One theory of the origins of reading disorders (i.e., dyslexia) is a language network which cannot effectively 'entrain' to speech, with cascading effects on the development of phonological skills. ...Low-gamma (low-γ, 30-45 Hz) neural activity, particularly in the left hemisphere, is thought to correspond to tracking at phonemic rates in speech. The main goals of the current study were to investigate temporal low-γ band-power during rest in a sample of children and adolescents with and without reading disorder (RD). Using a Bayesian statistical approach to analyze the power spectral density of EEG data, we examined whether (1) resting-state temporal low-γ power was attenuated in the left temporal region in RD; (2) low-γ power covaried with individual reading performance; (3) low-γ temporal lateralization was atypical in RD. Contrary to our expectations, results did not support the hypothesized effects of RD status and poor decoding ability on left hemisphere low-γ power or lateralization: post-hoc tests revealed that the lack of atypicality in the RD group was not due to the inclusion of those with comorbid attentional deficits. However, post-hoc tests also revealed a specific left-dominance for low-γ rhythms in children with reading deficits only, when participants with comorbid attentional deficits were excluded. We also observed an inverse relationship between decoding and left-lateralization in the controls, such that those with better decoding skills were less likely to show left-lateralization. We discuss these unexpected findings in the context of prior theoretical frameworks on temporal sampling. These results may reflect the importance of real-time language processing to evoke gamma rhythms in the phonemic range during childhood and adolescence.
Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition ...of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.
We established a robust capillary-flow data-independent acquisition MS platform capable of measuring 31 plasma proteomes per day without the need of repeated acquisition of the same sample. We ...acquired 1508 samples of the DiOGenes study (multicentered, Europa-wide caloric restriction weight loss and maintenance study of overweight and obese, non-diabetic participants). This was achieved using a single analytical column. Comprehensive biological reactions to weight loss and maintenance were observed.
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Highlights
•Robust capillary-flow DIA was established at 31 clinical samples per day.•1508 samples of dietary intervention study DiOGenes were measured on a single column.•Comprehensive biological reactions to weight loss and maintenance were observed.•Comparison to independent studies shows high reproducibility of potential biomarkers.
Comprehensive, high throughput analysis of the plasma proteome has the potential to enable holistic analysis of the health state of an individual. Based on our own experience and the evaluation of recent large-scale plasma mass spectrometry (MS) based proteomic studies, we identified two outstanding challenges: slow and delicate nano-flow liquid chromatography (LC) and irreproducibility of identification of data-dependent acquisition (DDA). We determined an optimal solution reducing these limitations with robust capillary-flow data-independent acquisition (DIA) MS. This platform can measure 31 plasma proteomes per day. Using this setup, we acquired a large-scale plasma study of the diet, obesity and genes dietary (DiOGenes) comprising 1508 samples. Proving the robustness, the complete acquisition was achieved on a single analytical column. Totally, 565 proteins (459 identified with two or more peptide sequences) were profiled with 74% data set completeness. On average 408 proteins (5246 peptides) were identified per acquisition (319 proteins in 90% of all acquisitions). The workflow reproducibility was assessed using 34 quality control pools acquired at regular intervals, resulting in 92% data set completeness with CVs for protein measurements of 10.9%.
The profiles of 20 apolipoproteins could be profiled revealing distinct changes. The weight loss and weight maintenance resulted in sustained effects on low-grade inflammation, as well as steroid hormone and lipid metabolism, indicating beneficial effects. Comparison to other large-scale plasma weight loss studies demonstrated high robustness and quality of biomarker candidates identified. Tracking of nonenzymatic glycation indicated a delayed, slight reduction of glycation in the weight maintenance phase. Using stable-isotope-references, we could directly and absolutely quantify 60 proteins in the DIA.
In conclusion, we present herein the first large-scale plasma DIA study and one of the largest clinical research proteomic studies to date. Application of this fast and robust workflow has great potential to advance biomarker discovery in plasma.
...immunity against infection might have already begun to wane by December, 2020, because of a general decrease in immune protection against SARS-CoV-2 after a first exposure. ...SARS-CoV-2 lineages ...might evade immunity generated in response to previous infection.15 Three recently detected SARS-CoV-2 lineages (B.1.1.7, B.1.351, and P.1), are unusually divergent and each possesses a unique constellation of mutations of potential biological importance.16–18 Of these, two are circulating in Brazil (B.1.1.7 and P.1) and one (P.1) was detected in Manaus on Jan 12, 2021.16 One case of SARS-CoV-2 reinfection has been associated with the P.1 lineage in Manaus19 that accrued ten unique spike protein mutations, including E484K and N501K.16 Moreover, the newly classified P.2 lineage (sublineage of B.1.128 that independently accrued the spike E484K mutation) has now been detected in several locations in Brazil, including Manaus.20 P.2 variants with the E484K mutation have been detected in two people who have been reinfected with SARS-CoV-2 in Brazil,21,22 and there is in-vitro evidence that the presence of the E484K mutation reduces neutralisation by polyclonal antibodies in convalescent sera.15 Fourth, SARS-CoV-2 lineages circulating in the second wave might have higher inherent transmissibility than pre-existing lineages circulating in Manaus. The protocols and findings of such studies should be coordinated and rapidly shared wherever such variants emerge and spread. Since rapid data sharing is the basis for the development and implementation of actionable disease control measures during public health emergencies, we are openly sharing in real-time monthly curated serosurvey data from blood donors through the Brazil–UK Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE) Centre GitHub website and will continue to share genetic sequence data and results from Manaus through openly accessible data platforms such as GISAID and Virological.
