Lineage-specific splicing regulation of MAPT gene in the primate brain.

Divergence of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is widespread in mammals, including primates, but the underlying mechanisms and functional impact are poorly understood. Here, we modeled cassette exon inclusion in primate brains as a quantitative trait and identified 1,170 (∼3%) exons with lineage-specific splicing shifts under stabilizing selection. Among them, microtubule-associated protein tau (MAPT) exons 2 and 10 underwent anticorrelated, two-step evolutionary shifts in the catarrhine and hominoid lineages, leading to their present inclusion levels in humans. The developmental-stage-specific divergence of exon 10 splicing, whose dysregulation can cause frontotemporal lobar degeneration (FTLD), is mediated by divergent distal intronic MBNL-binding sites. Competitive binding of these sites by CRISPR-dCas13d/gRNAs effectively reduces exon 10 inclusion, potentially providing a therapeutically compatible approach to modulate tau isoform expression. Our data suggest adaptation of MAPT function and, more generally, a role for AS in the evolutionary expansion of the primate brain.

Radiation-induced alteration of apatite on the surface of Mars: first in situ observations with SuperCam Raman onboard Perseverance.

Planetary exploration relies considerably on mineral characterization to advance our understanding of the solar system, the planets and their evolution. Thus, we must understand past and present processes that can alter materials exposed on the surface, affecting space mission data. Here, we analyze the first dataset monitoring the evolution of a known mineral target in situ on the Martian surface, brought there as a SuperCam calibration target onboard the Perseverance rover. We used Raman spectroscopy to monitor the crystalline state of a synthetic apatite sample over the first 950 Martian days (sols) of the Mars2020 mission. We note significant variations in the Raman spectra acquired on this target, specifically a decrease in the relative contribution of the Raman signal to the total signal. These observations are consistent with the results of a UV-irradiation test performed in the laboratory under conditions mimicking ambient Martian conditions. We conclude that the observed evolution reflects an alteration of the material, specifically the creation of electronic defects, due to its exposure to the Martian environment and, in particular, UV irradiation. This ongoing process of alteration of the Martian surface needs to be taken into account for mineralogical space mission data analysis.

Spaceflight effects on human vascular smooth muscle cell phenotype and function.

The cardiovascular system is strongly impacted by the hazards of spaceflight. Astronauts spending steadily increasing lengths of time in microgravity are subject to cardiovascular deconditioning resulting in loss of vascular tone, reduced total blood volume, and diminished cardiac output. Appreciating the mechanisms by which the cells of the vasculature are altered during spaceflight will be integral to understanding and combating these deleterious effects as the human presence in space advances. In this study, we performed RNA-Seq analysis coupled with review by QIAGEN Ingenuity Pathway Analysis software on human aortic smooth muscle cells (HASMCs) cultured for 3 days in microgravity and aboard the International Space Station to assess the transcriptomic changes that occur during spaceflight. The results of our RNA-Seq analysis show that SMCs undergo a wide range of transcriptional alteration while in space, significantly affecting 4422 genes. SMCs largely down-regulate markers of the contractile, synthetic, and osteogenic phenotypes including smooth muscle alpha actin (αSMA), matrix metalloproteinases (MMPs), and bone morphogenic proteins (BMPs). Additionally, components of several cellular signaling pathways were strongly impacted including the STAT3, NFκB, PI3K/AKT, HIF1α, and Endothelin pathways. This study highlights the significant changes in transcriptional behavior SMCs exhibit during spaceflight and puts these changes in context to better understand vascular function in space.

Purcell-enhanced single photons at telecom wavelengths from a quantum dot in a photonic crystal cavity.

Quantum dots are promising candidates for telecom single photon sources due to their tunable emission across the different low-loss telecommunications bands, making them compatible with existing fiber networks. Their suitability for integration into photonic structures allows for enhanced brightness through the Purcell effect, supporting efficient quantum communication technologies. Our work focuses on InAs/InP QDs created via droplet epitaxy MOVPE to operate within the telecoms C-band. We observe a short radiative lifetime of 340 ps, arising from a Purcell factor of 5, owing to integration of the QD within a low-mode-volume photonic crystal cavity. Through in-situ control of the sample temperature, we show both temperature tuning of the QD's emission wavelength and a preserved single photon emission purity at temperatures up to 25K. These findings suggest the viability of QD-based, cryogen-free C-band single photon sources, supporting applicability in quantum communication technologies.

