The identification of PSEN1 p.Tyr159Ser mutation in a non-canonic early-onset Alzheimer's disease family.

More than 300 missense mutations in PSEN1 gene have been correlated to the early-onset Alzheimer's disease (EOAD), but given the high diversity of PS1 (the PSEN1 gene product) substrates and the involvement of PS1 in multiple biological functions, different mutants may represent different EOAD etiologies, and how each mutant contributes to the EOAD remains to be further investigated. Here we report the identification of a novel PSEN1 p.Tyr159Ser in a family with multiple EOAD cases. The mutant PS1 protein (PS1Y159S) was analyzed for its activity in producing amyloid-ß (Aß) and for the efficiency in maturation in vitro. We also screened other mutations and SNPs that may modify the effect of PSEN1 p.Tyr159Ser on AD pathogenesis. The blood samples of the family were collected for whole-exome gene sequencing and analysis. The identified mutant PS1 and several other PS1 mutants were co-expressed with the APP Swedish mutant to compare the effects on APP processing and PS1 maturation.1. The proband and her siblings over 50 years old showed typical AD or MCI symptoms. Exon sequencing identified the p.Tyr159Ser mutation in the PSEN1 gene. As not until the age of 78 did the proband's mother who carried this mutation displayed the symptoms of uncharacterized neuropsychiatry instead of AD, but all the mutation bearing lower generation developed AD or MCI after the age of 50, we also analyzed mutations/SNPs that are different between the mother and the lower generation. By in vitro assays, we found that the Y159S substitution strongly increased Aß42/Aß40 ratio and significantly affected PS1 maturation. The newly discovered PSEN1 p.Tyr159Ser is an AD-causing mutation, yet, the carriers are not obligated AD patients. Mutations/SNPs in other gene may modify the effects of this mutation, and the identification of these mutations/SNPs may facilitate the discovery of AD-preventing mechanisms and methods.

Conditional Boundary Loss for Semantic Segmentation.

Improving boundary segmentation results has recently attracted increasing attention in the field of semantic segmentation. Since existing popular methods usually exploit the long-range context, the boundary cues are obscure in the feature space, leading to poor boundary results. In this paper, we propose a novel conditional boundary loss (CBL) for semantic segmentation to improve the performance of the boundaries. The CBL creates a unique optimization goal for each boundary pixel, conditioned on its surrounding neighbors. The conditional optimization of the CBL is easy yet effective. In contrast, most previous boundary-aware methods have difficult optimization goals or may cause potential conflicts with the semantic segmentation task. Specifically, the CBL enhances the intra-class consistency and inter-class difference, by pulling each boundary pixel closer to its unique local class center and pushing it away from its different-class neighbors. Moreover, the CBL filters out noisy and incorrect information to obtain precise boundaries, since only surrounding neighbors that are correctly classified participate in the loss calculation. Our loss is a plug-and-play solution that can be used to improve the boundary segmentation performance of any semantic segmentation network. We conduct extensive experiments on ADE20K, Cityscapes, and Pascal Context, and the results show that applying the CBL to various popular segmentation networks can significantly improve the mIoU and boundary F-score performance.

Classification of EEG Signals Based on Sparrow Search Algorithm-Deep Belief Network for Brain-Computer Interface.

In brain-computer interface (BCI) systems, challenges are presented by the recognition of motor imagery (MI) brain signals. Established recognition approaches have achieved favorable performance from patterns like SSVEP, AEP, and P300, whereas the classification methods for MI need to be improved. Hence, seeking a classification method that exhibits high accuracy and robustness for application in MI-BCI systems is essential. In this study, the Sparrow search algorithm (SSA)-optimized Deep Belief Network (DBN), called SSA-DBN, is designed to recognize the EEG features extracted by the Empirical Mode Decomposition (EMD). The performance of the DBN is enhanced by the optimized hyper-parameters obtained through the SSA. Our method's efficacy was tested on three datasets: two public and one private. Results indicate a relatively high accuracy rate, outperforming three baseline methods. Specifically, on the private dataset, our approach achieved an accuracy of 87.83%, marking a significant 10.38% improvement over the standard DBN algorithm. For the BCI IV 2a dataset, we recorded an accuracy of 86.14%, surpassing the DBN algorithm by 9.33%. In the SMR-BCI dataset, our method attained a classification accuracy of 87.21%, which is 5.57% higher than that of the conventional DBN algorithm. This study demonstrates enhanced classification capabilities in MI-BCI, potentially contributing to advancements in the field of BCI.

Comparison of adjuvant chemoradiotherapy versus radiotherapy in early-stage cervical cancer patients with intermediate-risk factors: A systematic review and meta-analysis.

