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Background African Traditional Medicine (ATM) is used for the healthcare of about 80% of the rural populations of the continent of Africa. The practices of ATM make use of plant-products, which are known to contain plant-based secondary metabolites or natural products (NPs), likely to play key roles in drug discovery, particularly as lead compounds. For various reasons, including resistance of strains of Plasmodium to known anti-malarial drugs, local African populations often resort to plant-based treatments and/or a combination of this and standard anti-malarial regimens. Emphasis has been laid in this review to present the anti-malarial virtue of the most recently published phytochemicals or natural products, which have been tested by in vitro and in vivo assays. Methods The data was based on the current version of the African Compound Libraries, which are constantly being updated based on inputs from journal articles and student theses (M.Sc/Ph.D) from African University libraries. Emphasis was laid on data published after 2012. In order to carry out the original data collection, currently being included in the African Compounds Database, individual journal websites were queried using the country names in Africa as search terms. Over 40,000 articles “hits” were originally retrieved, then reduced to about 9000 articles. The retained articles/theses was further queried with the search terms “malaria”, “malarial”, “plasmodium”, “plasmodial” and a combination of them, resulting in over 500 articles. Those including compounds with anti-malarial activities for which the measured activities fell within the established cut off values numbered 55, which were all cited in the review as relevant references. Results and discussion Pure compounds derived from African medicinal plants with demonstrated anti-malarial/antiplasmodial properties with activities ranging from “very active” to “weakly active” have been discussed. The majority of the 187 natural products were terpenoids (30%), followed by flavonoids (22%), alkaloids (19%) and quinones (15%), with each of the other compound classes being less than 5% of the entire compound collection. It was also observed that most of the plant species from which the compounds were identified were of the families Rubiaceae, Meliaceae and Asphodelaceae. The review is intended to continue laying the groundwork for an African-based anti-malarial drug discovery project.

An effective vaccine is needed to halt the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Recently, we reported safety, tolerability and antibody response data from an ongoing placebo-controlled, observer-blinded phase I/II coronavirus disease 2019 (COVID-19) vaccine trial with BNT162b1, a lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the receptor binding domain (RBD) of the SARS-CoV-2 spike protein 1 . Here we present antibody and T cell responses after vaccination with BNT162b1 from a second, non-randomized open-label phase I/II trial in healthy adults, 18–55 years of age. Two doses of 1–50 μg of BNT162b1 elicited robust CD4 + and CD8 + T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those seen in serum from a cohort of individuals who had recovered from COVID-19. Geometric mean titres of SARS-CoV-2 serum-neutralizing antibodies on day 43 were 0.7-fold (1-μg dose) to 3.5 - fold (50-μg dose) those of the recovered individuals. Immune sera broadly neutralized pseudoviruses with diverse SARS-CoV-2 spike variants. Most participants had T helper type 1 (T H 1)-skewed T cell immune responses with RBD-specific CD8 + and CD4 + T cell expansion. Interferon-γ was produced by a large fraction of RBD-specific CD8 + and CD4 + T cells. The robust RBD-specific antibody, T cell and favourable cytokine responses induced by the BNT162b1 mRNA vaccine suggest that it has the potential to protect against COVID-19 through multiple beneficial mechanisms. In a phase I/II dose-escalation clinical trial, the mRNA COVID-19 vaccine BNT162b1 elicits specific T cell and antibody responses that suggest it has protective potential.

Ice cliff distribution plays a major role in determining the melt of debris‐covered glaciers but its controls are largely unknown. We assembled a data set of 37,537 ice cliffs and determined their characteristics across 86 debris‐covered glaciers within High Mountain Asia (HMA). We find that 38.9% of the cliffs are stream‐influenced, 19.5% pond‐influenced and 19.7% are crevasse‐originated. Surface velocity is the main predictor of cliff distribution at both local and glacier scale, indicating its dependence on the dynamic state and hence evolution stage of debris‐covered glacier tongues. Supraglacial ponds contribute to maintaining cliffs in areas of thicker debris, but this is only possible if water accumulates at the surface. Overall, total cliff density decreases exponentially with debris thickness as soon as the debris layer reaches a thickness of over 10 cm. Plain Language Summary Debris‐covered glaciers are common throughout the world's mountain ranges and are characterized by the presence of steep ice cliffs among the debris‐covered ice. It is well‐known that the cliffs are responsible for a large portion of the melt of these glaciers but the controls on their formation, development and distribution across glaciers remains poorly understood. Novel mapping approaches combined with high‐resolution satellite and drone products enabled us to disentangle some of these controls and to show that the ice cliffs are generally formed and maintained by the surface hydrology (ponds or streams) or by the opening of crevasses. As a result, they depend both at the local and glacier scale on the dynamic state of the glaciers as well as the evolution stage of their debris cover. This provides a pathway to better represent their contribution to glacier melt in predictive glacier models. Key Points We derived an unprecedented data set of 37,537 ice cliffs and their characteristics across 86 debris‐covered glaciers in High Mountain Asia We find that 38.9% of the cliffs are stream‐influenced, 19.5% pond‐influenced and 19.7% are crevasse‐originated Ice cliff distribution can be predicted by velocity, as an indicator of the dynamics and state of evolution of debris‐covered glaciers