Biophotonics-Intraoperative Guidance During Partial Nephrectomy: A Systematic Review and Meta-analysis.

CONTEXT: Partial nephrectomy (PN) with intraoperative guidance by biophotonics has the potential to improve surgical outcomes due to higher precision. However, its value remains unclear since high-level evidence is lacking. OBJECTIVE: To provide a comprehensive analysis of biophotonic techniques used for intraoperative real-time assistance during PN. EVIDENCE ACQUISITION: We performed a comprehensive database search based on the PICO criteria, including studies published before October 2022. Two independent reviewers screened the titles and abstracts followed by full-text screening of eligible studies. For a quantitative analysis, a meta-analysis was conducted. EVIDENCE SYNTHESIS: In total, 35 studies were identified for the qualitative analysis, including 27 studies on near-infrared fluorescence (NIRF) imaging using indocyanine green, four studies on hyperspectral imaging, two studies on folate-targeted molecular imaging, and one study each on optical coherence tomography and 5-aminolevulinic acid. The meta-analysis investigated seven studies on selective arterial clamping using NIRF. There was a significantly shorter warm ischemia time in the NIRF-PN group (mean difference [MD]: -2.9; 95% confidence interval [CI]: -5.6, -0.1; p = 0.04). No differences were noted regarding transfusions (odds ratio [OR]: 0.5; 95% CI: 0.2, 1.7; p = 0.27), positive surgical margins (OR: 0.7; 95% CI: 0.2, 2.0; p = 0.46), or major complications (OR: 0.4; 95% CI: 0.1, 1.2; p = 0.08). In the NIRF-PN group, functional results were favorable at short-term follow-up (MD of glomerular filtration rate decline: 7.6; 95% CI: 4.6, 10.5; p < 0.01), but leveled off at long-term follow-up (MD: 7.0; 95% CI: -2.8, 16.9; p = 0.16). Remarkably, these findings were not confirmed by the included randomized controlled trial. CONCLUSIONS: Biophotonics comprises a heterogeneous group of imaging modalities that serve intraoperative decision-making and guidance. Implementation into clinical practice and cost effectiveness are the limitations that should be addressed by future research. PATIENT SUMMARY: We reviewed the application of biophotonics during partial removal of the kidney in patients with kidney cancer. Our results suggest that these techniques support the surgeon in successfully performing the challenging steps of the procedure.

Framework for a living systematic review and meta-analysis for the surgical treatment of bladder cancer: introducing EVIglance to urology.

Background: Knowledge of current and ongoing studies is critical for identifying research gaps and enabling evidence-based decisions for individualized treatment. However, the increasing number of scientific publications poses challenges for healthcare providers and patients in all medical fields to stay updated with the latest evidence. To overcome these barriers, we aim to develop a living systematic review and open-access online evidence map of surgical therapy for bladder cancer (BC), including meta-analyses. Methods: Following the guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement, a systematic literature search on uro-oncological therapy in BC will be performed across various literature databases. Within the scope of a meta-analysis and living systematic review, relevant randomized controlled trials will be identified. Data extraction and quantitative analysis will be conducted, along with a critical appraisal of the quality and risk of bias of each study. The available research evidence will be entered into an open-access framework (www.evidencemap.surgery) and will also be accessible via the EVIglance app. Regular semi-automatic updates will enable the implementation of a real-living review concept and facilitate resource-efficient screening. Discussion: A regularly updated evidence map provides professionals and patients with an open-access knowledge base on the current state of research, allowing for decision-making based on recent evidence. It will help identify an oversupply of evidence, thus avoiding redundant work. Furthermore, by identifying research gaps, new hypotheses can be formulated more precisely, enabling planning, determination of sample size, and definition of endpoints for future trials.

