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Abstract Amyloid polymorphism is a hallmark of almost all amyloid species, yet the mechanisms underlying the formation of amyloid polymorphs and their complex architectures remain elusive. Commonly, two main mesoscopic topologies are found in amyloid polymorphs characterized by non‐zero Gaussian and mean curvatures: twisted ribbons and helical fibrils, respectively. Here, a rich heterogeneity of configurations is demonstrated on insulin amyloid fibrils, where protofilament packing can occur, besides the common polymorphs, also in a combined mode forming mixed‐curvature polymorphs. Through AFM statistical analysis, an extended array of heterogeneous architectures that are rationalized by mesoscopic theoretical arguments are identified. Notably, an unusual fibrillization pathway is also unraveled toward mixed‐curvature polymorphs via the widespread recruitment and intertwining of protofilaments and protofibrils. The results present an original view of amyloid polymorphism and advance the fundamental understanding of the fibrillization mechanism from single protofilaments into mature amyloid fibrils.

IntroductionHuman physical growth, biological maturation, and intelligence have been documented as increasing for over 100 years. Comparing the timing of secular trends in these characteristics could provide insight into what underlies them. However, they have not been examined in parallel in the same cohort during different developmental phases. Thus, the aim of this study was to examine secular trends in body height, weight, and head circumference, biological maturation, and intelligence by assessing these traits concurrently at four points during development: the ages of 4, 9, 14, and 18 years.MethodsData derived from growth measures, bone age as an indicator of biological maturation, and full-scale intelligence tests were drawn from 236 participants of the Zurich Longitudinal Studies born between 1978 and 1993. In addition, birth weight was analyzed as an indicator of prenatal conditions.ResultsSecular trends for height and weight at 4 years were positive (0.35 SD increase per decade for height and an insignificant 0.27 SD increase per decade for weight) and remained similar at 9 and 14 years (height: 0.46 SD and 0.38 SD increase per decade; weight: 0.51 SD and 0.51 SD increase per decade, respectively) as well as for weight at age 18 years (0.36 SD increase per decade). In contrast, the secular trend in height was no longer evident at age 18 years (0.09 SD increase per decade). Secular trends for biological maturation at 14 years were similar to those of height and weight (0.54 SD increase per decade). At 18 years, the trend was non-significant (0.38 SD increase per decade). For intelligence, a positive secular trend was found at 4 years (0.54 SD increase per decade). In contrast, negative secular trends were observed at 9 years (0.54 SD decrease per decade) and 14 years (0.60 SD decrease per decade). No secular trend was observed at any of the four ages for head circumference (0.01, 0.24, 0.17, and − 0.04 SD increase per decade, respectively) and birth weight (0.01 SD decrease per decade).DiscussionThe different patterns of changes in physical growth, biological maturation, and intelligence between 1978 and 1993 indicate that distinct mechanisms underlie these secular trends.

The complex of methyltransferase-like proteins 3 and 14 (METTL3-14) is the major enzyme that deposits N6-methyladenosine (m6A) modifications on messenger RNA (mRNA) in humans. METTL3-14 plays key roles in various biological processes through its methyltransferase (MTase) activity. However, little is known about its substrate recognition and methyl transfer mechanism from its cofactor and methyl donor S-adenosylmethionine (SAM). Here, we study the MTase mechanism of METTL3-14 by a combined experimental and multiscale simulation approach using bisubstrate analogues (BAs), conjugates of a SAM-like moiety connected to the N6-atom of adenosine. Molecular dynamics simulations based on crystal structures of METTL3-14 with BAs suggest that the Y406 side chain of METTL3 is involved in the recruitment of adenosine and release of m6A. A crystal structure with a BA representing the transition state of methyl transfer shows a direct involvement of the METTL3 side chains E481 and K513 in adenosine binding which is supported by mutational analysis. Quantum mechanics/molecular mechanics (QM/MM) free energy calculations indicate that methyl transfer occurs without prior deprotonation of adenosine-N6. Furthermore, the QM/MM calculations provide further support for the role of electrostatic contributions of E481 and K513 to catalysis. The multidisciplinary approach used here sheds light on the (co)substrate binding mechanism, catalytic step, and (co)product release, and suggests that the latter step is rate-limiting for METTL3. The atomistic information on the substrate binding and methyl transfer reaction of METTL3 can be useful for understanding the mechanisms of other RNA MTases and for the design of transition state analogues as their inhibitors.

