM). Despite these degenerative events the cholinotrophic system is capable of cellular resilience and/or plasticity during the prodromal and later stages of the disease. In addition to neurotrophin dysfunction, studies indicate alterations in epigenetically regulated proteins occur within cholinotrophic nbM neurons during the progression of AD, suggesting a mechanism that may underlie changes in transcript expression. Findings that increased cerebrospinal fluid levels of proNGF mark the onset of MCI and the transition to AD suggests that this proneurotrophin is a potential disease biomarker. Novel therapeutics to treat NGF dysfunction include NGF gene therapy and the development of small molecule agonists for the cognate prosurvival NGF receptor TrkA and antagonists against the pan-neurotrophin p75
death receptor for the treatment of AD.
Current guidelines for healthcare of community-dwelling older people advocate screening for frailty to predict adverse health outcomes, but there is no consensus on the optimum instrument to use in ...such settings. The objective of this systematic review of population studies was to compare the ability of the frailty index (FI) and frailty phenotype (FP) instruments to predict all-cause mortality in older people.
Studies published before 27 July 2022 were identified using Ovid MEDLINE, Embase, Scopus, Web of Science and CINAHL databases. The eligibility criteria were population-based prospective studies of community-dwelling older adults (aged 65 years or older) and evaluation of both the FI and FP for prediction of all-cause mortality. The Scottish Intercollegiate Guidelines Network's Methodology checklist was used to assess study quality. The areas under the receiver operator characteristic curves (AUC) were compared, and the proportions of included studies that achieved acceptable discriminatory power (AUC>0.7) were calculated for each frailty instrument. The results were stratified by the use of continuous or categorical formats of each instrument. The review was reported in accordance with the PRISMA and SWiM guidelines.
Among 8 studies (range: 909 to 7713 participants), both FI and FP had comparable predictive power for all-cause mortality. The AUC values ranged from 0.66 to 0.84 for FI continuous, 0.60 to 0.80 for FI categorical, 0.63 to 0.80 for FP continuous and 0.57 to 0.79 for FP categorical. The proportion of studies achieving acceptable discriminatory power were 75%, 50%, 63%, and 50%, respectively. The predictive ability of each frailty instrument was unaltered by the number of included items.
Despite differences in their content, both the FI and FP instruments had modest but comparable ability to predict all-cause mortality. The use of continuous rather than categorical formats in either instrument enhanced their ability to predict all-cause mortality.
Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor, respiratory and autonomic control, ...cognitive impairment, autistic-like behaviors and increased risk of seizures. RTT patients and Mecp2-null mice exhibit reduced expression of brain-derived neurotrophic factor (BDNF), which has been linked in mice to increased respiratory frequency, a hallmark of RTT. The present study was undertaken to test the hypotheses that BDNF deficits in Mecp2 mutants are associated with reduced activation of the BDNF receptor, TrkB, and that pharmacologic activation of TrkB would improve respiratory function. We characterized BDNF protein expression, TrkB activation and respiration in heterozygous female Mecp2 mutant mice (Het), a model that recapitulates the somatic mosaicism for mutant MECP2 found in typical RTT patients, and evaluated the ability of a small molecule TrkB agonist, LM22A-4, to ameliorate biochemical and functional abnormalities in these animals. We found that Het mice exhibit (1) reduced BDNF expression and TrkB activation in the medulla and pons and (2) breathing dysfunction, characterized by increased frequency due to periods of tachypnea, and increased apneas, as in RTT patients. Treatment of Het mice with LM22A-4 for 4 weeks rescued wild-type levels of TrkB phosphorylation in the medulla and pons and restored wild-type breathing frequency. These data provide new insight into the role of BDNF signaling deficits in the pathophysiology of RTT and highlight TrkB as a possible therapeutic target in this disease.
In investigating the role of metal ions in the pathogenesis of Huntington's disease, we examined the effects of clioquinol, a metal-binding compound currently in clinical trials for Alzheimer's ...disease treatment, on mutant huntingtin-expressing cells. We found that PC12 cells expressing polyglutamine-expanded huntingtin exon 1 accumulated less mutant protein and showed decreased cell death when treated with clioquinol. This effect was polyglutamine-length-specific and did not alter mRNA levels or protein degradation rates. Clioquinol treatment of transgenic Huntington's mice (R6/2) improved behavioral and pathologic phenotypes, including decreased huntingtin aggregate accumulation, decreased striatal atrophy, improved rotarod performance, reduction of weight loss, normalization of blood glucose and insulin levels, and extension of lifespan. Our results suggest that clioquinol is a candidate therapy for Huntington's disease and other polyglutamine-expansion diseases.
Contemporary cardiovascular disease (CVD) risk prediction models are rarely applied in routine clinical practice in China due to substantial regional differences in absolute risks of major CVD types ...within China. Moreover, the inclusion of blood lipids in most risk prediction models also limits their use in the Chinese population. We developed 10-year CVD risk prediction models excluding blood lipids that may be applicable to diverse regions of China.
We derived sex-specific models separately for ischemic heart disease (IHD), ischemic stroke (IS), and hemorrhagic stroke (HS) in addition to total CVD in the China Kadoorie Biobank. Participants were age 30-79 years without CVD at baseline. Predictors included age, systolic and diastolic blood pressure, use of blood pressure-lowering treatment, current daily smoking, diabetes, and waist circumference. Total CVD risks were combined in terms of conditional probability using the predicted risks of 3 submodels. Risk models were recalibrated in each region by 2 methods (practical and ideal) and risk prediction was estimated before and after recalibration.
Model derivation involved 489,596 individuals, including 45,947 IHD, 43,647 IS, and 11,168 HS cases during 11 years of follow-up. In women, the Harrell C was 0.732 (95% CI 0.706-0.758), 0.759 (0.738-0.779), and 0.803 (0.778-0.827) for IHD, IS, and HS, respectively. The Harrell C for total CVD was 0.734 (0.732-0.736), 0.754 (0.752-0.756), and 0.774 (0.772-0.776) for models before recalibration, after practical recalibration, and after ideal recalibration. The calibration performances improved after recalibration, with models after ideal recalibration showing the best model performances. The results for men were comparable to those for women.
Our CVD risk prediction models yielded good discrimination of IHD and stroke subtypes in addition to total CVD without including blood lipids. Flexible recalibration of our models for different regions could enable more widespread use using resident health records covering the overall Chinese population.
This study provides Class I evidence that a prediction model incorporating accessible clinical variables predicts 10-year risk of IHD, IS, and HS in the Chinese population age 30-79 years.
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