N6-methyladenosine in 7SK small nuclear RNA underlies RNA polymerase II transcription regulation.

N6-methyladenosine (m6A) modifications play crucial roles in RNA metabolism. How m6A regulates RNA polymerase II (RNA Pol II) transcription remains unclear. We find that 7SK small nuclear RNA (snRNA), a regulator of RNA Pol II promoter-proximal pausing, is highly m6A-modified in non-small cell lung cancer (NSCLC) cells. In A549 cells, we identified eight m6A sites on 7SK and discovered methyltransferase-like 3 (METTL3) and alkB homolog 5 (ALKBH5) as the responsible writer and eraser. When the m6A-7SK is specifically erased by a dCasRx-ALKBH5 fusion protein, A549 cell growth is attenuated due to reduction of RNA Pol II transcription. Mechanistically, removal of m6A leads to 7SK structural rearrangements that facilitate sequestration of the positive transcription elongation factor b (P-TEFb) complex, which results in reduction of serine 2 phosphorylation (Ser2P) in the RNA Pol II C-terminal domain and accumulation of RNA Pol II in the promoter-proximal region. Taken together, we uncover that m6A modifications of a non-coding RNA regulate RNA Pol II transcription and NSCLC tumorigenesis.

C4 leaf development and evolution.

C4 photosynthesis is more efficient than C3 photosynthesis for two reasons. First, C4 plants have evolved efficient C4 enzymes to suppress wasteful photorespiration and enhance CO2 fixation. Second, C4 leaves have Kranz anatomy in which the veins are surrounded by one layer of bundle sheath (BS) cells and one layer of mesophyll (M) cells. The BS and M cells are functionally well differentiated and also well coordinated for rapid assimilation of atmospheric CO2 and transport of photo-assimilates between the two types of cells. Recent comparative transcriptomics of developing M and BS cells in young maize embryonic leaves revealed not only potential regulators of BS and M cell differentiation but also rapid early BS cell differentiation whereas slower, more prolonged M cell differentiation, contrary to the traditional view of a far simpler process of M cell development. Moreover, new upstream regulators of Kranz anatomy development have been identified and a number of gene co-expression modules for early vascular development have been inferred. Also, a candidate gene regulatory network associated with Kranz anatomy and vascular development has been constructed. Additionally, how whole genome duplication (WGD) may facilitate C4 evolution has been studied and the reasons for why the same WGD event led to successful C4 evolution in Gynandropsis gynandra but not in the sister species Tarenaya hassleriana have been proposed. Finally, new future research directions are suggested.

Digital Therapeutics in Urology: An Innovative Approach to Patient Care and Management.

Digital therapeutics (DTx) are a new class of intervention involving evidence-based software applications and have been used in neurology and psychiatry. To assess the potential of DTx in urology, we conducted a survey to assess the current prevalence of the digital infrastructure required for DTx, areas of support expected by patients, and requirements for uptake. Between November 2022 and January 2023, we conducted an anonymized survey at two German academic centers among patients with urologic conditions. We found that among patients aged <65 yr versus ≥65 yr, digital devices including smartphones (93.6% vs 77.3%; p < 0.001), computers (80.4% vs 70.1%; p < 0.001), tablets (51.7% vs 38.1%; p < 0.001), and smartwatches (24.7% vs 7.7%; p < 0.001) are already widely used, especially in the younger age group. Apps (95.6% vs 74.4%; p < 0.001) and health apps (57.6% vs 30.4%; p < 0.001) are already frequently used, but certified DTx apps are not (7.3% vs 5.4%; p = 0.25). Patients favor solutions that provide access to validated information (49.6%), give medical advice based on data or symptoms captured by the app (43.0%), or replace a physiotherapist (41.7%). Patients feel that optimization of therapy (78.4%), significant positive health outcomes (76.9%), and better patient autonomy (73.4%) are important requirements for DTx in urology. Regulatory and reimbursement changes mean that DTx might play an increasing role in urology. Patient summary: Patients can use digital therapeutics (DTx), which are mainly smartphone apps, to improve their health status or treat medical conditions. We assessed the current and future use of DTx in urology. Patients are already widely using smartphones and frequently use uncertified health apps, but do not use DTx. Patients would like to use DTx to optimize therapy that provides a significant health improvement.

