Hallmarks of neurodegenerative diseases.

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks of NDD: pathological protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. We describe the hallmarks, their biomarkers, and their interactions as a framework to study NDDs using a holistic approach. The framework can serve as a basis for defining pathogenic mechanisms, categorizing different NDDs based on their primary hallmarks, stratifying patients within a specific NDD, and designing multi-targeted, personalized therapies to effectively halt NDDs.

Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures.

The urea cycle (UC) is the main pathway by which mammals dispose of waste nitrogen. We find that specific alterations in the expression of most UC enzymes occur in many tumors, leading to a general metabolic hallmark termed "UC dysregulation" (UCD). UCD elicits nitrogen diversion toward carbamoyl-phosphate synthetase2, aspartate transcarbamylase, and dihydrooratase (CAD) activation and enhances pyrimidine synthesis, resulting in detectable changes in nitrogen metabolites in both patient tumors and their bio-fluids. The accompanying excess of pyrimidine versus purine nucleotides results in a genomic signature consisting of transversion mutations at the DNA, RNA, and protein levels. This mutational bias is associated with increased numbers of hydrophobic tumor antigens and a better response to immune checkpoint inhibitors independent of mutational load. Taken together, our findings demonstrate that UCD is a common feature of tumors that profoundly affects carcinogenesis, mutagenesis, and immunotherapy response.

Supramolecular assembly of polycation/mRNA nanoparticles and in vivo monocyte programming.

Size-dependent phagocytosis is a well-characterized phenomenon in monocytes and macrophages. However, this size effect for preferential gene delivery to these important cell targets has not been fully exploited because commonly adopted stabilization methods for electrostatically complexed nucleic acid nanoparticles, such as PEGylation and charge repulsion, typically arrest the vehicle size below 200 nm. Here, we bridge the technical gap in scalable synthesis of larger submicron gene delivery vehicles by electrostatic self-assembly of charged nanoparticles, facilitated by a polymer structurally designed to modulate internanoparticle Coulombic and van der Waals forces. Specifically, our strategy permits controlled assembly of small poly(ß-amino ester)/messenger ribonucleic acid (mRNA) nanoparticles into particles with a size that is kinetically tunable between 200 and 1,000 nm with high colloidal stability in physiological media. We found that assembled particles with an average size of 400 nm safely and most efficiently transfect monocytes following intravenous administration and mediate their differentiation into macrophages in the periphery. When a CpG adjuvant is co-loaded into the particles with an antigen mRNA, the monocytes differentiate into inflammatory dendritic cells and prime adaptive anticancer immunity in the tumor-draining lymph node. This platform technology offers a unique ligand-independent, particle-size-mediated strategy for preferential mRNA delivery and enables therapeutic paradigms via monocyte programming.

Long-term outcomes of pulmonary embolism in children and adolescents.

ABSTRACT: Knowledge regarding the long-term consequences of pulmonary embolism (PE) in children is limited. This cohort study describes the long-term outcomes of PE in children who were followed-up at a single-center institution using a local protocol that included clinical evaluation, chest imaging, echocardiography, pulmonary function tests, and cardiopulmonary exercise tests at follow-up, starting 3 to 6 months after acute PE. Children objectively diagnosed with PE at age 0 to 18 years, who had ≥6 months of follow-up were included. Study outcomes consisted of PE resolution, PE recurrence, death, and functional outcomes (dyspnea, impaired pulmonary or cardiac function, impaired aerobic capacity, and post-PE syndrome). The frequency of outcomes was compared between patients with/without underlying conditions. In total, 150 patients were included; median age at PE was 16 years (25th-75th percentile, 14-17 years); 61% had underlying conditions. PE did not resolve in 29%, recurrence happened in 9%, and death in 5%. One-third of patients had at least 1 documented abnormal functional finding at follow-up (ventilatory impairments, 31%; impaired aerobic capacity, 31%; dyspnea, 26%; and abnormal diffusing capacity of the lungs to carbon monoxide, 22%). Most abnormalities were transient. When alternative explanations for the impairments were considered, the frequency of post-PE syndrome was lower, ranging between 0.7% and 8.5%. Patients with underlying conditions had significantly higher recurrence, more pulmonary function and ventilatory impairments, and poorer exercise capacity. Exercise intolerance was, in turn, most frequently because of deconditioning than to respiratory or cardiac limitation, highlighting the importance of physical activity promotion in children with PE.

