Beta Form Research Articles

Inhibition of amyloid beta oligomer, fibrils, and peptide using nanoparticles to disrupt Alzheimer's pathogenesis.

The Aβ peptide, which is connected to the development of Alzheimer's disease, forms highly neurotoxic prefibrillar oligomeric aggregates, which are challenging to study due to their fleeting, low prevalence, and diverse nature. These aggregates are considered to play a role in the pathogenesis of numerous neurodegenerative diseases. The potential approach of blocking or disrupting the buildup of amyloid peptides, particularly amyloid-β (AβOs), by using nanoparticles that specifically bind or prevent their aggregation to develop new medications and treatments for Alzheimer's disease (AD) could be a promising solution. Nanoparticles have been proposed as a potential solution to modify the protein fibrillation process. Recently, Researchers have design and created some nanoparticles for inhibition of amyloid-β oligomer and (Aβ) peptide aggregation, involved in Alzheimer’s disease (AD). In this concise review, we concentrated on the mechanism and formation of amyloid beta oligomers, fibrils, peptides, and it’s role in Alzheimer's disease. Secondly, we discussed small molecules that can detect various forms of amyloid beta for early diagnosis. Lastly, we primarily focused on nanoparticles that possess the ability to inhibit and disaggregate amyloid beta oligomers fibrils, and peptide which are the primary hallmarks of Alzheimer's disease. Here for the first time we also summarize some of the nanoparticles and nanomaterials which can dis-aggregate the exis-ting amyloid-β oligomer and (Aβ) peptide which are challenging for many researcher.

Investigation of a liquid-mediated defect-healing treatment in zeolite beta

We report the application of a liquid-mediated defect-healing treatment based on tetraethylammonium (TEA+) hydroxide and ammonium fluoride, and variants thereof, to the H+ form of zeolite beta. Through comparison between H-beta of high (730) and lower (28.6) SiO2: Al2O3 ratios, and characterisation of the treated samples before and after calcination, insights into the interaction of TEA+ and F− with H-beta under hydrothermal conditions were gained. In general, the treatments resulted in the loss of crystallinity and the generation of relatively large mesopores in the more siliceous samples, but improvements in long-range order and the development of relatively small mesopores in the less siliceous samples. The healing of silanol defects was observed for most of the treatments. A partial mechanism is proposed to explain the action of defect-healing treatments based on pore-occupying cations and F−; fluorine may be essential in some cases because it balances the charge of the organic cations, preventing the “trapping” of silanol groups as charge-balancing silanolate groups which resist healing.

Health Effects of Ionizing Radiation on the Human Body.

Radioactivity is a process in which the nuclei of unstable atoms spontaneously decay, producing other nuclei and releasing energy in the form of ionizing radiation in the form of alpha (α) and beta (β) particles as well as the emission of gamma (γ) electromagnetic waves. People may be exposed to radiation in various forms, as casualties of nuclear accidents, workers in power plants, or while working and using different radiation sources in medicine and health care. Acute radiation syndrome (ARS) occurs in subjects exposed to a very high dose of radiation in a very short period of time. Each form of radiation has a unique pathophysiological effect. Unfortunately, higher organisms-human beings-in the course of evolution have not acquired receptors for the direct "capture" of radiation energy, which is transferred at the level of DNA, cells, tissues, and organs. Radiation in biological systems depends on the amount of absorbed energy and its spatial distribution, particularly depending on the linear energy transfer (LET). Photon radiation with low LET leads to homogeneous energy deposition in the entire tissue volume. On the other hand, radiation with a high LET produces a fast Bragg peak, which generates a low input dose, whereby the penetration depth into the tissue increases with the radiation energy. The consequences are mutations, apoptosis, the development of cancer, and cell death. The most sensitive cells are those that divide intensively-bone marrow cells, digestive tract cells, reproductive cells, and skin cells. The health care system and the public should raise awareness of the consequences of ionizing radiation. Therefore, our aim is to identify the consequences of ARS taking into account radiation damage to the respiratory system, nervous system, hematopoietic system, gastrointestinal tract, and skin.

