Miracle-dz/UniFAR-FTUs huggingface dataset:
Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal‐dominant Alzheimer's disease

Although pathogenic variants in PSEN1 leading to autosomal‐dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non‐carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre‐symptomatic and symptomatic phases of disease as compared to CY, using both cross‐sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ‐secretase and the generation of toxic β‐amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.
Challenges and opportunities for improvement when people with an intellectual disability or serious mental illness also need palliative care: A qualitative meta-ethnography

Background: People with diagnoses of intellectual disability or serious mental illness have higher mortality rates due to physical comorbidities; better understanding is needed to guide best practice in provision of palliative care for these populations. Aims: To identify multivoiced perspectives, drawn from lived experience of: what works, and what does not, in palliative care for people with intellectual disability or serious mental illness; challenges in, and opportunities to improve, palliative care. Design: A systematically constructed qualitative meta-ethnography. Protocol published (PROSPERO: CRD42021236616). Data sources: MEDLINE, PsychINFO, CINAHL PLUS and Embase used without date limitations. Papers published in English, containing qualitative data on palliative care provision for people with a diagnosis of intellectual disability or serious mental illness were included. Global five-point strength score applied for relevance/quality appraisal. Results: Familiarity (of location, people and/or things) is important for good palliative care. Assumptions and misunderstandings about the role of mental capacity assessment to appropriately involve the patient in decision-making are common. Adapting training for palliative care staff to address concerns and beliefs about mental illness is one of the methods that helps avoid diagnostic overshadowing. Proactive identification of service arrangements to meet needs of persons with personality, psychotic, delusional and bipolar affective disorders will help optimise care. Conclusions: Evidence, including the voices of people with intellectual disability or serious mental illness is urgently needed to guide efforts to improve their access to and experience of palliative care. More evidence is especially needed to understand, develop and implement best practice for people with psychosis, bipolar affective disorder, mania and personality disorder.
Touch to learn: Multisensory input supports word learning and processing

Infants experience language in rich multisensory environments. For example, they may first be exposed to the word applesauce while touching, tasting, smelling, and seeing applesauce. In three experiments using different methods we asked whether the number of distinct senses linked with the semantic features of objects would impact word recognition and learning. Specifically, in Experiment 1 we asked whether words linked with more multisensory experiences were learned earlier than words linked fewer multisensory experiences. In Experiment 2, we asked whether 2-year-olds’ known words linked with more multisensory experiences were better recognized than those linked with fewer. Finally, in Experiment 3, we taught 2-year-olds labels for novel objects that were linked with either just visual or visual and tactile experiences and asked whether this impacted their ability to learn the new label-to-object mappings. Results converge to support an account in which richer multisensory experiences better support word learning. We discuss two pathways through which rich multisensory experiences might support word learning.
Timing is everything, but does it really matter? Impact of 8-weeks morning versus evening iron supplementation in ballet and contemporary dancers

ABSTRACT The effectiveness of a morning versus evening oral iron supplement strategy to increase iron stores was explored. Ballet and contemporary dancers with serum ferritin (sFer) < 50μg/L (n = 14), were supplemented daily with 105 mg elemental oral iron in either the morning (FeAM) or evening (FePM) for 8 weeks. A control group (n = 6) with sFer >50μg/L were given no supplement over the same period. Dancers’ sFer were measured at baseline and post-intervention. Assessment of daily training load, dietary intake, and menstruation were made. A significant interaction (p < 0.001) showed the within group sFer change over the 8-week intervention in FeAM (+25.9 ± 10.5μg/L) and FePM, (+22.3 ± 13.6μg/L) was significantly different to CON (−30.17 ± 28.7μg/L; both p = 0.001). This change was not different between FeAM and FePM (p = 0.778). sFer levels within FeAM and FePM significantly increased over the 8-weeks; however, they significantly decreased in the CON group (all p < 0.05). Post-intervention sFer levels were no longer different between the three groups (p > 0.05). Training load, dietary intake, and number of menstrual cycles incurred were similar between FeAM and FePM (p > 0.05). Oral iron supplementation in either the morning or evening appears equally effective in increasing sFer levels in dancers with sub-optimal iron status. Highlights 8 weeks of oral iron supplements increases serum ferritin levels in elite dancers. Dancers not consuming an iron supplement showed a decline in serum ferritin over the 8-week period. Consuming the iron supplement in either the morning or the evening appeared equally effective in improving serum ferritin stores.
Adaptive observer-based fault estimation for a class of Lipschitz nonlinear systems