The presence of intermediate risk factors reduces the predictability of radical hysterectomy, demanding the use of adjuvant therapy for treatment of Early stage cervical cancer (ESCC) patients. Adjuvant radiotherapy (RT) and chemoradiotherapy (CRT) has been widely used with varied efficacy and safety issues. Therefore, the aim of this systematic review and meta-analysis was to update the available evidence and assess the effect of post-surgical adjuvant RT versus adjuvant CRT on survival rate and complications/toxicities in management of ESCC patients with intermediate risk factors. PubMed, EMBASE and Web of Science (WOS) and CENTRAL were searched using a combination of relevant keywords. All studies comparing outcomes of adjuvant RT versus CRT in ESCC patients with intermediate-risk factors in terms of recurrence free survival (RFS), overall survival (OS) and toxicities/complications were included. Both qualitative and quantitative analysis was carried out. The risk of bias assessment was done using Newcastle-Ottawa scale (NOS) for retrospective cohort studies and Cochrane risk of bias assessment tool was used for randomized clinical trials. Eleven retrospective cohort studies and two randomized clinical trials were included in this review. Adjuvant CRT was found to have better RFS with ESCC patients with multiple intermediate risk factors with OR 3.11 95% CI [1.04, 4.99], p < 0.0001; i2 = 6%. However, similar benefit was observed between both regimens in presence of a single intermediate risk factor OR 1.80 95% CI [0.96, 3.36], p = 0.07; i2 = 0%. Grade 3 or 4 haematological toxicity among patients receiving post-surgical adjuvant RT versus adjuvant CRT showed increased association of toxicity with adjuvant CRT with OR 7.73 95%CI [3.40, 17.59], p < 0.0001; i2 = 62%. Adjuvant CRT shows favourable RFS and OS in ESCC patients with multiple intermediate risk factors. CRT also showed greater incidence of grade 3 or 4 haematological and non-haematiological toxicity, however, the same could be well tolerated when used within the recommended dosage.

Targeting Approaches of Nanomedicines in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a hematological malignancy, which is commonly associated with high incidence and mortality among adult patients. The standard induction regimen for AML has been substantially unchanged over the past 40 years, for which novel nanomedicines have represented a promising strategy in AML therapies. Despite developments of multiple nanoparticles formulated with drugs or genes, less there is not much information available about approaches in AML is available. This review presents an overview of nanomedicines currently being evaluated in AML. First, it briefly summarized conventional chemotherapies in use. Second, nanomedicines presently ongoing in clinical trials or preclinical researches were classified and described, with illustrative examples from recent literatures. Finally, limitations and potential safety issues concerns in clinical translation of AML treatment were discussed as well.

Pathological tau deposition in Motor Neurone Disease and frontotemporal lobar degeneration associated with TDP-43 proteinopathy.

It has been suggested that patients with motor neurone disease (MND) and those with MND combined with behavioural variant frontotemporal dementia (bvFTD) (ie FTD + MND) or with FTD alone might exist on a continuum based on commonalities of neuropathology and/or genetic risk. Moreover, it has been reported that both a neuronal and a glial cell tauopathy can accompany the TDP-43 proteinopathy in patients with motor neurone disease (MND) with cognitive changes, and that the tauopathy may be fundamental to disease pathogenesis and clinical phenotype. In the present study, we sought to substantiate these latter findings, and test this concept of a pathological continuum, in a consecutive series of 41 patients with MND, 16 with FTD + MND and 23 with FTD without MND. Paraffin sections of frontal, entorhinal, temporal and occipital cortex and hippocampus were immunostained for tau pathology using anti-tau antibodies, AT8, pThr(175) and pThr(217), and for amyloid ß protein (Aß) using 4G8 antibody. Twenty four (59 %) patients with MND, 7 (44 %) patients with FTD + MND and 10 (43 %) patients with FTD showed 'significant' tau pathology (ie more than just an isolated neurofibrillary tangle or a few neuropil threads in one or more brain regions examined). In most instances, this bore the histological characteristics of an Alzheimer's disease process involving entorhinal cortex, hippocampus, temporal cortex, frontal cortex and occipital cortex in decreasing frequency, accompanied by a deposition of Aß up to Thal phase 3, though 2 patients with MND, and 1 with FTD did show tau pathology beyond Braak stage III. Four other patients with MND showed novel neuronal tau pathology, within the frontal cortex alone, specifically detected by pThr(175) antibody, which was characterised by a fine granular or more clumped aggregation of tau without neurofibrillary tangles or neuropil threads. However, none of these 4 patients had clinically evident cognitive disorder, and this type of tau pathology was not seen in any of the FTD + MND or FTD patients. Finally, two patients, one with MND and one with FTD, showed a tau pathology consistent with Argyrophilic Grain Disease (AGD). Western blotting and use of 3- and 4-repeat tau antibodies confirmed the histological interpretation of Alzheimer's disease type pathology in all instances except for those patients with accompanying AGD where a banding pattern on western blot, and immunohistochemistry, confirmed 4-repeat tauopathy. In all 3 patient groups, amyloid pathology was more likely to be present in patients dying after 65 years of age, and in the presence of APOE ε4 allele. We conclude that tau pathological changes are equally common amongst patients with MND, FTD + MND and FTD though, in most instances, these are limited in extent. In patients with MND, when cognitive impairment is present this is most likely due to an accompanying/evolving (coincidental) Alzheimer's disease process or, as in a single case, Dementia with Lewy bodies, within the cerebral cortex rather than as a result of TDP-43 proteinopathy. Conversely, in FTD and FTD + MND dementia is more likely to be associated with TDP-43 proteinopathy than tau. Hence, present study shows no progression in severity of (tau) pathology from MND through FTD + MND to FTD, and does not support the concept of these conditions forming a continuum of clinical or pathological change.