Donanemab in Japanese Patients with Early Alzheimer's Disease: Subpopulation Analysis of the TRAILBLAZER-ALZ 2 Randomized Trial.

Donanemab, a monoclonal antibody directed against an insoluble, modified, N-terminal truncated form of amyloid beta, demonstrated efficacy and safety in patients with early, symptomatic Alzheimer's disease (AD) in the phase 3 TRAILBLAZER-ALZ 2 trial. Here, we report clinical outcomes, biomarkers, and safety results for the Japanese subpopulation. TRAILBLAZER-ALZ 2 (N = 1736) was conducted in eight countries, including Japan (enrollment June 2020-November 2021; database lock April 2023). Participants (60-85years) with early, symptomatic AD (mild cognitive impairment/mild dementia), Mini-Mental State Examination score 20-28, and confirmed amyloid and tau pathology were randomized 1:1 (stratified by tau status) to intravenous donanemab (700mg for three doses, then 1400mg/dose) or placebo every 4weeks for 72weeks. Primary outcome was change from baseline to week 76 in integrated Alzheimer's Disease Rating Scale (iADRS) score. Other outcomes included clinical measures of cognitive and functional impairment, biomarkers, and safety. Of 88 Japanese participants (43 placebo, 45 donanemab), 7 in each group discontinued. Least-squares mean (LSM) change from baseline in iADRS score at week 76 was smaller with donanemab than with placebo in the combined (low-medium tau and high tau) and low-medium tau (N = 76) subpopulations (LSM change difference: 4.43 and 3.99, representing 38.8% and 40.2% slowing of disease progression, respectively). Slowing of AD progression with donanemab was also observed for other clinical outcomes. Marked decreases in amyloid plaque and plasma phosphorylated tau 217 were observed; amyloid clearance (< 24.1 Centiloids) was observed in 83.3% of the combined donanemab and 0% of the combined placebo groups. Amyloid-related imaging abnormalities of edema/effusions occurred in ten (22.2%) donanemab-treated participants (one [2.2%] symptomatic) and one (2.3%) placebo-treated participant. The overall efficacy and safety of donanemab in Japanese participants were similar to the global TRAILBLAZER-ALZ 2 population. ClinicalTrials.gov identifier: NCT04437511.

Use of Fracture Risk Assessment Tool in clinical practice and Fracture Risk Assessment Tool future directions.

Fracture Risk Assessment Tool is a free, online fracture risk calculator which can be used to predict 10-year fracture risk for women and men over age 50 years. It incorporates seven clinical risk factors and bone density to give a 10-year risk of major osteoporotic fracture and hip fracture. This dynamic tool can be used with patients at the bedside to help guide treatment decisions. There are some limitations to Fracture Risk Assessment Tool, with the most central limitation being the fact that inputs are binary. Much research has been done to try to refine Fracture Risk Assessment Tool to allow for more accurate risk prediction, and this article describes the data for adjusting Fracture Risk Assessment Tool depending on the clinical scenario such as the dose of glucocorticoid use, presence of diabetes and others. Recently, the new FRAXplus tool has been developed to address many of these concerns and will likely replace the old Fracture Risk Assessment Tool in the future. At the current time, it is available in beta form.

The Oligomeric Form of Amyloid Beta Triggers Astrocyte Activation, Independent of Neurons.

