461 research outputs found
Alzheimer's Disease Biomarkers Revisited From the Amyloid Cascade Hypothesis Standpoint
Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Amyloid beta (Aβ) is one of the proteins which aggregate in AD, and its key role in the disease pathogenesis is highlighted in the amyloid cascade hypothesis, which states that the deposition of Aβ in the brain parenchyma is a crucial initiating step in the future development of AD. The sensitivity of instruments used to measure proteins in blood and cerebrospinal fluid has significantly improved, such that Aβ can now successfully be measured in plasma. However, due to the peripheral production of Aβ, there is significant overlap between diagnostic groups. The presence of pathological Aβ within the AD brain has several effects on the cells and surrounding tissue. Therefore, there is a possibility that using markers of tissue responses to Aβ may reveal more information about Aβ pathology and pathogenesis than looking at plasma Aβ alone. In this manuscript, using the amyloid cascade hypothesis as a starting point, we will delve into how the effect of Aβ on the surrounding tissue can be monitored using biomarkers. In particular, we will consider whether glial fibrillary acidic protein, triggering receptor expressed on myeloid cells 2, phosphorylated tau, and neurofilament light chain could be used to phenotype and quantify the tissue response against Aβ pathology in AD
Binding Small Molecules to a cis-Dicarbonyl -PNP Complex via Metal–Ligand Cooperativity
Metal–ligand cooperativity is a powerful tool for the activation of various bonds but has rarely, if ever, been studied with the radioactive transition metal Tc. In this work, we explore this bond activation pathway with the dearomatized PNP complex cis-[99TcI(PyrPNPtBu*)(CO)2] (4), which was synthesized by deprotonation of trans-[99TcI(PyrPNPtBu)(CO)2Cl] with KOtBu. Analogous to its rhenium congener, the dearomatized compound reacts with CO2 to form the carboxy complex cis-[99TcI(PyrPNPtBu–COO)(CO)2] and with H2 to form the mono-hydride complex cis-[99TcI(PyrPNPtBu)(CO)2H] (7). Substrates with weakly acidic protons are deprotonated by the Brønsted basic pincer backbone of 4, yielding a variety of intriguing complexes. Reactions with terminal alkynes enable the isolation of acetylide complexes. The deprotonation of an imidazolium salt results in the in situ formation and coordination of a carbene ligand. Furthermore, a study with heterocyclic substrates allowed for the isolation of pyrrolide and pyrazolide complexes, which is uncommon for Tc. The spectroscopic analyses and their solid-state structures are reported
Induced rearrangements in {M(CO)} complexes (M = Re, Tc) by a PNP ligand
The fac–mer isomerisation in [MX(CO)] (M = Re, Tc) is induced by a PNP pincer-type ligand in the presence of a halide scavenger. The adaptation to the aqueous and saline chemistry of Tc yields mer-[Tc(PNP)(CO)]
Towards 99mTc- and Re-based multifunctional silica platforms for theranostic applications
Taking advantage of the radiation properties of 99mTc and 186/188Re and the photophysical characteristics of the {M(CO)3}+ moiety (M = Re), we developed a multifunctional silica platform with the theranostic pair 99mTc/Re with high potential for (nano)medical applications. Starting with a general screening to evaluate the most suitable mesoporous silica construct and the development of appropriate chelate systems, multifunctional mesoporous silica microparticles (SBA-15) were synthesized. These particles act as a model towards the synthesis of the corresponding nanoconstructs. The particles can be modified at the external surface with a targeting function and labeled with the {M(CO)3}+ moiety (M = 99mTc, Re) at the pore surface. Thus, a silica platform is realized, whose bioprofile is not altered by the loaded modalities. The described synthetic procedures can be applied to establish a target-specific theranostic nanoplatform, which enables the combination of fluorescence and radio imaging, with the possibility of radio- and chemotherapy
Serum Neurofilament Light and Multiple Sclerosis Progression Independent of Acute Inflammation
Introduction
Efforts to explore the utility of neurofilament light (NfL) as a biomarker associated with disability
progression in multiple sclerosis (MS) have accelerated in recent years in the absence of
pharmacodynamic or treatment response markers for clinical trials or patient care.1
The International
Progressive MS Alliance stated in 2020 that serum NfL (sNfL) measurements may serve as a useful
biomarker associated with progressive MS, although further work is needed to define the relative
contributions of inflammatory activity and neurodegeneration to longitudinal changes in disability
and sNfL.2 Using data from a large clinical trial of patients with secondary progressive MS (a phase 3,