Probing and Control of Guided Exciton-Polaritons in a 2D Semiconductor-Integrated Slab Waveguide.

Guided 2D exciton-polaritons, resulting from the strong coupling of excitons in semiconductors with nonradiating waveguide modes, provide an attractive approach toward developing novel on-chip optical devices. These quasiparticles are characterized by long propagation distances and efficient nonlinear interactions but cannot be directly accessed from the free space. Here we demonstrate a powerful approach for probing and manipulating guided polaritons in a Ta2O5 slab integrated with a WS2 monolayer using evanescent coupling through a high-index solid immersion lens. Tuning the nanoscale lens-sample gap allows for extracting all of the intrinsic parameters of the system. We also demonstrate the transition from weak to strong coupling accompanied by the onset of the motional narrowing effect: with the increase of exciton-photon coupling strength, the inhomogeneous contribution to polariton line width, inherited from the exciton resonance, becomes fully lifted. Our results enable the development of integrated optics employing room-temperature exciton-polaritons in 2D semiconductor-based structures.

Getting specific: participation preference in urooncological decision-making.

BACKGROUND: Shared decision-making is the gold standard for good clinical practice, and thus, psychometric instruments have been established to assess patients' generic preference for participation (e.g., the Autonomy Preference Index, API). However, patients' preferences may vary depending on the specific disease and with respect to the specific decision context. With a modified preference index (API-Uro), we assessed patients' specific participation preference in preference-sensitive decisions pertaining to urological cancer treatments and compared this with their generic participation preference. METHODS: In Study 1, we recruited (N = 469) urological outpatients (43.1% urooncological) at a large university hospital. Participation preference was assessed with generic measures (API and API case vignettes) and with the disease-specific API-Uro (urooncological case vignettes describing medical decisions of variable difficulty). A polychoric exploratory factor analysis was used to establish factorial validity and reduce items. In Study 2, we collected data from N = 204 bladder cancer patients in a multicenter study to validate the factorial structure with confirmatory factor analysis. Differences between the participation preference for different decision contexts were analyzed. RESULTS: Study 1: Scores on the specific urooncological case vignettes (API-Uro) correlated with the generic measure (r = .44) but also provided incremental information. Among the disease-specific vignettes of the API-Uro, there were two factors with good internal consistency (α ≥ .8): treatment versus diagnostic decisions. Patients desired more participation for treatment decisions (77.8%) than for diagnostic decisions (22%), χ2(1) = 245.1, p ≤ .001. Study 2: Replicated the correlation of the API-Uro with the API (r = .39) and its factorial structure (SRMR = .08; CFI = .974). Bladder cancer patients also desired more participation for treatment decisions (57.4%) than for diagnostic decisions (13.3%), χ²(1) =84, p ≤ .001. CONCLUSIONS: The desire to participate varies between treatment versus diagnostic decisions among urological patients. This underscores the importance of assessing participation preference for specific contexts. Overall, the new API-Uro has good psychometric properties and is well suited to assess patients' preferences. In routine care, measures of participation preference for specific decision contexts may provide incremental, allowing clinicians to better address their patients' individual needs.

A self-supervised vision transformer to predict survival from histopathology in renal cell carcinoma.