Preclinical efficacy of the potent, selective menin-KMT2A inhibitor JNJ-75276617 (bleximenib) in KMT2A- and NPM1-altered leukemias.

ABSTRACT: The interaction between menin and histone-lysine N-methyltransferase 2A (KMT2A) is a critical dependency for KMT2A- or nucleophosmin 1 (NPM1)-altered leukemias and an emerging opportunity for therapeutic development. JNJ-75276617 (bleximenib) is a novel, orally bioavailable, potent, and selective protein-protein interaction inhibitor of the binding between menin and KMT2A. In KMT2A-rearranged (KMT2A-r) and NPM1-mutant (NPM1c) acute myeloid leukemia (AML) cells, JNJ-75276617 inhibited the association of the menin-KMT2A complex with chromatin at target gene promoters, resulting in reduced expression of several menin-KMT2A target genes, including MEIS1 and FLT3. JNJ-75276617 displayed potent antiproliferative activity across several AML and acute lymphoblastic leukemia (ALL) cell lines and patient samples harboring KMT2A or NPM1 alterations in vitro. In xenograft models of AML and ALL, JNJ-75276617 reduced leukemic burden and provided a significant dose-dependent survival benefit accompanied by expression changes of menin-KMT2A target genes. JNJ-75276617 demonstrated synergistic effects with gilteritinib in vitro in AML cells harboring KMT2A-r. JNJ-75276617 further exhibited synergistic effects with venetoclax and azacitidine in AML cells bearing KMT2A-r in vitro, and significantly increased survival in mice. Interestingly, JNJ-75276617 showed potent antiproliferative activity in cell lines engineered with recently discovered mutations (MEN1M327I or MEN1T349M) that developed in patients refractory to the menin-KMT2A inhibitor revumenib. A cocrystal structure of menin in complex with JNJ-75276617 indicates a unique binding mode distinct from other menin-KMT2A inhibitors, including revumenib. JNJ-75276617 is being clinically investigated for acute leukemias harboring KMT2A or NPM1 alterations, as a monotherapy for relapsed/refractory acute leukemia (NCT04811560), or in combination with AML-directed therapies (NCT05453903).

Multilevel cultural evolution: From new theory to practical applications.

Evolutionary science has led to many practical applications of genetic evolution but few practical uses of cultural evolution. This is because the entire study of evolution was gene centric for most of the 20th century, relegating the study and application of human cultural change to other disciplines. The formal study of human cultural evolution began in the 1970s and has matured to the point of deriving practical applications. We provide an overview of these developments and examples for the topic areas of complex systems science and engineering, economics and business, mental health and well-being, and global change efforts.

Structural analysis of a U-superfamily conotoxin containing a mini-granulin fold: Insights into key features that distinguish between the ICK and granulin folds.

We are entering an exciting time in structural biology where artificial intelligence can be used to predict protein structures with greater accuracy than ever before. Extending this level of accuracy to the predictions of disulfide-rich peptide structures is likely to be more challenging, at least in the short term, given the tight packing of cysteine residues and the numerous ways that the disulfide bonds can potentially be linked. It has been previously shown in many cases that several disulfide bond connectivities can be accommodated by a single set of NMR-derived structural data without significant violations. Disulfide-rich peptides are prevalent throughout nature, and arguably the most well-known are those present in venoms from organisms such as cone snails. Here, we have determined the first three-dimensional structure and disulfide connectivity of a U-superfamily cone snail venom peptide, TxVIIB. TxVIIB has a VI/VII cysteine framework that is generally associated with an inhibitor cystine knot (ICK) fold; however, AlphaFold predicted that the peptide adopts a mini-granulin fold with a granulin disulfide connectivity. Our experimental studies using NMR spectroscopy and orthogonal protection of cysteine residues indicate that TxVIIB indeed adopts a mini-granulin fold but with the ICK disulfide connectivity. Our findings provide structural insight into the underlying features that govern formation of the mini-granulin fold rather than the ICK fold and will provide fundamental information for prediction algorithms, as the subtle complexity of disulfide isomers may be not adequately addressed by the current prediction algorithms.

Long-term outcomes of a decentralized, nurse-led, statewide model of care for hepatitis C among people in prison in Victoria, Australia.