BackgroundThere is growing scientific evidence for the therapeutic benefits of the Amazonian plant-based psychedelic “ayahuasca” for neuropsychiatric disorders such as depression and anxiety. However, there are certain challenges when incorporating botanical ayahuasca into biomedical research and clinical therapy environments. Formulations inspired by ayahuasca, which contain specific and standardized active components, are a potential remedy.MethodsWe investigated subjective acute and persisting effects of a novel formulation containing the reversible monoamine oxidase inhibitor harmine (orodispersible tablet containing 100 mg MAO-I) and N,N-dimethyltryptamine (incremental intranasal dosing of up to 100 mg DMT), compared with two other conditions, namely harmine alone and placebo, in a crossover RCT in 31 healthy male subjects.ResultsDMT + harmine, but not harmine alone, induced a psychedelic experience assessed with the 5D-ASC rating scale [global score: F(2,60) = 80.21, p

AimThis cross-sectional analysis investigates how neuromotor functions of two independent cohorts of approximately 45- and 65-year-old individuals are different from 18-year-old adolescents using the Zurich Neuromotor Assessment-2 (ZNA-2).MethodsA total of 186 individuals of the Zurich Longitudinal Studies (ZLS) born in the 1950s (mean age 65.1 years, SD = 1.2 year, range of ages 59.0–67.5 years, n = 151, 82 males) and 1970s (mean age 43.6 years, SD = 1.3 year, range of ages 40.8–46.6 years, n = 35, 16 males) were tested with the ZNA-2 on 14 motor tasks combined in 5 motor components: fine motor, pure motor, balance, gross motor, and associated movements. Motor performance measures were converted into standard deviation scores (SDSs) using the normative data for 18-year-old individuals as reference.ResultsThe motor performance of the 45-year-old individuals was remarkably similar to that of the 18-year-olds (SDS from −0.22 to 0.25) apart from associated movements (−0.49 SDS). The 65-year-olds showed lower performance than the 18-year-olds in all components of the ZNA-2, with the smallest difference observed for associated movements (−0.67 SDS) and the largest for gross motor skills (−2.29 SDS). Higher body mass index (BMI) was associated with better performance on gross motor skills for 45-year-olds but with worse performance for 65-year-olds. More educational years had positive effects on gross motor skills for both ages.InterpretationWith the exception of associated movements, neuromotor functions as measured with the ZNA-2 are very similar in 45- and 18-year-olds. In contrast, at age 65 years, all neuromotor components show significantly lower function than the norm population at 18 years. Some evidence was found for the last-in-first-out hypothesis: the functions that developed later during adolescence, associated movements and gross motor skills, were the most vulnerable to age-related decline.

Objectives To compare the rates and injury sites among competitors in European and Swiss karate tournaments and to identify differences in these incidence rates by sex and age.Methods This prospective cohort study collected data from two European and four national tournaments in Switzerland between 2011 and 2019. The on-site medical staff completed an anonymised report sheet with demographic data and injury characteristics in all injuries requiring medical treatment. The incidence rates per 1000 exposed athletes (AoE) and 1000 min of exposition (MoE) were analysed. Furthermore, the relative risk of injury related to sex and age was calculated and compared.Results In total, 228 injuries were observed in 2404 fights, for an incidence rate of 47.4 per 1000 AoE (95% CI 41.5 to 54.0) or 22.5 injuries per 1000 MoE (95% CI 19.7 to 25.6), respectively. The oldest age group (senior) of both sexes had a 3.6-fold (95% CI 2.7 to 4.8) significantly higher relative risk of injury than younger participants. Furthermore, there was a 2.9-fold (95% CI 1.6 to 5.6) statistically higher risk of injury for males in the senior age group compared with senior females. The most injured body part was the head, followed by the lower extremity, trunk and upper extremity.Conclusion Senior athletes, especially senior males, had significantly more injuries compared with younger and female senior competitors. Medical staff should be aware of the increased propensity for injury among this age and sex group to facilitate injury prevention and intervention.