Disruptive behavior disorders (DBD) are heterogeneous at the clinical and the biological level. Therefore, the aims were to dissect the heterogeneous neurodevelopmental deviations of the affective brain circuitry and provide an integration of these differences across modalities. We combined two novel approaches. First, normative modeling to map deviations from the typical age-related pattern at the level of the individual of (i) activity during emotion matching and (ii) of anatomical images derived from DBD cases (n = 77) and controls (n = 52) aged 8-18 years from the EU-funded Aggressotype and MATRICS consortia. Second, linked independent component analysis to integrate subject-specific deviations from both modalities. While cases exhibited on average a higher activity than would be expected for their age during face processing in regions such as the amygdala when compared to controls these positive deviations were widespread at the individual level. A multimodal integration of all functional and anatomical deviations explained 23% of the variance in the clinical DBD phenotype. Most notably, the top marker, encompassing the default mode network (DMN) and subcortical regions such as the amygdala and the striatum, was related to aggression across the whole sample. Overall increased age-related deviations in the amygdala in DBD suggest a maturational delay, which has to be further validated in future studies. Further, the integration of individual deviation patterns from multiple imaging modalities allowed to dissect some of the heterogeneity of DBD and identified the DMN, the striatum and the amygdala as neural signatures that were associated with aggression.

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes. Epilepsy is a brain network disorder with associated genetic risk factors. Here, the authors show that spatial patterns of transcriptomic vulnerability co-vary with structural brain network alterations in focal and generalized epilepsy.

A common challenge in drug design pertains to finding chemical modifications to a ligand that increases its affinity to the target protein. An underutilized advance is the increase in structural biology throughput, which has progressed from an artisanal endeavor to a monthly throughput of hundreds of different ligands against a protein in modern synchrotrons. However, the missing piece is a framework that turns high-throughput crystallography data into predictive models for ligand design. Here, we designed a simple machine learning approach that predicts protein–ligand affinity from experimental structures of diverse ligands against a single protein paired with biochemical measurements. Our key insight is using physics-based energy descriptors to represent protein–ligand complexes and a learning-to-rank approach that infers the relevant differences between binding modes. We ran a high-throughput crystallography campaign against the SARS-CoV-2 main protease (MPro), obtaining parallel measurements of over 200 protein–ligand complexes and their binding activities. This allows us to design one-step library syntheses which improved the potency of two distinct micromolar hits by over 10-fold, arriving at a noncovalent and nonpeptidomimetic inhibitor with 120 nM antiviral efficacy. Crucially, our approach successfully extends ligands to unexplored regions of the binding pocket, executing large and fruitful moves in chemical space with simple chemistry.