Fault input channels represent a major challenge for observer design for fault estimation. Most works in this ﬁeld assume that faults enter in such a way that the transfer functions be-tween these faults and a number of measured outputs are strictly positive real (SPR), that is, the observer matching condition is satisﬁed. This paper presents a systematic approach to adaptive observer design for joint estimation of the state and faults when the SPR requirement is not veriﬁed. The proposed method deals with a class of Lipschitz nonlinear systems subjected to piecewise constant multiplicative faults. The novelty of the proposed approach is that it uses a rank condition similar to the observer matching condition to construct the adaptation law used to obtain fault estimates. The problem of ﬁnding the adaptive observer matrices is formulated as a Linear Matrix Inequality (LMI) optimization problem. The proposed scheme is tested on the nonlinear model of a single link ﬂexible joint robot system.
Reversing vemurafenib‐resistance in primary melanoma cells by combined romidepsin and type I IFN treatment through blocking of tumorigenic signals and induction of immunogenic effects

BRAFV600 mutations are the most common oncogenic alterations in melanoma cells, supporting proliferation, invasion, metastasis and immune evasion. In patients, these aberrantly activated cellular pathways are inhibited by BRAFi whose potent antitumor effect and therapeutic potential are dampened by the development of resistance. Here, by using primary melanoma cell lines, generated from lymph node lesions of metastatic patients, we show that the combination of two FDA‐approved drugs, the histone deacetylate inhibitor (HDCAi) romidepsin and the immunomodulatory agent IFN‐α2b, reduces melanoma proliferation, long‐term survival and invasiveness and overcomes acquired resistance to the BRAFi vemurafenib (VEM). Targeted resequencing revealed that each VEM‐resistant melanoma cell line and the parental counterpart are characterized by a distinctive and similar genetic fingerprint, shaping the differential and specific antitumor modulation of MAPK/AKT pathways by combined drug treatment. By using RNA‐sequencing and functional in vitro assays, we further report that romidepsin‐IFN‐α2b treatment restores epigenetically silenced immune signals, modulates MITF and AXL expression and induces both apoptosis and necroptosis in sensitive and VEM‐resistant primary melanoma cells. Moreover, the immunogenic potential of drug‐treated VEM‐resistant melanoma cells results significantly enhanced, given the increased phagocytosis rate of these cells by dendritic cells, which in turn exhibit also a selective down‐modulation of the immune checkpoint TIM‐3. Overall, our results provide evidence that combined epigenetic‐immune drugs can overcome VEM resistance of primary melanoma cells by oncogenic and immune pathways reprogramming, and pave the way for rapidly exploiting this combination to improve BRAFi‐resistant metastatic melanoma treatment, also via reinforcement of immune checkpoint inhibitor therapy.
Evidence of horizontal gene transfer within porB in 19 018 whole-genome Neisseria spp. isolates: a global phylogenetic analysis

The PorB porins are the major pore-forming proteins in the genus Neisseria . The trimeric PorB porins consist of 16 highly conserved transmembrane domains that form an amphipathic β-sheet connected by short periplasmic turns and eight extracellular hydrophilic loops. These loops are immunogenic and also play an important role in mediating antimicrobial influx. This study sought to (i) characterize the variations in Neisserial loop 3(355–438 bp) associated with intermediate resistance to penicillin/tetracycline and (ii) evaluate if there was evidence of horizontal gene transfer in any of the loops. We collated an integrated database consisting of 19 018 Neisseria spp. genomes – 17 882 Neisseria gonorrhoeae , 114 Neisseria meningitidis and 1022 commensal Neisseria spp. To identify the porB alleles, a gene-by-gene approach (chewBBACA) was employed. To evaluate the presence of recombination events, the Recombination Detection Programme (RDP4) was used. In total, 3885 porB alleles were detected. Paralogues were identified in 17 Neisseria isolates. Putative recombination was identified in loop regions. Intraspecies recombination among N. gonorrhoeae isolates and interspecies recombination between N. meningitidis and commensal Neisseria spp. , and N. gonorrhoeae and N. lactamica were identified. Here, we present a large-scale study of 19 018 Neisseria isolates to describe recombination and variation in the porB gene. Importantly, we found putative recombination in loop regions between the pathogenic and non-pathogenic Neisseria spp. These findings suggest the need for pheno- and genotypic surveillance of antimicrobial susceptibility in commensal Neisseria spp. to prevent the emergence of AMR in the pathogenic Neisseria . This article contains data hosted by Microreact.
Cerebral aneurysms: Germany-wide real-world outcome data of endovascular or neurosurgical treatment from 2007 to 2019