Atomistic simulations of biological processes offer insights at a high level of spatial and temporal resolution, but accelerated sampling is often required for probing timescales of biologically relevant processes. The resulting data need to be statistically reweighted and condensed in a concise yet faithful manner to facilitate interpretation. Here, we provide evidence that a recently proposed approach for the unsupervised determination of optimized reaction coordinate (RC) can be used for both analysis and reweighting of such data. We first show that for a peptide interconverting between helical and collapsed configurations, the optimal RC permits efficient reconstruction of equilibrium properties from enhanced sampling trajectories. Upon RC-reweighting, kinetic rate constants and free energy profiles are in good agreement with values obtained from equilibrium simulations. In a more challenging test, we apply the method to enhanced sampling simulations of the unbinding of an acetylated lysine-containing tripeptide from the bromodomain of ATAD2. The complexity of this system allows us to investigate the strengths and limitations of these RCs. Overall, the findings presented here underline the potential of the unsupervised determination of reaction coordinates and the synergy with orthogonal analysis methods, such as Markov state models and SAPPHIRE analysis. [ABSTRACT FROM AUTHOR]

IntroductionEnvironmental changes, including globalization, urbanization, social and cultural changes in society, and exposure to modern digital technology undoubtedly have an impact on children’s activity and lifestyle behavior. In fact, marked reductions in children’s physical activity levels have been reported over the years and sedentary behavior has increased around the world. The question arises whether these environmental changes had an impact on general motor performance in children and adolescents. The study aimed to investigate secular trends of motor performance in Swiss children and adolescents, aged between 7 and 18 years, over a period of 35 years from 1983 to 2018.MethodsLongitudinal data on the five motor components of the Zurich Neuromotor Assessment (ZNA) – pure motor (PM), fine motor (FM), dynamic balance (DB), static balance (SB), and contralateral associated movements (CAM) – were pooled with cross-sectional data on PM and FM from eight ZNA studies between 1983 and 2018. Regression models were used to estimate the effect of the year of birth on motor performance and body mass index (BMI) measurements. Models were adjusted for age, sex, and socioeconomic status.ResultsThe secular trend estimates in standard deviation scores (SDS) per 10 years were − 0.06 [−0.33; 0.22, 95% Confidence Interval] for PM, −0.11 [−0.41; 0.20] for FM, −0.38 [−0.66; −0.09] for DB (−0.42 when controlled for BMI), −0.21 [−0.47; 0.06] for SB, and − 0.01 [−0.32; 0.31] for CAM. The mean change in BMI data was positive with 0.30 SDS [0.07; 0.53] over 10 years.DiscussionDespite substantial societal changes since the 1980s, motor performance has remained relatively stable across generations. No secular trend was found in FM, PM, SB, and CAM over a period of 35 years. A secular trend in DB was present independent of the secular trend in body mass index.