Importance Telomere length is associated with the development of age-related diseases and structural differences in multiple brain regions. It remains unclear, however, whether change in telomere length is linked to brain structure change, and to what extent telomere length can be influenced through mental training. Objectives To assess the dynamic associations between leukocyte telomere length (LTL) and cortical thickness (CT), and to determine whether LTL is affected by a longitudinal contemplative mental training intervention. Design, Setting, and Participants An open-label efficacy trial of three 3-month mental training modules with healthy, meditation-naive adults was conducted. Data on LTL and CT were collected 4 times over 9 months between April 22, 2013, and March 31, 2015, as part of the ReSource Project. Data analysis was performed between September 23, 2016, and June 21, 2019. Of 1582 eligible individuals, 943 declined to participate; 362 were randomly selected for participation and assigned to training or retest control cohorts, with demographic characteristics matched. The retest control cohorts underwent all testing but no training. Intention-to-treat analysis was performed. Interventions Training cohort participants completed 3 modules cultivating interoception and attention (Presence), compassion (Affect), or perspective taking (Perspective). Main Outcomes and Measures Change in LTL and CT. Results Of the 362 individuals randomized, 30 participants dropped out before study initiation (initial sample, 332). Data were available for analysis of the training intervention in 298 participants (n = 222 training; n = 76 retest control) (175 women [58.7%]; mean [SD] age, 40.5 [9.3] years). The training modules had no effect on LTL. In 699 observations from all 298 participants, mean estimated changes in the relative ratios of telomere repeat copy number to single-copy gene (T/S) were for no training, 0.004 (95% CI, −0.010 to 0.018); Presence, −0.007 (95% CI, −0.025 to 0.011); Affect, −0.005 (95% CI, −0.019 to 0.010); and Perspective, −0.001 (95% CI, −0.017 to 0.016). Cortical thickness change data were analyzed in 167 observations from 67 retest control participants (37 women [55.2%], mean [SD] age, 39.6 [9.0] years). In this retest control cohort subsample, naturally occurring LTL change was related to CT change in the left precuneus extending to the posterior cingulate cortex (meant161 = 3.22;P < .001;r = 0.246). At the individual participant level, leukocyte telomere shortening as well as lengthening were observed. Leukocyte telomere shortening was related to cortical thinning (t77 = 2.38;P = .01;r = 0.262), and leukocyte telomere lengthening was related to cortical thickening (t77 = 2.42;P = .009;r = 0.266). All analyses controlled for age, sex, and body mass index. Conclusions and Relevance The findings of this trial indicate an association between short-term change in LTL and concomitant change in plasticity of the left precuneus extending to the posterior cingulate cortex. This result contributes to the evidence that LTL changes more dynamically on the individual level than previously thought. Further studies are needed to determine potential long-term implications of such change in relation to cellular aging and the development of neurodegenerative disorders. No effect of contemplative mental training was noted in what may be, to date, the longest intervention with healthy adults. Trial Registration ClinicalTrials.gov identifier:NCT01833104

Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab—a human IgG1 VEGFR-2 antagonist—or placebo in this patient population. We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96–4·47] vs 2·76 months [2·60–2·96]; hazard ratio [HR] 0·757, 95% CI 0·607–0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8–30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4–18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. Eli Lilly and Company.

The hippocampus is a highly plastic brain structure supporting functions central to human cognition. Morphological changes in the hippocampus have been implicated in development, aging, as well as in a broad range of neurological and psychiatric disorders. A growing body of research suggests that hippocampal plasticity is closely linked to the actions of brain-derived neurotrophic factor (BDNF). However, evidence on the relationship between hippocampal volume (HCV) and peripheral BDNF levels is scarce and limited to elderly and patient populations. Further, despite evidence that BDNF expression differs throughout the hippocampus and is implicated in adult neurogenesis specifically in the dentate gyrus, no study has so far related peripheral BDNF levels to the volumes of individual hippocampal subfields. Besides its clinical implications, BDNF-facilitated hippocampal plasticity plays an important role in regulating cognitive and affective processes. In the current registered report, we investigated how serum BDNF (sBDNF) levels relate to volumes of the hippocampal formation and its subfields in a large sample of healthy adults (N = 279, 160 f) with a broad age range (20–55 years, mean 40.5) recruited in the context of the ReSource Project. We related HCV to basal sBDNF and, in a subsample (n = 103, 57 f), to acute stress-reactive change in sBDNF. We further tested the role of age as a moderator of both associations. Contrary to our hypotheses, neither basal sBDNF levels nor stress-reactive sBDNF change were associated with total HCV or volume of the dentate gyrus/cornu ammonis 4 (DG/CA4) subfield. We also found no evidence for a moderating effect of age on any of these associations. Our null results provide a first point of reference on the relationship between sBDNF and HCV in healthy mid-age, in contrast to patient or aging populations. We suggest that sBDNF levels have limited predictive value for morphological differences of the hippocampal structure when notable challenge to its neuronal integrity or to neurotrophic capacity is absent.

Supported gold and platinum particles on titanium oxide catalysts were evaluated in the oxidative depolymerization of lignins toward high added value aromatics under mild conditions (T: 150 °C, Pair: 20 bar, CNaOH: 10 g/L, 1 h). Kraft and ethanol Organosolv lignins were engaged in the study. Gold catalyst showed a strong tendency to further oxidize aromatics produced from lignin depolymerization to volatile compounds leading to very low yield in target molecules. On the contrary, platinum-based catalysts were allowed to observe enhanced yields that were attributed to its ability to preserve lignin’s substructure during the reaction. A kinetic model was constructed based on the results observed, which allowed us to identify the occurrence of condensation reactions during lignin oxidation and degradation of the produced aromatic compounds as the main limitations to reach high product yields. Insights on lignin oxidation and the catalyst’s role lead through this study would help to reach higher control over lignin valorization.