The most common aging-related neurodegenerative disorder is Alzheimer's disease (AD), of which the main symptom is memory disturbance. Though the mechanism of AD pathogenesis is not fully defined, abnormal aggregation of amyloid beta (Aβ) plaques and tau have been considered as key factors and main histological hallmarks of the disease. Astrocyte is responsible for the control of cells and the environment around brain and spinal cord cells. Astrocytes have been implicated with AD. However, the exact function of astrocytes in AD has not been established. In this study, we investigated the regulation of astrocytes in the AD model using primary cultures. We have demonstrated that oligomerized Aβ is toxic to neurons and can induce cell death in primary cultures. In the primary cultures containing neurons and astrocytes, amyloid beta uptake was observed in both neurons and astrocytes. To verify if the uptake of amyloid beta in astrocytes is dependent on neurons, we separated and cultured primary astrocytes with no neurons. Amyloid uptake was still observed in this pure astrocyte culture, suggesting that the uptake of amyloid beta is a neuron-independent function of astrocytes. Astrocyte activation was observed in both pure and mixed cultures. Taken together, our data suggest that astrocyte is activated by oligomerized Aβ and uptakes it, which is independent of neurons.

Masking the transmembrane region of the amyloid β precursor protein as a safe means to lower amyloid β production.

Reducing brain levels of both soluble and insoluble forms of amyloid beta (Aβ) remains the primary goal of most therapies that target Alzheimer's disease (AD). However, no treatment has so far resulted in patient benefit, and clinical trials of the most promising drug candidates have generally failed due to significant adverse effects. This highlights the need for safer and more selective ways to target and modulate Aβ biogenesis. Peptide technology has advanced to allow reliable synthesis, purification, and delivery of once-challenging hydrophobic sequences. This is opening up new routes to target membrane processes associated with disease. Here we deploy a combination of atomic detail molecular dynamics (MD) simulations, living-cell Förster resonance energy transfer (FRET), and in vitro assays to elucidate the atomic-detail dynamics, molecular mechanisms, and cellular activity and selectivity of a membrane-active peptide that targets the Aβ precursor protein (APP). We demonstrate that Aβ biogenesis can be downregulated selectively using an APP occlusion peptide (APPOP). APPOP inhibits Aβ production in a dose-dependent manner, with a mean inhibitory concentration (IC50) of 450nM toward exogenous APP and 50nM toward endogenous APP in primary rat cortical neuronal cultures. APPOP does not impact the γ-secretase cleavage of Notch-1, or exhibit toxicity toward cultured primary rat neurons, suggesting that it selectively shields APP from proteolysis. Drugs targeting AD need to be given early and for very long periods to prevent the onset of clinical symptoms. This necessitates being able to target Aβ production precisely and without affecting the activity of key cellular enzymes such as γ-secretase for other substrates. Peptides offer a powerful way for targeting key pathways precisely, thereby reducing the risk of adverse effects. Here we show that protecting APP from proteolytic processing offers a promising route to safely and specifically lower Aβ burden. In particular, we show that the amyloid pathway can be targeted directly and specificically. This reduces the risk of off-target effects and paves the way for a safe prophylactic treatment.

Donepezil to lecanemab-advancements in targeted therapy of Alzheimer’s disease so far

Alzheimer's disease (AD) first identified as Alois Alzheimer in 1907, is a slowly progressing dementia that affects cognition, behaviour and functional status. There is no cure for AD since precise pathophysiological mechanisms underlying it is not completely known. Drugs may temporarily reduce the symptoms associated with disorder, but condition is ultimately fatal. Objective of treatment of AD is to reduce behaviour issues associated with memory loss and improve cognition. Single acetylcholinesterase inhibitors donepezil and galantamine, as well as the dual AChE and butyrylcholinesterase (BuChE) inhibitor rivastigmine, are now utilized in treatment of AD. Cholinesterase inhibitors have shown dose-dependent impact on cognition and functional activities in clinical trials. Memantine NMDA receptor antagonist is used to minimize neurotoxicity that's suspected to contribute to conditions like Alzheimer's and other neurodegenerative disorders. Estrogen administration post menopause can result in modulation of synaptogenesis, enhanced cerebral blood flow, mediation of crucial neurotransmitters and hormones, protection against apoptosis. Aducanumab is 1st disease modifying drug and monoclonal antibody that targets beta-amyloid clusters in mild AD. Recent advancement in therapy, lecanemab, a recombinant IgG1 monoclonal antibody is targeted against aggregated soluble and insoluble forms of amyloid beta, thereby minimizing Aβ plaques and preventing Aβ deposition in the brain. As research advances, molecular basis of disease becomes more apparent leading to the advent of plausible targeted therapy.