BACKGROUND: Prisons provide a key strategic opportunity to upscale hepatitis C testing and treatment in a high prevalence setting and are crucial for elimination efforts. METHODS: A decentralized, statewide nurse-led model of care offering hepatitis C treatment for people in prison was implemented in Victoria, Australia in 2015. The program provides hepatitis C care to all 14 adult prison sites in the jurisdiction. We prospectively evaluated treatment uptake between 1 November 2015 and 31 December 2021. Data on all people in prison treated were recorded in a clinical database. The primary outcomes were i) total number of people in prison with hepatitis C treated; ii) total number of DAA treatment courses. RESULTS: 3,133 DAA treatment courses were prescribed to 2,768 people in prison. The proportion of total Victoria DAA prescriptions the program was responsible for increased from 6% in 2016 to a peak of 23% in 2020. Of those treated, median age was 39 years, 91% were male and 9% had cirrhosis. Few (20%) had previously engaged in hepatitis C care in the community and at first treatment course in prison, only 6% had previously accessed hepatitis C treatment. Complete follow up data were available for 1,757/2,768 (63%) treated, with 1,627/1,757 (93%) achieving SVR12. CONCLUSIONS: A decentralized, nurse-led, statewide model of care was highly effective in treating large numbers of people in prison with hepatitis C and achieved high rates of SVR12. Nurse-led prison programs are playing a crucial role in eliminating hepatitis C as a public health threat in Australia.

Unlocking Biradical Character in Diborepins.

Systems that possess open- and closed-shell behavior attract significant attention from researchers due to their inherent redox and charge transport properties. Herein, we report the synthesis of the first diborepin biradicals. They display tunable biradical character based on the steric and electronic profile of the stabilizing ligand and the resulting geometric deviation of the diborepin core from planarity. While there are numerous all-carbon-based biradical systems, boron-based biradical compounds are comparatively rare, particularly ones in which the radical sites are disjointed. Calculations using density functional theory (DFT) and multireference methods demonstrate that the fused diborepin scaffold exhibits high biradical character, up to 95%. Use of a nonsterically demanding diaminocarbene promotes the planarization of the pentacyclic framework, resulting in the synthetic realization of a diborepin containing a dibora-quinoidal core, which possesses a closed-shell ground state and thermally accessible triplet state. The biradicals were structurally authenticated and characterized by both solution and solid-state electron paramagnetic resonance (EPR) spectroscopy. Half-field transitions were observed at low temperatures (about 170 K), confirming the presence of the triplet state. Initial reactivity studies of the biradicals led to the isolation and structural characterization of bis(borepin hydride) and bis(borepin dianion).

Unveiling Three Interconvertible Redox States of Boraphenalene.

Neutral 1-boraphenalene displays the isoelectronic structure of the phenalenyl carbocation and is expected to behave as an attractive organoboron multi-redox system. However, the isolation of new redox states have remained elusive even though the preparation of neutral boron(III)-containing phenalene compounds have been extensively studied. Herein, we have adopted an N-heterocyclic carbene ligand stabilization approach to achieve the first isolation of the stable and ambipolar 1-boraphenalenyl radical 1•. The 1-boraphenalenyl cation 1+ and anion 1- have also been electrochemically observed and chemically isolated, representing new redox forms of boraphenalene for the study of non-Kekulé polynuclear benzenoid molecules. Experimental and theoretical investigations suggest that the interconvertible three-redox-state species undergo reversible electronic structure modifications, which primarily take place on the polycyclic framework of the molecules, exhibiting atypical behavior compared to known donor-stabilized organoboron compounds. Initial reactivity studies, aromaticity evaluations, and photophysical studies show redox-state-dependent trends. While 1+ is luminescent in both the solution and solid states, 1• exhibits boron-centered reactivity and 1- undergoes substitution chemistry on the boraphenalenyl skeleton and serves as a single-electron transfer reductant.

Radiomics analysis to predict pulmonary nodule malignancy using machine learning approaches.