randomized, double-blind, placebo-controlled trial exploring the effect of natalizumab on disease
progression in participants with Secondary Progressive Multiple Sclerosis [ASCEND in SPMS];
NCT01416181), we investigated whether sNfL could be used as a dynamic biomarker associated with
progressive MS disease course. That is, we investigated whether longitudinal changes in sNfL
concentration were associated with disability progression measures in the absence of relapses and
magnetic resonance imaging (MRI) evidence of inflammatory activit
Synergistic effects of levosimendan and convalescence plasma as bailout strategy in acute cardiogenic shock in COVID-19: A case report
Parallel Data Mining on Multicore Clusters”, gcc
Abstract-The ever increasing number of cores per chip will be accompanied by a pervasive data deluge whose size will probably increase even faster than CPU core count over the next few years. This suggests the importance of parallel data analysis and data mining applications with good multicore, cluster and grid performance. This paper considers data clustering, mixture models and dimensional reduction presenting a unified framework applicable to bioinformatics, cheminformatics and demographics. Deterministic annealing is used to lessen effect of local minima. We present performance results on clusters of 2-8 core systems identifying effects from cache, runtime fluctuations, synchronization and memory bandwidth. We discuss needed programming model and compare with MPI and other approaches
Acceptability and feasibility of plasma phosphorylated-tau181 in two memory services
BACKGROUND: Plasma phosphorylated-tau181 (p-tau181) represents a novel blood-based biomarker of Alzheimer's disease pathology. We explored clinicians' experience of the utility of plasma p-tau181 in Camden and Islington Memory Services. METHODS: Patients were identified by their clinician as appropriate for p-tau181. Their p-tau181 result was plotted on a reference range graph provided to clinicians. This was discussed with the patient at diagnostic feedback appointment. RESULTS: Twenty-nine participants' plasma p-tau181 samples were included (mean age 74 SD 8.5, 65% female). Nine clinicians participated in the study. Eighty-six percent of clinicians found the p-tau181 result to be helpful and in 93% of cases it was clearly understandable. The p-tau181 result was useful in making the diagnosis in 44% of cases. CONCLUSIONS: Plasma p-tau181 is a feasible test for use in memory services and acceptable to clinicians. Clinician feedback on utility in dementia diagnoses was mixed. Further work is required to provide education and training in understanding and interpreting ambiguity in biomarker results
BRain health and healthy AgeINg in retired rugby union players, the BRAIN Study: study protocol for an observational study in the UK.
INTRODUCTION: Relatively little is known about the long-term health of former elite rugby players, or former sportspeople more generally. As well as the potential benefits of being former elite sportspersons, there may be potential health risks from exposures occurring during an individual's playing career, as well as following retirement. Each contact sport has vastly different playing dynamics, therefore exposing its players to different types of potential traumas. Current evidence suggests that these are not necessarily comparable in terms of pathophysiology, and their potential long-term adverse effects might also differ. There is currently limited but increasing evidence that poorer age-related and neurological health exists among former professional sportsmen exposed to repetitive concussions; however the evidence is limited on rugby union players, specifically. METHODS AND ANALYSIS: We present the protocol for a cross-sectional study to assess the association between self-reported history of concussion during a playing career, and subsequent measures of healthy ageing and neurological and cognitive impairment. We are recruiting a sample of approximately 200 retired rugby players (former Oxford and Cambridge University rugby players and members of the England Rugby International Club) aged 50 years or more, and collecting a number of general and neurological health-related outcome measures though validated assessments. Biomarkers of neurodegeneration (neurofilaments and tau) will be also be measured. Although the study is focusing on rugby union players specifically, the general study design and the methods for assessing neurological health are likely to be relevant to other studies of former elite sportspersons. ETHICS AND DISSEMINATION: The study has been approved by the Ethical Committee of London School of Hygiene and Tropical Medicine (reference: 11634-2). It is intended that results of this study will be published in peer-reviewed medical journals, communicated to participants, the general public and all relevant stakeholders
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