Background Evidence on clinical outcome after endovascular treatment (EVT) vs neurosurgical clipping of intracranial aneurysms (IAs) is based on one randomized and one pseudo-randomized trial for ruptured aneurysms. Herein, we analyze nationwide real-world hospital outcomes after EVT vs clipping of ruptured and unruptured IAs. Methods This cohort study analyzed all EVT and clipping procedures for IAs in Germany between 2007 and 2019. The data basis was the billing-data of all German hospitals from the German Federal Statistical Office. EVT and clipping interventions, comorbidities, and in-hospital outcomes were identified using International Classification of Diseases (ICD) and Operation and Procedure (OPS) codes. Discharge type was used as a surrogate marker for functional independence. Poor clinical outcome at discharge was additionally defined by the dichotomous US National Inpatient Sample-Subarachnoid hemorrhage Outcome Measure score (NIH-SOM). Secondary outcomes included length of hospital stay, prolonged mechanical ventilation (>48 hour), and hospital reimbursement. Results We analyzed 90 039 procedures (62.6% EVT, 35.52% clipping, 1.8% combined) for the treatment of IAs. After adjustment in-hospital mortality was equal after EVT compared with clipping, in ruptured IAs (adjusted OR (aOR) 0.98, p=0.707) and unruptured IAs (aOR 0.92, p=0.482). Functional independence was more likely after EVT for ruptured (aOR 0.81, p<0.001) and unruptured IAs (aOR 0.4, p<0.001). Poor clinical outcome was more likely after clipping for ruptured (aOR 0.67, p<0.001) and unruptured IAs (aOR 0.56, p<0.001). Conclusions In German clinical practice, we observed higher rates of functional independence and lower rates of poor outcomes at discharge with equal mortality for EVT.
Integrated transcriptome and metabolome analysis reveals antioxidant machinery in grapevine exposed to salt and alkali stress.

Plant acclimation to salt and alkali stress is closely linked to the ability of the antioxidant system to mediate the scavenging of reactive oxygen species (ROS). In this study, we investigated the effects of salt stress and alkali stress on ROS, antioxidant enzymes, transcriptome, and metabolome. The results showed that the levels of superoxide anions, hydrogen peroxide, malondialdehyde, and electrolyte leakage increased under salt and alkali stress, with higher concentrations observed under alkali stress than salt stress. The activities of superoxide dismutase (EC 1.15.1.1), peroxidase (EC 1.11.1.7), catalase (EC 1.11.1.6), ascorbate peroxidase (EC 1.11.1.11), glutathione reductase (EC 1.6.4.2), dehydroascorbate reductase (EC 1.8.5.1), and monodehydroascorbate reductase (EC 1.6.5.4) varied under salt and alkali stress. The transcriptome analysis revealed the induction of signal transduction and metabolic processes and differential expression of genes encoding antioxidant enzymes in response to salt and alkali stress. The metabolome analysis demonstrated increased ascorbic acid and glutathione under salt stress, while most phenolic acids, flavonoids, and alkaloids increased under salt and alkali stress. Integrative analysis of the metabolome and transcriptome data revealed that the flavonoid biosynthesis pathway played a key role in the grapevine's response to salt stress. The total flavonoid content increased under salt and alkali stress, but the accumulation of flavonoids was higher under salt stress than alkali stress. In conclusion, our findings indicate significant differences in the antioxidant defense of grapevines under these two stresses, providing insight into distinct acclimation mechanisms in grapevine under salt and alkali stress. This article is protected by copyright. All rights reserved.
Synaptic memory and CaMKII

CaMKII and long-term potentiation (LTP) were discovered within a decade of each other and have been inextricably intertwined ever since. However, like many marriages, it has had its up and downs. Based on the unique biochemical properties of CaMKII, it was proposed as a memory molecule before any direct physiological linkage was made to LTP. This review will assess the state of this marriage 40 years on. How well does the physiological evidence support the role of CaMKII in synaptic memory and what are the remaining outstanding issues?
Sodium appetite and thirst do not require angiotensinogen production in astrocytes or hepatocytes

In addition to its renal and cardiovascular functions, angiotensin signalling is thought to be responsible for the increases in salt and water intake caused by hypovolaemia. However, it remains unclear whether these behaviours require angiotensin production in the brain or liver. Here, we use in situ hybridization to identify tissue‐specific expression of the genes required for producing angiotensin peptides, and then use conditional genetic deletion of the angiotensinogen gene (Agt) to test whether production in the brain or liver is necessary for sodium appetite and thirst. In the mouse brain, we identified expression of Agt (the precursor for all angiotensin peptides) in a large subset of astrocytes. We also identified Ren1 and Ace (encoding enzymes required to produce angiotensin II) expression in the choroid plexus, and Ren1 expression in neurons within the nucleus ambiguus compact formation. In the liver, we confirmed that Agt is widely expressed in hepatocytes. We next tested whether thirst and sodium appetite require angiotensinogen production in astrocytes or hepatocytes. Despite virtually eliminating expression in the brain, deleting astrocytic Agt did not reduce thirst or sodium appetite. Despite markedly reducing angiotensinogen in the blood, eliminating Agt from hepatocytes did not reduce thirst or sodium appetite, and in fact, these mice consumed the largest amounts of salt and water after sodium deprivation. Deleting Agt from both astrocytes and hepatocytes also did not prevent thirst or sodium appetite. Our findings suggest that angiotensin signalling is not required for sodium appetite or thirst and highlight the need to identify alternative signalling mechanisms.
Nonclassical solutions of hyperbolic conservation laws.