The beta thalassaemia trait in Jamaica.

The objective of this study was to review the prevalence and features of the beta thalassaemia trait in Jamaican populations. Screening of 221,306 newborns over the last 46 years has given an indication of the distribution and prevalence of beta thalassaemia genes, and screening of 16,612 senior school students in Manchester parish, central Jamaica, has provided their haematological features. The prevalence of the beta thalassaemia trait predicted from double heterozygotes was 0.8% of 100,000 babies in Kingston, 0.9% of 121,306 newborns in southwest Jamaica, and 0.9% of school students in Manchester. Mild beta+ thalassaemia variants (-88 C>T, -29 A>G, -90 C>T, polyA T>C) accounted for 75% of Kingston newborns, 76% of newborns in southwest Jamaica, and 89% of Manchester students. Severe beta+ thalassaemia variants were uncommon. Betao thalassaemia variants occurred in 43 patients and resulted from 11 different variants of which the IVSII-849 A>G accounted for 25 (58%) subjects. Red cell indices in IVSII-781 C>G did not differ significantly from HbAA, and this is probably a harmless polymorphism rather than a form of beta+ thalassaemia; the removal of 6 cases in school screening had a minimal effect on the frequency of the beta thalassaemia trait. Red cell indices in the beta+ and betao thalassaemia traits followed established patterns, although both were associated with increased HbF levels. The benign nature of beta+ thalassaemia genes in Jamaica means that cases of sickle cell-beta+ thalassaemia are likely to be overlooked, and important clinical questions such as the role of pneumococcal prophylaxis remain to be answered.

Monitoring oligomeric forms of amyloid beta in the early stages of aggregation using hybrid X-ray footprinting mass spectrometry with inline fluorescence.

The aggregation-prone Amyloid Beta (Aβ) peptide has been the target of the majority of efforts to develop Alzheimer's Disease therapeutics, most of which have failed or have shown mixed results. It is no longer widely believed that buildup of amyloid fibrils is a causal factor in cognitive decline associated with the disease, and a growing body of evidence now suggests that low molecular weight oligomeric forms of Aβ may be the culprits in disease progression. However, while numerous Aβ fibril structures have been characterized, primarily by NMR and cryo-EM, obtaining structural information on oligomeric forms of Aβ that presumably precede and/or seed fibril formation has proved challenging. These transient forms are heterogeneous, and depend heavily on experimental conditions such as buffer, temperature, concentration, and degree of quiescence during measurement. Here, we present a new approach to delineating structural features of early-stage low molecular weight Aβ oligomers using a solvent accessibility assay in conjunction with inline fluorescence measurements. In this method, inline fluorescence is collected nearly simultaneously from samples during collection of X-ray footprinting mass spectrometry (XFMS) data. In the XFMS method, X-ray irradiation dissociates solvent water to produce hydroxyl radicals, which covalently modify solvent accessible side chains. Liquid chromatography-mass spectrometry is subsequently used to analyze the covalent modifications produced, and the data provide a “water map” at the single residue level, which is used to determine protein structure. This new hybrid approach circumvents issues in batch-to-batch variability of Aβ aggregation which has made this peptide so difficult to study, and provides a method to combine residue-specific structural information nearly simultaneously with global protein structure readouts from either intrinsic protein fluorescence or fluorophores such as Thioflavin T.