BACKGROUND: Low-dose CT screening can reduce lung cancer-related mortality. However, most screen-detected pulmonary abnormalities do not develop into cancer and it often remains challenging to identify malignant nodules, particularly among indeterminate nodules. We aimed to develop and assess prediction models based on radiological features to discriminate between benign and malignant pulmonary lesions detected on a baseline screen. METHODS: Using four international lung cancer screening studies, we extracted 2060 radiomic features for each of 16 797 nodules (513 malignant) among 6865 participants. After filtering out low-quality radiomic features, 642 radiomic and 9 epidemiological features remained for model development. We used cross-validation and grid search to assess three machine learning (ML) models (eXtreme Gradient Boosted Trees, random forest, least absolute shrinkage and selection operator (LASSO)) for their ability to accurately predict risk of malignancy for pulmonary nodules. We report model performance based on the area under the curve (AUC) and calibration metrics in the held-out test set. RESULTS: The LASSO model yielded the best predictive performance in cross-validation and was fit in the full training set based on optimised hyperparameters. Our radiomics model had a test-set AUC of 0.93 (95% CI 0.90 to 0.96) and outperformed the established Pan-Canadian Early Detection of Lung Cancer model (AUC 0.87, 95% CI 0.85 to 0.89) for nodule assessment. Our model performed well among both solid (AUC 0.93, 95% CI 0.89 to 0.97) and subsolid nodules (AUC 0.91, 95% CI 0.85 to 0.95). CONCLUSIONS: We developed highly accurate ML models based on radiomic and epidemiological features from four international lung cancer screening studies that may be suitable for assessing indeterminate screen-detected pulmonary nodules for risk of malignancy.

Emerging Strategies to Prevent Bacterial Infections on Titanium-Based Implants.

Titanium and titanium alloys remain the gold standard for dental and orthopedic implants. These materials are heavily used because of their bioinert nature, robust mechanical properties, and seamless integration with bone. However, implant-associated infections (IAIs) remain one of the leading causes of implant failure. Eradicating an IAI can be difficult since bacteria can form biofilms on the medical implant, protecting the bacterial cells against systemic antibiotics and the host's immune system. If the infection is not treated promptly and aggressively, device failure is inevitable, leading to costly multi-step revision surgeries. To circumvent this dire situation, scientists and engineers continue to develop novel strategies to protect the surface of medical implants from bacteria. In this review, details on emerging strategies to prevent infection in titanium implants are reported. These strategies include anti-adhesion properties provided by polymers, superhydrophobic, superhydrophilic, and liquid-infused surface coatings, as well as strategies and coatings employed to lyse the bacteria. Additionally, commercially available technologies and those under preclinical trials are examined while discussing current and future trends.

Bioorthogonal Radiolabeling of Azide-Modified Bacteria Using [18F]FB-sulfo-DBCO.

Purpose: This study was motivated by the need for better positron emission tomography (PET)-compatible tools to image bacterial infection. Our previous efforts have targeted bacteria-specific metabolism via assimilation of carbon-11 labeled d-amino acids into the bacterial cell wall. Since the chemical determinants of this incorporation are not fully understood, we sought a high-throughput method to label d-amino acid derived structures with fluorine-18. Our strategy employed a chemical biology approach, whereby an azide (-N3) bearing d-amino acid is incorporated into peptidoglycan muropeptides, with subsequent "click" cycloaddition with an 18F-labeled strained cyclooctyne partner. Procedures: A water-soluble, 18F-labeled and dibenzocyclooctyne (DBCO)-derived radiotracer ([18F]FB-sulfo-DBCO) was synthesized. This tracer was incubated with pathogenic bacteria treated with azide-bearing d-amino acids, and incorporated 18F was determined via gamma counting. In vitro uptake in bacteria previously treated with azide-modified d-amino acids was compared to that in cultures treated with amino acid controls. The biodistribution of [18F]FB-sulfo-DBCO was studied in a cohort of healthy mice with implications for future in vivo imaging. Results: The new strain-promoted azide-alkyne cycloaddition (SPAAC) radiotracer [18F]FB-sulfo-DBCO was synthesized with high radiochemical yield and purity via N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB). Accumulation of [18F]FB-sulfo-DBCO was significantly higher in several bacteria treated with azide-modified d-amino acids than in controls; for example, we observed 7 times greater [18F]FB-sulfo-DBCO ligation in Staphylococcus aureus cultures incubated with 3-azido-d-alanine versus those incubated with d-alanine. Conclusions: The SPAAC radiotracer [18F]FB-sulfo-DBCO was validated in vitro via metabolic labeling of azide-bearing peptidoglycan muropeptides. d-Amino acid-derived PET radiotracers may be more efficiently screened via [18F]FB-sulfo-DBCO modification.

Synthesis and Structure Optimization of Star Copolymers as Tunable Macromolecular Carriers for Minimal Immunogen Vaccine Delivery.