This dissertation studies the nonclassical shock waves which appears as limits of certain type diffusive-dispersive regularisation to hyperbolic of conservation laws. Such shocks occur very often when the flux function lacks the convexity especially when the initial conditions for Riemann problem belong to different region of convexity. They have negative entropy dissipation. They do not verify the classical Oleinik entropy criterion. The cubic function is taken as a flux function. The existence and uniqueness of such shock waves are studied. They are constructed as limits of traveling-wave solutions for diffusive-dispersive regularisation. A kinetic relation is introduced to choose a unique nonclassical solution to the Riemann problem. The numerical simulations are investigated using a transport-equilibrium scheme to enable computing the nonclassical solution at the discrete level of kinetic function. The method is composed of an equilibrium step containing the kinetic relation at any nonclassical shock and a transport step advancing the discontinuity with time.
Detection in SAR images based on multi-dimensional generalized low rank model

In this paper, a novel method is proposed for ship detection in polarimetric SAR images. This method employs the multi-dimensional generalized low rank model (GLRM) to model the polarimetric SAR image used for ship detection. An induced multi-dimensional robust principle component analysis (RPCA) framework with a developed fast alternating direction method (ADM) is used to decompose a polarimetric image as a sum of a low rank component, a noise component and a sparse component associated with ships. For comparison, the Polarimetric Whitening Filter (PWF) and Generalized Optimization of Polarimetric Contrast Enhancement (GOPCE) are also used. Experiments results with the RADARSAT-2 C-band image over Singapore Strait show that the proposed method can correctly detect the ships from sea clutter, demonstrating a robust detection performance.
The Study of Relationship between Circular Orbit Cone Beam Reconstruction Error and Cone Angle

Objective The Study of Relationship between Circular Orbit Cone Beam Reconstruction Error and Cone Angle. Method: Compared with 2-D CT reconstruction, Cone-Beam reconstruction has several advantages, and now it has been implemented more and more widely. Circular orbit based Cone-Beam reconstruction algorithms, which are mathematically simpler and more feasible than other algorithms, are more favorable. However, because of the limitation by circular orbit, we cant obtain all the data in Radon Space which means that the result becomes better with the cone angle decreases. So it is important to study the relationship between the cone angle and the reconstruct quality further. Results: In this paper we obtain a relationship between the error and the cone angle with some approximation. Conclusion: Then we propose some ways to improve circular orbit based Cone-Beam algorithms.
Extraradical hyphae exhibit more plastic nutrient‐acquisition strategies than roots under nitrogen enrichment in ectomycorrhiza‐dominated forests

Ectomycorrhizal (ECM) functional traits related to nutrient acquisition are impacted by nitrogen (N) deposition. However, less is known about whether these nutrient‐acquisition traits associated with roots and hyphae differentially respond to increased N deposition in ECM‐dominated forests with different initial N status. We conducted a chronic N addition experiment (25 kg N ha−1 year−1) in two ECM‐dominated forests with contrasting initial N status, that is, a Pinus armandii forest (with relatively low N availability) and a Picea asperata forest (with relatively high N availability), to assess nutrient‐mining and nutrient‐foraging strategies associated with roots and hyphae under N addition. We show that nutrient‐acquisition strategies of roots and hyphae differently respond to increased N addition. Root nutrient‐acquisition strategies showed a consistent response to N addition, regardless of initial forest nutrient status, shifting from organic N mining toward inorganic N foraging. In contrast, the hyphal nutrient‐acquisition strategy showed diverse responses to N addition depending on initial forest N status. In the Pinus armandii forest, trees increased belowground carbon (C) allocation to ECM fungi thus enhancing hyphal N‐mining capacity under increased N availability. By comparison, in the Picea asperata forest, ECM fungi enhanced both capacities of P foraging and P mining in response to N‐induced P limitation. In conclusion, our results demonstrate that ECM fungal hyphae exhibit greater plasticity in nutrient‐mining and nutrient‐foraging strategies than roots do in response to changes of nutrient status induced by N deposition. This study highlights the importance of ECM associations in tree acclimation and forest function stability under changing environments.