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Those who had baseline leptin levels above the median had a greater risk of developing arterial stiffening (odds ratio 2.5, p  less then  0.05) and a greater increase in pulse pressure over time (beta 2.1, p  less then  0.05), also after adjustment for confounders. The results of this prospective study indicate a predictive role of circulating leptin levels for vascular damage, independent of body weight and blood pressure.Organotypic models of patient-specific tumours are revolutionizing our understanding of cancer heterogeneity and its implications for personalized medicine. These advancements are, in part, attributed to the ability of organoid models to stably preserve genetic, proteomic, morphological and pharmacotypic features of the parent tumour in vitro, while also offering unprecedented genomic and environmental manipulation. Despite recent innovations in organoid protocols, current techniques for cancer organoid culture are inherently uncontrolled and irreproducible, owing to several non-standardized facets including cancer tissue sources and subsequent processing, medium formulations, and animal-derived three-dimensional matrices. Given the potential for cancer organoids to accurately recapitulate the intra- and intertumoral biological heterogeneity associated with patient-specific cancers, eliminating the undesirable technical variability accompanying cancer organoid culture is necessary to establish reproducible platforms that accelerate translatable insights into patient care. Here we describe the current challenges and recent multidisciplinary advancements and opportunities for standardizing next-generation cancer organoid systems.Cyanophycin is a natural biopolymer produced by a wide range of bacteria, consisting of a chain of poly-L-Asp residues with L-Arg residues attached to the β-carboxylate sidechains by isopeptide bonds. Cyanophycin is synthesized from ATP, aspartic acid and arginine by a homooligomeric enzyme called cyanophycin synthetase (CphA1). CphA1 has domains that are homologous to glutathione synthetases and muramyl ligases, but no other structural information has been available. Here, we present cryo-electron microscopy and X-ray crystallography structures of cyanophycin synthetases from three different bacteria, including cocomplex structures of CphA1 with ATP and cyanophycin polymer analogs at 2.6 Å resolution. These structures reveal two distinct tetrameric architectures, show the configuration of active sites and polymer-binding regions, indicate dynamic conformational changes and afford insight into catalytic mechanism. Accompanying biochemical interrogation of substrate binding sites, catalytic centers and oligomerization interfaces combine with the structures to provide a holistic understanding of cyanophycin biosynthesis.Despite the enormous therapeutic potential of immune checkpoint blockade (ICB), it benefits only a small subset of patients. Some chemotherapeutics can switch 'immune-cold' tumours to 'immune-hot' to synergize with ICB. However, safe and universal therapeutic platforms implementing such immune effects remain scarce. We demonstrate that sphingomyelin-derived camptothecin nanovesicles (camptothesomes) elicit potent granzyme-B- and perforin-mediated cytotoxic T lymphocyte (CTL) responses, potentiating PD-L1/PD-1 co-blockade to eradicate subcutaneous MC38 adenocarcinoma with developed memory immunity. In addition, camptothesomes improve the pharmacokinetics and lactone stability of camptothecin, avoid systemic toxicities, penetrate deeply into the tumour and outperform the antitumour efficacy of Onivyde. Camptothesome co-load the indoleamine 2,3-dioxygenase inhibitor indoximod into its interior using the lipid-bilayer-crossing capability of the immunogenic cell death inducer doxorubicin, eliminating clinically relevant advanced orthotopic CT26-Luc tumours and late-stage B16-F10-Luc2 melanoma, and achieving complete metastasis remission when combined with ICB and folate targeting. The sphingomyelin-derived nanotherapeutic platform and doxorubicin-enabled transmembrane transporting technology are generalizable to various therapeutics, paving the way for transformation of the cancer immunochemotherapy paradigm.Non-invasive, high-throughput spectroscopic techniques can identify chiral indices (n,m) of carbon nanotubes down to the single-tube level1-6. Yet, for complete characterization and to unlock full functionality, the handedness, the structural property associated with mirror symmetry breaking, also needs to be identified accurately and efficiently7-14. So far, optical methods fail in the handedness characterization of single nanotubes because of the extremely weak chiroptical signals (roughly 10-7) compared with the excitation light15,16. Here we demonstrate the complete structure identification of single nanotubes in terms of both chiral indices and handedness by Rayleigh scattering circular dichroism. Our method is based on the background-free feature of Rayleigh scattering collected at an oblique angle, which enhances the nanotube's chiroptical signal by three to four orders of magnitude compared with conventional absorption circular dichroism. We measured a total of 30 single-walled carbon nanotubes including both semiconducting and metallic nanotubes and found that their absolute chiroptical signals show a distinct structure dependence, which can be qualitatively understood through tight-binding calculations. Our strategy enables the exploration of handedness-related functionality of single nanotubes and provides a facile platform for chiral discrimination and chiral device exploration at the level of individual nanomaterials.As the most primordial signaling pathway in animal physiology, the Hippo pathway and innate immunity play crucial roles not only in sensing cellular conditions or infections, but also in various metabolite homeostasis and tumorigenesis. However, the correlation between cellular homeostasis and antiviral defense is not well understood. The core kinase LATS1/2, could either enhance or inhibit the anti-tumor immunity in different cellular contexts. In this study, we found that LATS2 can interact with PQBP1, the co-factor of cGAS, thus enhanced the cGAS-STING mediated innate immune response to HIV-1 challenge. LATS2 was observed to upregulate type-I interferon (IFN-I) and cytokines in response to HIV-1 reverse-transcribed DNA and inhibited HIV-1 infection. Due to the involvement of PQBP1, the function of LATS2 in regulating cGAS activity is not relying on the downstream YAP/TAZ as that in the canonical Hippo pathway. The related kinase activity of LATS2 was verified, and the potential phosphorylation site of PQBP1 was identified. Our study established a novel connection between Hippo signaling and innate immunity, thus may provide new potential intervention target on antiviral therapeutics.Due to the favorable test characteristics of the non-invasive prenatal test (NIPT) in the screening of fetal aneuploidy, there has been a strong and growing demand for implementation. In the Netherlands, NIPT is offered within a governmentally supported screening program as a first-tier screening test for all pregnant women (TRIDENT-2 study). However, concerns have been raised that the test's favorable characteristics might lead to uncritical use, also referred to as routinization. This study addresses women's perspectives on prenatal screening with NIPT by evaluating three aspects related to routinization informed choice, freedom to choose and (personal and societal) perspectives on Down syndrome. Nationwide, a questionnaire was completed by 751 pregnant women after receiving counseling for prenatal screening. Of the respondents, the majority (75.5%) made an informed choice for prenatal screening as measured by the multidimensional measure of informed choice (MMIC). Education level and religious affiliation were significant predictors of informed choice. The main reason to accept screening was "seeking reassurance" (25.5%), and the main reason to decline was "every child is welcome" (30.6%). The majority of respondents (87.7%) did not perceive societal pressure to test. Differences between test-acceptors and test-decliners in personal and societal perspectives on Down syndrome were found. Our study revealed high rates of informed decision-making and perceived freedom to choose regarding fetal aneuploidy screening, suggesting that there is little reason for concern about routinization of NIPT based on the perspectives of Dutch pregnant women. Our findings highlight the importance of responsible implementation of NIPT within a national screening program.