PURPOSE: To develop and validate an interpretable deep learning model to predict overall and disease-specific survival (OS/DSS) in clear cell renal cell carcinoma (ccRCC). METHODS: Digitised haematoxylin and eosin-stained slides from The Cancer Genome Atlas were used as a training set for a vision transformer (ViT) to extract image features with a self-supervised model called DINO (self-distillation with no labels). Extracted features were used in Cox regression models to prognosticate OS and DSS. Kaplan-Meier for univariable evaluation and Cox regression analyses for multivariable evaluation of the DINO-ViT risk groups were performed for prediction of OS and DSS. For validation, a cohort from a tertiary care centre was used. RESULTS: A significant risk stratification was achieved in univariable analysis for OS and DSS in the training (n = 443, log rank test, p < 0.01) and validation set (n = 266, p < 0.01). In multivariable analysis, including age, metastatic status, tumour size and grading, the DINO-ViT risk stratification was a significant predictor for OS (hazard ratio [HR] 3.03; 95%-confidence interval [95%-CI] 2.11-4.35; p < 0.01) and DSS (HR 4.90; 95%-CI 2.78-8.64; p < 0.01) in the training set but only for DSS in the validation set (HR 2.31; 95%-CI 1.15-4.65; p = 0.02). DINO-ViT visualisation showed that features were mainly extracted from nuclei, cytoplasm, and peritumoural stroma, demonstrating good interpretability. CONCLUSION: The DINO-ViT can identify high-risk patients using histological images of ccRCC. This model might improve individual risk-adapted renal cancer therapy in the future.

Choroid plexus mis-splicing and altered cerebrospinal fluid composition in myotonic dystrophy type 1.

Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. These expanded repeats are transcribed and produce toxic CUG RNAs that sequester and inhibit activities of the MBNL family of developmental RNA processing factors. Although myotonic dystrophy is classified as a muscular dystrophy, the brain is also severely affected by an unusual cohort of symptoms, including hypersomnia, executive dysfunction, as well as early onsets of tau/MAPT pathology and cerebral atrophy. To address the molecular and cellular events that lead to these pathological outcomes, we recently generated a mouse Dmpk CTG expansion knock-in model and identified choroid plexus epithelial cells as particularly affected by the expression of toxic CUG expansion RNAs. To determine if toxic CUG RNAs perturb choroid plexus functions, alternative splicing analysis was performed on lateral and hindbrain choroid plexi from Dmpk CTG knock-in mice. Choroid plexus transcriptome-wide changes were evaluated in Mbnl2 knockout mice, a developmental-onset model of myotonic dystrophy brain dysfunction. To determine if transcriptome changes also occurred in the human disease, we obtained post-mortem choroid plexus for RNA-seq from neurologically unaffected (two females, three males; ages 50-70 years) and myotonic dystrophy type 1 (one female, three males; ages 50-70 years) donors. To test that choroid plexus transcriptome alterations resulted in altered CSF composition, we obtained CSF via lumbar puncture from patients with myotonic dystrophy type 1 (five females, five males; ages 35-55 years) and non-myotonic dystrophy patients (three females, four males; ages 26-51 years), and western blot and osmolarity analyses were used to test CSF alterations predicted by choroid plexus transcriptome analysis. We determined that CUG RNA induced toxicity was more robust in the lateral choroid plexus of Dmpk CTG knock-in mice due to comparatively higher Dmpk and lower Mbnl RNA levels. Impaired transitions to adult splicing patterns during choroid plexus development were identified in Mbnl2 knockout mice, including mis-splicing previously found in Dmpk CTG knock-in mice. Whole transcriptome analysis of myotonic dystrophy type 1 choroid plexus revealed disease-associated RNA expression and mis-splicing events. Based on these RNA changes, predicted alterations in ion homeostasis, secretory output and CSF composition were confirmed by analysis of myotonic dystrophy type 1 CSF. Our results implicate choroid plexus spliceopathy and concomitant alterations in CSF homeostasis as an unappreciated contributor to myotonic dystrophy type 1 CNS pathogenesis.

Observation of Zitterbewegung in photonic microcavities.

We present and experimentally study the effects of the photonic spin-orbit coupling on the real space propagation of polariton wavepackets in planar semiconductor microcavities and polaritonic analogues of graphene. In particular, we demonstrate the appearance of an analogue Zitterbewegung effect, a term which translates as 'trembling motion' in English, which was originally proposed for relativistic Dirac electrons and consisted of the oscillations of the centre of mass of a wavepacket in the direction perpendicular to its propagation. For a planar microcavity, we observe regular Zitterbewegung oscillations whose amplitude and period depend on the wavevector of the polaritons. We then extend these results to a honeycomb lattice of coupled microcavity resonators. Compared to the planar cavity, such lattices are inherently more tuneable and versatile, allowing simulation of the Hamiltonians of a wide range of important physical systems. We observe an oscillation pattern related to the presence of the spin-split Dirac cones in the dispersion. In both cases, the experimentally observed oscillations are in good agreement with theoretical modelling and independently measured bandstructure parameters, providing strong evidence for the observation of Zitterbewegung.