The microbial transglutaminase (TGase) from Streptomyces mobaraensis (MTGase) is widely used for industrial applications. However, in the last decades, TGases from other bacteria have been described. We focused our attention on TGase, from Kutzneria albida (KalbTGase), recently characterized as more selective than MTGase and proposed for applications in drug delivery. By comparison of the crystallographic structures, the volume of the catalytic site results smaller in KalbTGase. We compared KalbTGase and MTGase structural flexibility by molecular dynamics (MD) simulations at different conditions. KalbTGase is more rigid than MTGase at 300 K, but the catalytic site has a preserved conformation in both structures. Preliminary studies at higher temperatures suggest that KalbTGase acquires enhanced conformational flexibility far from the active site region. The volume of the catalytic active site pocket of KalbTGase at room temperature is smaller than that of MTGase, and decreases at 335 K, remaining stable after further temperature increase. On the contrary, in MTGase the pocket volume continues to decrease as the temperature increases. Overall, the results of our study suggest that at room temperature the enhanced specificity of KalbTGase could be related to a more closed catalytic pocket and lower flexibility than MTGase. Moreover, by preliminary results at higher temperature, KalbTGase structural flexibility suggests an adaptability to different substrates not recognized at room temperature. Lower adaptability of MTGase at higher temperature with a reduction of the catalytic pocket, instead, suggests a reduction of its activity.

Amyloid polymorphism is a hallmark of almost all amyloid species, yet the mechanisms underlying the formation of amyloid polymorphs and their complex architectures remain elusive. Commonly, two main mesoscopic topologies are found in amyloid polymorphs characterized by non‐zero Gaussian and mean curvatures: twisted ribbons and helical fibrils, respectively. Here, a rich heterogeneity of configurations is demonstrated on insulin amyloid fibrils, where protofilament packing can occur, besides the common polymorphs, also in a combined mode forming mixed‐curvature polymorphs. Through AFM statistical analysis, an extended array of heterogeneous architectures that are rationalized by mesoscopic theoretical arguments are identified. Notably, an unusual fibrillization pathway is also unraveled toward mixed‐curvature polymorphs via the widespread recruitment and intertwining of protofilaments and protofibrils. The results present an original view of amyloid polymorphism and advance the fundamental understanding of the fibrillization mechanism from single protofilaments into mature amyloid fibrils. [ABSTRACT FROM AUTHOR]

We report new chemical entities for disrupting the interactions between N6-methyladenosine (m6A) mRNA and its reader YT521-B homology-domain-containing protein 1 (YTHDC1). High-throughput docking was used to screen commercially available databases of small molecules, and molecular dynamics simulations were employed to evaluate the binding stability of m6A nucleotide analogues. The poses of 25 fragment-like new binders were confirmed by X-ray crystallography. The structure-based merging of two weak fragments resulted in a ligand-efficient binder (compound 6) which shows an equilibrium dissociation constant of 1.7 ​μM in isothermal titration calorimetry measurements and a ligand efficiency value of 0.66 ​kcal ​mol−1 nHA−1.

Globally, >100 million cases and >2.6 million deaths had been attributed to coronavirus disease (COVID-19) as of March 14, 2021 (2). Most cases have been reported in Europe and the [...]

Relatively few coronavirus disease cases and deaths have been reported from sub-Saharan Africa, although the extent of its spread remains unclear. During August 10–September 11, 2020, we recruited 2,214 participants for a representative household-based cross-sectional serosurvey in Juba, South Sudan. We found 22.3% of participants had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain IgG titers above prepandemic levels. After accounting for waning antibody levels, age, and sex, we estimated that 38.3% (95% credible interval 31.8%–46.5%) of the population had been infected with SARS-CoV-2. At this rate, for each PCR–confirmed SARS-CoV-2 infection reported by the Ministry of Health, 103 (95% credible interval 86–126) infections would have been unreported, meaning SARS-CoV-2 has likely spread extensively within Juba. We also found differences in background reactivity in Juba compared with Boston, Massachusetts, USA, where the immunoassay was validated. Our findings underscore the need to validate serologic tests in sub-Saharan Africa populations.