ENVISION: A phase 3b/4 randomized, double‐blind, placebo‐controlled, parallel‐group study to verify the clinical benefit of aducanumab in participants with early Alzheimer’s disease

AbstractBackgroundAducanumab is a human monoclonal antibody selective for aggregated forms of amyloid beta approved in the United States by the Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease on June 7, 2021 under the accelerated approval pathway, which requires a randomized‐controlled trial with an appropriate control to verify the clinical benefit of aducanumab. On March 25, 2022 the sponsor submitted the final protocol for this trial, named ENVISION, to the FDA.MethodENVISION (NCT05310071) is a multicenter, randomized, double‐blind, placebo‐controlled, parallel group study in participants with mild cognitive impairment due to Alzheimer’s disease (Stage 3) and mild Alzheimer’s disease dementia (Stage 4), designed to verify the clinical efficacy and safety of aducanumab. Key enrollment criteria include MMSE score of 22‐30, age 60‐85, CDR‐G of 0.5 or 1.0, regardless of ApoE ε4 status. Participants will be randomized, to receive aducanumab or placebo in a 2:1 ratio and will be titrated to 10 mg/kg aducanumab or placebo by intravenous infusion every 4 weeks for a treatment duration of 24 months.The primary objective is to assess the clinical benefit of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by change of CDR‐SB score at 18 months as compared to placebo. Key secondary endpoints include change in ADCS‐ADL‐MCI, ADAS‐Cog13, iADRS, MMSE, and NPI‐10; other secondary endpoints include change in amyloid PET and tau PET signal. Safety endpoints include incidence of ARIA events and SAEs. Exploratory endpoints include CSF and plasma biomarkers.Approximately 1512 participants will be enrolled across 220 centers globally. A racially/ethnically representative population will be included in the United States, with an enrollment goal of 18% Black/African American and LatinX/Hispanic patients.ResultENVISION will begin in Q2 2022 and read out approximately 4 years after first patient in. Primary analysis read‐out of clinical, biomarker, and safety data will be at 18 months, with additional longer‐term data on aducanumab treatment effect up to 24 months.ConclusionThe confirmatory ENVISION trial will further explore clinical efficacy, biomarker profile, and safety of aducanumab in a racially/ethnically representative population.

The ryanodine receptor-calstabin interaction stabilizer S107 protects hippocampal neurons from GABAergic synaptic alterations induced by Abeta42 oligomers.

The oligomeric form of the peptide amyloid beta 42 (Abeta42) contributes to the development of synaptic abnormalities and cognitive impairments associated with Alzheimer's disease (AD). To date, there is a gap in knowledge regarding how Abeta42 alters the elementary parameters of GABAergic synaptic function. Here we found that Abeta42 increased the frequency and amplitude of miniature GABAergic currents as well as the amplitude of evoked inhibitory postsynaptic currents. When we focused on paired pulse depression (PPD) to establish whether GABA release probability was affected by Abeta42, we did not observe any significant change. On the other hand, a more detailed investigation of the presynaptic effects induced by Abeta42 by means of multiple probability fluctuation analysis and cumulative amplitude analysis showed an increase in both the size of the readily releasable pool responsible for synchronous release and the number of release sites. We further explored whether ryanodine receptors (RyRs) contributed to exacerbating these changes by stabilizing the interaction between RyRs and the accessory protein calstabin. We observed that the RyR-calstabin interaction stabilizer S107 restored the synaptic parameters to values comparable to those measured in control conditions. In conclusion, our results clarify the mechanisms of potentiation of GABAergic synapses induced by Abeta42. We further suggest that RyRs are involved in the control of synaptic activity during the early stage of AD onset and that their stabilization could represent a new therapeutical approach for AD treatment. KEY POINTS: Accumulation of the peptide amyloid beta 42 (Abeta42) is a key characteristic of Alzheimer's disease (AD) and causes synaptic dysfunctions. To date, the effects of Abeta42 accumulation on GABAergic synapses are poorly understood. The findings reported here suggest that, similarly to what is observed on glutamatergic synapses, Abeta42 modifies GABAergic synapses by targeting ryanodine receptors and causing calcium dysregulation. The GABAergic impairments can be restored by the ryanodine receptor-calstabin interaction stabilizer S107. Based on this research, RyRs stabilization may represent a novel pharmaceutical strategy for preventing or delaying AD.