When attitudes and beliefs get in the way of shared decision-making: A mediation analysis of participation preference.

INTRODUCTION: Certain sociodemographic characteristics (e.g., older age) have previously been identified as barriers to patients' participation preference in shared decision-making (SDM). We aim to demonstrate that this relationship is mediated by the perceived power imbalance that manifests itself in patients' negative attitudes and beliefs about their role in decision-making. METHODS: We recruited a large sample (N = 434) of outpatients with a range of urological diagnoses (42.2% urooncological). Before the medical consultation at a university hospital, patients completed the Patients' Attitudes and Beliefs Scale and the Autonomy Preference Index. We evaluated attitudes as a mediator between sociodemographic factors and participation preference in a path model. RESULTS: We replicated associations between relevant sociodemographic factors and participation preference. Importantly, attitudes and beliefs about one's own role as a patient mediated this relationship. The mediation path model explained a substantial proportion of the variance in participation preference (27.8%). Participation preferences and attitudes did not differ for oncological and nononcological patients. CONCLUSION: Patients' attitudes and beliefs about their role determine whether they are willing to participate in medical decision-making. Thus, inviting patients to participate in SDM should encompass an assessment of their attitudes and beliefs. Importantly, negative attitudes may be accessible to change. Unlike stable sociodemographic characteristics, such values are promising targets for interventions to foster more active participation in SDM. PATIENT OR PUBLIC CONTRIBUTION: This study was part of a larger project on implementing SDM in urological practice. Several stakeholders were involved in the design, planning and conduction of this study, for example, three authors are practising urologists, and three are psychologists with experience in patient care. In addition, the survey was piloted with patients, and their feedback was integrated into the questionnaire. The data presented in this study is based on patients' responses. Results may help to empower our patients.

Patient Compliance in Assessing Electronic Patient-Reported Outcome Measures after Urologic Surgery.

INTRODUCTION: This study aimed to assess patient compliance with a newly established electronic patient-reported outcome measure (ePROM) system after urologic surgery and to identify influencing factors. METHODS: Digital surveys were provided to patients undergoing cystectomy, radical or partial nephrectomy, or transurethral resection of bladder tumor via a newly established ePROM system. Participants received a baseline survey preoperatively and several follow-up surveys postoperatively. Multivariable regression analysis was performed to identify factors predicting compliance. RESULTS: Of N = 435 eligible patients, n = 338 completed the baseline survey (78.0%). Patients who did not participate were significantly more likely male (p = 0.004) and older than 70 years (p = 0.005). Overall, 206/337 patients (61.3%) completed the survey at 1-month, 167/312 (53.5%) at 3-month, and 142/276 (51.4%) at 6-month follow-up. Lower baseline quality of life (odds ratio: 2.27; p = 0.004) was a significant predictor for dropout at 1-month follow-up. Low educational level was significantly associated with low compliance at 3- (OR: 1.92; p = 0.01) and 6-month follow-up (OR: 2.88; p < 0.001). CONCLUSION: Acceptable compliance rates can be achieved with ePROMs following urologic surgery. Several factors influence compliance and should be considered when setting-up ePROM surveys.

Simultaneous detection of miRNA and mRNA at the single-cell level in plant tissues.