Alternative splicing plays a critical role in mouse neurodevelopment, regulating neurogenesis, cortical lamination, and synaptogenesis, yet few human neurodevelopmental disorders are known to result from pathogenic variation in splicing regulator genes. Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a ubiquitously expressed splicing regulator not known to underlie a Mendelian disorder.

Exome sequencing and rare variant family-based genomics was performed as a part of the Baylor-Hopkins Center for Mendelian Genomics Initiative. learn more Additional families were identified via GeneMatcher.

We identified six patients from three unrelated families with homozygous loss-of-function variants in NSRP1. Clinical features include developmental delay, epilepsy, variable microcephaly (Z-scores -0.95 to -5.60), hypotonia, and spastic cerebral palsy. Brain abnormalities included simplified gyral pattern, underopercularization, and/or vermian hypoplasia. Molecular analysis identified three pathogenic NSRP1 predicted loss-of-function variant alleles c.1359_1362delAAAG (p.Glu455AlafsTer20), c.1272dupG (p.Lys425GlufsTer5), and c.52C>T (p.Gln18Ter). The two frameshift variants result in a premature termination codon in the last exon, and the mutant transcripts are predicted to escape nonsense mediated decay and cause loss of a C-terminal nuclear localization signal required for NSRP1 function.

We establish NSRP1 as a gene for a severe autosomal recessive neurodevelopmental disease trait characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.

We establish NSRP1 as a gene for a severe autosomal recessive neurodevelopmental disease trait characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.

We evaluated the impact of personal melanoma genomic risk information on sun-related behaviors and psychological outcomes.

In this parallel group, open, randomized controlled trial, 1,025 Australians of European ancestry without melanoma and aged 18-69 years were recruited via the Medicare database (3% consent). Participants were randomized to the intervention (n = 513; saliva sample for genetic testing, personalized melanoma risk booklet based on a 40-variant polygenic risk score, telephone-based genetic counseling, educational booklet) or control (n = 512; educational booklet). Wrist-worn ultraviolet (UV) radiation dosimeters (10-day wear) and questionnaires were administered at baseline, 1 month postintervention, and 12 months postbaseline.

At 12 months, 948 (92%) participants completed dosimetry and 973 (95%) the questionnaire. For the primary outcome, there was no effect of the genomic risk intervention on objectively measured UV exposure at 12 months, irrespective of traditional risk factors. For secondary outcomes at 12 months, the intervention reduced sunburns (risk ratio 0.