Much progress has been made in research on the causal mechanisms of developmental dyslexia. In recent years, the "temporal sampling" account of dyslexia has evolved considerably, with contributions ...from neurogenetics and novel imaging methods resulting in a much more complex etiological view of the disorder. The original temporal sampling framework implicates disrupted neural entrainment to speech as a causal factor for atypical phonological representations. Yet, empirical findings have not provided clear evidence of a low-level etiology for this endophenotype. In contrast, the neural noise hypothesis presents a theoretical view of the manifestation of dyslexia from the level of genes to behavior. However, its relative novelty (published in 2017) means that empirical research focused on specific predictions is sparse. The current paper reviews dyslexia research using a dual framework from the temporal sampling and neural noise hypotheses and discusses the complementary nature of these two views of dyslexia. We present an argument for an integrated model of sensory temporal sampling as an etiological pathway for dyslexia. Finally, we conclude with a brief discussion of outstanding questions.
The age-related loss of skeletal muscle mass and function is caused, at least in part, by a reduced muscle protein synthetic response to protein ingestion. The magnitude and duration of the ...postprandial muscle protein synthetic response to ingested protein is dependent on the quantity and quality of the protein consumed. This review characterises the anabolic properties of animal-derived and plant-based dietary protein sources in older adults. While approximately 60 % of dietary protein consumed worldwide is derived from plant sources, plant-based proteins generally exhibit lower digestibility, lower leucine content and deficiencies in certain essential amino acids such as lysine and methionine, which compromise the availability of a complete amino acid profile required for muscle protein synthesis. Based on currently available scientific evidence, animal-derived proteins may be considered more anabolic than plant-based protein sources. However, the production and consumption of animal-derived protein sources is associated with higher greenhouse gas emissions, while plant-based protein sources may be considered more environmentally sustainable. Theoretically, the lower anabolic capacity of plant-based proteins can be compensated for by ingesting a greater dose of protein or by combining various plant-based proteins to provide a more favourable amino acid profile. In addition, leucine co-ingestion can further augment the postprandial muscle protein synthetic response. Finally, prior exercise or n-3 fatty acid supplementation have been shown to sensitise skeletal muscle to the anabolic properties of dietary protein. Applying one or more of these strategies may support the maintenance of muscle mass with ageing when diets rich in plant-based protein are consumed.
Primary analyses of a study in young women aged 16–26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and ...disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years.
We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16–26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543.
Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0–99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related.
The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide.
Merck & Co, Inc.
Many clinical studies reported deficits in basic and complex cognitive functions in adults with Attention-Deficit/Hyperactivity Disorder (ADHD). However, the extent in which deficits in basic ...functions (i.e., processing speed and distractibility) contribute to complex cognitive impairments (i.e., working memory, planning, cognitive flexibility, memory functions) in adults with ADHD is not well-studied. So far, literature show only one study, revealing that basic functions explain 27-74% of executive dysfunctions. Yet, the authors reported that findings could be affected by the selection of neuropsychological tests. The goal of the present research is to replicate such a finding using a different sample and a different set of neuropsychological tests.
Forty-eight adult patients with ADHD were compared with 48 healthy controls in basic cognitive functions, namely processing speed and distractibility and more complex cognitive functions, namely selective attention, cognitive flexibility, planning, working memory, verbal fluency, and verbal memory. Basic and complex cognitive functions were assessed using the Vigilance and Sustained Attention, Selective Attention, N-Back, Tower of London, Trail Making Test, Word Fluency, and Verbal Learning and Memory.
Logistic regression analyses showed that impairments in complex cognitive functions explained 25% of the variance in ADHD diagnosis. The explained variance dropped from 25% to 9% after considering basic functions of processing speed and distractibility. This 64% reduction highlights the importance of basic functions for impairments in complex functions in patients with ADHD.
Carboxylate esters have many desirable features as electrophiles for catalytic cross‐coupling: they are easy to access, robust during multistep synthesis, and mass‐efficient in coupling reactions. ...Alkenyl carboxylates, a class of readily prepared non‐aromatic electrophiles, remain difficult to functionalize through cross‐coupling. We demonstrate that Pd catalysis is effective for coupling electron‐deficient alkenyl carboxylates with arylboronic acids in the absence of base or oxidants. Furthermore, these reactions can proceed by two distinct mechanisms for C−O bond activation. A Pd0/II catalytic cycle is viable when using a Pd0 precatalyst, with turnover‐limiting C−O oxidative addition; however, an alternative pathway that involves alkene carbopalladation and β‐carboxyl elimination is proposed for PdII precatalysts. This work provides a clear path toward engaging myriad oxygen‐based electrophiles in Pd‐catalyzed cross‐coupling.
Carboxylate, activate! Pd catalysis is generally assumed to be ineffective for cross‐coupling with most oxygen‐based electrophiles. It is demonstrated not only that alkenyl carboxylates are able to couple with boronic acids under extremely mild conditions, but that there are two distinct pathways for C−O activation. The result is an operationally simple arylation of many pharmaceutically relevant (hetero)cyclic cores with excellent functional‐group tolerance.
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