Characterization of IMG Microglial Cell Line as a Valuable In Vitro Tool for NLRP3 Inflammasome Studies.

Microglial cells constantly surveil the cerebral microenvironment and become activated following injury and disease to mediate inflammatory responses. The nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasome, which is abundantly expressed in microglial cells, plays a key role in these responses as well as in the development of many neurological disorders. Microglial cell lines are a valuable tool to study the causes and possible treatments for neurological diseases which are linked to inflammation. Here, we investigated whether the mouse microglial cell line IMG is suitable to study NLRP3 inflammasome by incubating cells with different concentrations of NLRP3 inflammasome priming and activating agents lipopolysaccharide (LPS) and ATP, respectively, and applying short (4h) or long (24h) LPS incubation times. After short LPS incubation, the mRNA levels of most pro-inflammatory and NLRP3 inflammasome-associated genes were more upregulated than after long incubation. Moreover, the combination of higher LPS and ATP concentrations with short incubation time resulted in greater levels of active forms of caspase-1 and interleukin-1 beta (IL-1β) proteins than low LPS and ATP concentrations or long incubation time. We also demonstrated that treatment with NLRP3 inflammasome inhibitor glibenclamide suppressed NLRP3 inflammasome activation in IMG cells, as illustrated by the downregulation of gasdermin D N-fragment and mature caspase-1 and IL-1β protein levels. In addition, we conducted similar experiments with primary microglial cells and BV-2 cell line to determine the similarities and differences in their responses. Overall, our results indicate that IMG cell line could be a valuable tool for NLRP3 inflammasome studies. In IMG cells, 4-h incubation with lipopolysaccharide (LPS) induces a stronger upregulation of NLRP3 inflammasome-associated pro-inflammatory genes compared to 24-h incubation. NLRP3 inflammasome is robustly activated only after the addition of 3mM of ATP following short LPS incubation time.

Activity concentrations and radiation hazard in the soil of Ashaka Cement PLC Gombe state, Nigeria with a multivariate statistical approach

Humans are exposed externally and internally in their environment to natural background radiation from radionuclides such as 40K, 238, U and 232Th which emit gamma, alpha, beta and other forms of radiation through their decay processes. These radionuclides are found in the soil, food and the water we consume. Human activities such as the mining of uranium, oil exploration, building materials, coal-fired power station can ignite the Naturally Occurring Radioactive Materials (NORMs). The aim was to assess radiation impact in Ashaka cement factory, Gombe state for their potential radiological hazards in order to maintain a safe environment. A prospective cross-sectional survey design was adopted and using a purposive sampling technique, fifteen (15) soil samples were collected using a geographical positioning system (GPS). The activity concentrations of these natural radionuclides were measured due to Gamma radiation by using a High Purity Germanium detector. Samples were analysed at the Radiation Protection Institute of Ghana Atomic Energy Commission, Kwanbeya District, at Accra, Ghana. Fifteen (15) soil samples were collected from within the Ashaka Cement factory (Zone 1) and environment (Zone 2). Data was analyzed by the use of SPSS Version 22.0 (IBM Corp. Armonk NY, 2011). Descriptive statistics was employed to obtain the Mean and Standard deviation of the radioactivity concentrations. Inferential statistics was carried out to compare the radionuclides and radiological parameters. Statistical significance was considered at p ≤ 0.05. The mean activity concentrations of 238U, 232Th and 40K in soil samples at Zone 1 are 42.70 Bqkg-1, 29.00 Bqkg-1, 375 Bqkg-1 and Zone 2 is 46.11 Bqkg-1, 35.00 Bqkg-1, 780.30 Bqkg-1respectively. Radiation hazard indices at Zone 1 and 2 shows the mean for External Hazard index, Internal Hazard index, Gamma Index, External Absorbed Dose Rate, Annual Effective Does Rate, External Annual Effective Does Rate, Excess Lifetime Cancer Risk and Annual Gonadal Effective Dose is 0.31, 0.42, 0.83, 38.80nGyh-1, 0.32x10-3, 0.048mSvyr-1, 0.17mSvyr-1, 371mSvyr-1 and 0.42, 0.55, 1.18, 45.70nGyhr-1, 0.46mSvyr-1, 0.056mSvyr-1, 0.20x10-3, 533.80mSvyr-1 respectively. This implies that both staffs and members of the public in the factory might be at risk due to cumulative effect of radiation exposure high activity concentration from 238U and Annual Gonal effective dose exceeding the world average limits.