This article discusses a case of a young heifer that died suddenly on a farm, showing symptoms of increased respiratory rate and elevated temperature. The necropsy revealed necrohemorrhagic myocarditis and myositis, with the presence of Clostridium chauvoei, the causative agent of blackleg disease. Blackleg is a common disease in young, well-fed cattle and can cause limb weakness, fever, and muscle swelling. The article emphasizes the importance of recognizing and diagnosing blackleg in order to prevent further outbreaks. The disease is characterized by the production of toxins that lead to localized tissue damage and systemic toxemia. Vaccination is available and has been shown to be effective in protecting animals from severe clinical disease. The presence of C. chauvoei can be confirmed through various testing methods, and the spores can be transmitted through environmental exposure or contaminated feed. [Extracted from the article]

Background: There is growing scientific evidence for the therapeutic benefits of the Amazonian plant-based psychedelic "ayahuasca" for neuropsychiatric disorders such as depression and anxiety. However, there are certain challenges when incorporating botanical ayahuasca into biomedical research and clinical therapy environments. Formulations inspired by ayahuasca, which contain specific and standardized active components, are a potential remedy. Methods: We investigated subjective acute and persisting effects of a novel formulation containing the reversible monoamine oxidase inhibitor harmine (orodispersible tablet containing 100 mg MAO-I) and N,N-dimethyltryptamine (incremental intranasal dosing of up to 100 mg DMT), compared with two other conditions, namely harmine alone and placebo, in a crossover RCT in 31 healthy male subjects. Results: DMT + harmine, but not harmine alone, induced a psychedelic experience assessed with the 5D-ASC rating scale [global score: F(2,60) = 80.21, p < 0.001] and acute experience sampling items over time, characterized by psychological insights [PIQ, F(2,58.5) = 28.514, p < 0.001], emotional breakthroughs [EBI, F(2,60) = 26.509, p < 0.001], and low scores on the challenging experience questionnaire [CEQ, F(2,60) = 12.84, p < 0.001]. Participants attributed personal and spiritual significance to the experience (GSR) with mainly positive persisting effects (PEQ) at 1- and 4-months follow-up. Acute drug effects correlated positively with persisting effects. We found no changes in trait measures of personality, psychological flexibility, or general well-being, and no increases in psychopathology (SCL-90-R) were reported. Discussion and Conclusion: Our results suggest that the experience induced by the standardized DMT + harmine formulation induces a phenomenologically rich psychedelic experience, demonstrates good psychological safety and tolerability, is well tolerated, and induces beneficial psychological processes that could possibly support psychotherapy. Further studies are required to investigate the psychotherapeutic potential in patients. [ABSTRACT FROM AUTHOR]

Evidence is accumulating that individual and environmental factors in childhood and adolescence should be considered when investigating adult health and aging-related processes. The data required for this is gathered by comprehensive long-term longitudinal studies. This article describes the protocol of the Zurich Longitudinal Studies (ZLS), a set of three comprehensive cohort studies on child growth, health, and development that are currently expanding into adulthood. Between 1954 and 1961, 445 healthy infants were enrolled in the first ZLS cohort. Their physical, motor, cognitive, and social development and their environment were assessed comprehensively across childhood, adolescence, and into young adulthood. In the 1970s, two further cohorts were added to the ZLS and assessed with largely matched study protocols: Between 1974 and 1979, the second ZLS cohort included 265 infants (103 term-born and 162 preterm infants), and between 1970 and 2002, the third ZLS cohort included 327 children of participants of the first ZLS cohort. Since 2019, the participants of the three ZLS cohorts have been traced and invited to participate in a first wave of assessments in adulthood to investigate their current health and development. This article describes the ZLS study protocol and discusses opportunities, methodological and conceptual challenges, and limitations arising from a long-term longitudinal cohort recruited from a study about development in early life. In the future, the ZLS will provide data to investigate childhood antecedents of adult health outcomes and, ultimately, will help respond to the frequent call of scientists to shift the focus of aging research into the first decades of life and, thus, to take a lifespan perspective on aging.