Detecting the simultaneous presence of a microRNA (miRNA) and a mRNA in a specific tissue can provide support for the prediction that the miRNA regulates the mRNA. Although two such methods have been developed for mammalian tissues, they have a low signal-noise ratio and/or poor resolution at the single-cell level. To overcome these drawbacks, we develop a method that uses sequence-specific miRNA-locked nucleic acid (LNA) and mRNA-LNA probes. Moreover, it augments the detection signal by rolling circle amplification, achieving a high signal-noise ratio at the single-cell level. Dot signals are counted for determining the expression levels of mRNA and miRNA molecules in specific cells. We show a high sequence specificity of our miRNA-LNA probe, revealing that it can discriminate single-base mismatches. Numerical quantification by our method is tested in transgenic rice lines with different gene expression levels. We conduct several applications. First, the spatial expression profiling of osa-miR156 and OsSPL12 in rice leaves reveals their specific expression in mesophyll cells. Second, studying rice and its mutant lines with our method reveals opposite expression patterns of miRNA and its target mRNA in tissues. Third, the dynamic expression profiles of ZmGRF8 and zma-miR396 during maize leaf development provide evidence that zma-miR396 regulates the preferential spatial expression of ZmGRF8 in bundle sheath cells. Finally, our method can be scaled up to simultaneously detect multiple miRNAs and mRNAs in a tissue. Thus, it is a sensitive and versatile technique for studying miRNA regulation of plant tissue development.

A randomized controlled trial showing safety and efficacy of a whole sporozoite vaccine against endemic malaria.

A highly effective malaria vaccine remains elusive despite decades of research. Plasmodium falciparum sporozoite vaccine (PfSPZ Vaccine), a metabolically active, nonreplicating, whole parasite vaccine demonstrated safety and vaccine efficacy (VE) against endemic P. falciparum for 6 months in Malian adults receiving a five-dose regimen. Safety, immunogenicity, and VE of a three-dose regimen were assessed in adults in Balonghin, Burkina Faso in a two-component study: an open-label dose escalation trial with 32 participants followed by a double-blind, randomized, placebo-controlled trial (RCT) with 80 participants randomized to receive three doses of 2.7 × 106 PfSPZ (N = 39) or normal saline (N = 41) just before malaria season. To clear parasitemia, artesunate monotherapy was administered before first and last vaccinations. Thick blood smear microscopy was performed on samples collected during illness and every 4 weeks for 72 weeks after last vaccinations, including two 6-month malaria transmission seasons. Safety outcomes were assessed in all 80 participants who received at least one dose and VE for 79 participants who received three vaccinations. Myalgia was the only symptom that differed between groups. VE (1 - risk ratio; primary VE endpoint) was 38% at 6 months (P = 0.017) and 15% at 18 months (0.078). VE (1 - hazard ratio) was 48% and 46% at 6 and 18 months (P = 0.061 and 0.018). Two weeks after the last dose, antibodies to P. falciparum circumsporozoite protein and PfSPZ were higher in protected versus unprotected vaccinees. A three-dose regimen of PfSPZ Vaccine demonstrated safety and efficacy against malaria infection in malaria-experienced adults.

The sound of a Martian dust devil.

Dust devils (convective vortices loaded with dust) are common at the surface of Mars, particularly at Jezero crater, the landing site of the Perseverance rover. They are indicators of atmospheric turbulence and are an important lifting mechanism for the Martian dust cycle. Improving our understanding of dust lifting and atmospheric transport is key for accurate simulation of the dust cycle and for the prediction of dust storms, in addition to being important for future space exploration as grain impacts are implicated in the degradation of hardware on the surface of Mars. Here we describe the sound of a Martian dust devil as recorded by the SuperCam instrument on the Perseverance rover. The dust devil encounter was also simultaneously imaged by the Perseverance rover's Navigation Camera and observed by several sensors in the Mars Environmental Dynamics Analyzer instrument. Combining these unique multi-sensorial data with modelling, we show that the dust devil was around 25 m large, at least 118 m tall, and passed directly over the rover travelling at approximately 5 m s-1. Acoustic signals of grain impacts recorded during the vortex encounter provide quantitative information about the number density of particles in the vortex. The sound of a Martian dust devil was inaccessible until SuperCam microphone recordings. This chance dust devil encounter demonstrates the potential of acoustic data for resolving the rapid wind structure of the Martian atmosphere and for directly quantifying wind-blown grain fluxes on Mars.