Chlorpyrifos oxon crosslinking of amyloid beta 42 peptides is a new route for generation of self-aggregating amyloidogenic oligomers that promote Alzheimer's disease

Epidemiological evidence suggests that people chronically exposed to organophosphorus pesticides are at increased risk of neurodegenerative disease. Covalently linked amyloid beta dimers have been isolated from the brains of Alzheimer's patients. The toxic forms of amyloid beta are amyloid dimers that spontaneously oligomerize. In the present report we treated recombinant and synthetic amyloid beta (1–42) with 1 mM chlorpyrifos oxon or 1 mM paraoxon. The trypsin-digested samples were analyzed by liquid chromatography tandem mass spectrometry on an Orbitrap Fusion Lumos mass spectrometer. Data were searched with Protein Prospector software. We found two new types of crosslinks in amyloid dimers. An isopeptide Asp-Asp link occurred between the N-terminal amine of Asp 1 in one peptide and the beta carboxyl group of Asp 1 in another peptide. An Asp-Arg link occurred between the guanidino group of Arg 5 in one peptide and the beta carboxyl group of Asp 1 in another peptide. These results show that the active metabolites of the pesticides chlorpyrifos and parathion catalyze the crosslinking of amyloid beta (1–42) into toxic dimers. It was concluded that the increased risk of neurodegenerative disease in people exposed to organophosphorus pesticides could be explained by the crosslinking activity of these chemicals. Data are available via ProteomeXchange with identifier PXD034163.

2,3,5-Tri-O-benzyl-d-xylofuranose

The synthesis and crystallization of 2,3,5-tri-O-benzyl-d-xylofuranose permitted us to isolate the alpha anomer with a small contamination of the beta form (ca 10%), whose first crystallographic structure obtained in the P212121 space group was determined at 100 K up to a resolution of sin θmax/λ = 0.71 Å−1 and refined to an R1 value of 0.0171 with a Hirshfeld atom refinement (HAR) approach.

Development of the International Spinal Cord Injury Basic Data Set for informal caregivers.

Study designMixed-methods, including expert consensus for initial development and a multi-center repeated measures design for field testing.ObjectivesTo develop an International Spinal Cord Injury Basic Data Set for caregivers of individuals with spinal cord injury/disorder (SCI/D) for use in research and clinical care settings.SettingInternational, multi-disciplinary working group with field testing in five North American pediatric rehabilitation hospitals.MethodsThe data set was developed iteratively through meetings and online surveys with a working group of experts in pediatric and adult SCI/D rehabilitation and caregivers of individuals with SCI/D. Initial reliability was examined through repeat administration of a beta form with a sample of caregivers recruited by convenience. The sample was characterized with descriptive statistics. Intra-rater reliability of variables was assessed using Intra-Class Correlations.ResultsThe beta test form included 27 items, covering 3 domains: (1) demographic information for persons providing care; (2) caregiver’s allocation of time and satisfaction; and (3) perceived burden of caregiving. Thirty-nine caregivers completed both administrations. Mean time for completion was 10 min. There was moderate to excellent reliability for the majority of variables, but results indicated necessary revisions to improve reliability and decrease respondent burden. The final version of the data form contains 7 items and is intended for self-administration among informal caregivers of individuals with SCI/D across the lifespan.ConclusionsThe International SCI Basic Data Set for Informal Caregivers can be used to standardize data collection and reporting about informal caregivers for individuals with SCI/D to advance our understanding of this population and the data form has additional utility to screen for caregiver needs in clinical settings.

Statistical properties of ion and electron temperature fluctuations in the edge of the COMPASS tokamak

This paper presents measurements of the plasma turbulence with an emphasis on the ion temperature fluctuations in comparison to the electron temperature and the ion saturation current fluctuations in the edge of the COMPASS tokamak. The ion temperature values are obtained by using a fast swept ball-pen probe, with temporal resolution up to 10 µs, accompanied by independent 1 µs measurements of the electron temperature and ion saturation current. The experimental results obtained for a wide range of line-averaged densities show that statistical properties of the fluctuations are in good agreement with a form of beta or gamma distribution function. In addition, the dependence of the averaged ion and electron temperatures on the line-averaged density is studied in the near and main scrape off layer region.

Monitoring low molecular weight oligomeric forms of amyloid beta in the early stages of aggregation using X-ray footprinting mass spectrometry

The aggregation-prone Amyloid Beta (Aβ) peptide has been the target of the majority of efforts to develop Alzheimer’s Disease therapeutics, most of which have failed or have shown mixed results. Although clinical trials are ongoing, the failure of many efforts to slow or block pathogenesis by targeting Aβ over the past two decades calls for an urgent development of novel therapeutic concepts. In particular, the role of amyloid aggregation has come into question as it relates to Alzheimer's disease progression and it is no longer widely believed that buildup of amyloid fibrils in brain tissue is a causal factor in cognitive decline associated with the disease.

ICARE AD‐US: Design of a prospective, single‐arm, multicenter, noninterventional real‐world study of aducanumab in the United States

AbstractBackgroundAducanumab is a human monoclonal antibody that selectively targets aggregated forms of amyloid beta (Aβ), including soluble oligomers and insoluble fibrils, and, at the writing of this abstract, is currently under review by the US Food and Drug Administration (FDA), European Medicines Agency, and Pharmaceuticals and Medical Devices Agency (Japan). The efficacy and safety of aducanumab have been evaluated in 2 identically designed, randomized, placebo‐controlled, double‐blind Phase 3 studies in early Alzheimer’s disease (AD); however, should aducanumab be approved, it will be critical to effectively evaluate its long‐term impact in the real world.MethodICARE AD‐US is a prospective, single‐arm, multicenter, noninterventional study of aducanumab, as prescribed in a postmarketing, real‐world US setting. This Phase 4 observational study is designed to evaluate the safety and effectiveness of aducanumab in real‐world clinical practice per its FDA‐approved labeling in the US. The primary objective of the ICARE AD‐US study is to evaluate progression of AD in aducanumab‐treated patients as determined by a predefined, uniform set of cognitive, functional, and neuropsychiatric and global severity measures and to characterize the longitudinal impact of aducanumab on quality of life, disease burden, and health care resource utilization. ICARE AD‐US will also assess the long‐term safety of aducanumab as measured by the incidence of serious adverse events and the incidence of amyloid‐related imaging abnormalities‐edema (ARIA‐E). Biobanking of collected blood (plasma and serum) will provide the opportunity for future biomarker studies.ResultICARE AD‐US aims to enroll approximately 6000 patients with AD over 4 years, including approximately 500 African American and 500 Hispanic/Latinx patients, from approximately 200 sites in the US. Patients will be monitored in a real‐world setting for a period of up to 5 years.ConclusionThe evidence generated in the ICARE AD‐US study will not only enable the collection of consistent long‐term efficacy and safety data to assess the impact of aducanumab treatment in the real world but will also support the measurement and characterization of AD progression and the optimization of clinical practice through standardization of the diagnosis of early AD and identification of individuals who may benefit from treatment.