Minimal immunogen vaccines are being developed to focus antibody responses against otherwise challenging targets, including human immunodeficiency virus (HIV), but multimerization of the minimal peptide immunogen on a carrier platform is required for activity. Star copolymers comprising multiple hydrophilic polymer chains ("arms") radiating from a central dendrimer unit ("core") were recently reported to be an effective platform for arraying minimal immunogens for inducing antibody responses in mice and primates. However, the impact of different parameters of the star copolymer (e.g., minimal immunogen density and hydrodynamic size) on antibody responses and the optimal synthetic route for controlling those parameters remains to be fully explored. We synthesized a library of star copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide] hydrophilic arms extending from poly(amidoamine) dendrimer cores with the aim of identifying the optimal composition for use as minimal immunogen vaccines. Our results show that the length of the polymer arms has a crucial impact on the star copolymer hydrodynamic size and is precisely tunable over a range of 20-50 nm diameter, while the dendrimer generation affects the maximum number of arms (and therefore minimal immunogens) that can be attached to the surface of the dendrimer. In addition, high-resolution images of selected star copolymer taken by a custom-modified environmental scanning electron microscope enabled the acquisition of high-resolution images, providing new insights into the star copolymer structure. Finally, in vivo studies assessing a star copolymer vaccine comprising an HIV minimal immunogen showed the criticality of polymer arm length in promoting antibody responses and highlighting the importance of composition tunability to yield the desired biological effect.

Scalar and Tensor Charmonium Resonances in Coupled-Channel Scattering from Lattice QCD.

We determine J^{PC}=0^{++} and 2^{++} hadron-hadron scattering amplitudes in the charmonium energy region up to 4100 MeV using lattice QCD, a first-principles approach to QCD. Working at m_{π}≈391 MeV, more than 200 finite-volume energy levels are computed and these are used in extensions of the Lüscher formalism to determine infinite-volume coupled-channel scattering amplitudes. We find that this energy region contains a single χ_{c0} and a single χ_{c2} resonance. Both are found as pole singularities on the closest unphysical Riemann sheet, just below 4000 MeV with widths around 70 MeV. The largest couplings are to kinematically closed D^{*}D[over ¯]^{*} channels in S-wave, and couplings to several decay channels consisting of pairs of open-charm mesons are found to be large and significant in both cases. Above the ground state χ_{c0}, no other scalar bound states or near-DD[over ¯] threshold resonances are found, in contrast to several theoretical and experimental studies.

Prediction of Covalent Metal-Metal Bonding in Cp-M-M'-Nacnac Complexes of Group 2 and 12 Metals (Be, Mg, Ca, Zn, Cd, Hg).

Bimetallic CpMM'Nacnac molecules with group 2 and 12 metals (M=Be, Mg, Ca, Zn, Cd, Hg) that contain novel metal-metal bonding have been investigated in a theoretical study of their molecular and electronic structure, thermodynamic stability, and metal-metal bonding. In all cases the metal-metal bonds are characterized as electron-sharing covalent single bonds from natural bond orbital (NBO) and energy-decomposition analysis with natural orbitals of chemical valence (EDA-NOCV) analysis. The sum of [MM'] charges is relatively constant, with all complexes exhibiting a [MM']2+ core. Quantum theory of atoms in molecules (QTAIM) analysis indicates the presence of non-nuclear attractors (NNA) in the metal-metal bonds of the BeBe, MgMg, and CaCa complexes. There is substantial electron density (0.75-1.33 e) associated with the NNAs, which indicates that these metal-metal bonds, while classified as covalent electron-sharing bonds, retain significant metallic character that can be associated with reducing reactivity of the complex. The predicted stability of these complexes, combined with their novel covalent metal-metal bonding and potential as reducing agents, make them appealing targets for the synthesis of new metal-metal bonds.

Direct C4 and C2 C-H Amination of Heteroarenes Using I(III) Reagents via a Cross Azine Coupling.

Aminated nitrogen heterocycles are valuable motifs across numerous chemical industries, perhaps most notably in small molecule drug discovery. While numerous strategies for installing nitrogen atoms onto azaarenes exist, most require prefunctionalization and methods for direct C-H amination are almost entirely limited to position C2. Herein, we report a method for the direct C2 and C4 C-H amination of fused azaarenes via in situ activation with a bispyridine-ligated I(III) reagent, [(Py)2IPh]2OTf, or Py-HVI. Unlike commonly used N-oxide chemistry, the method requires no preoxidation of the azaarene and provides unprecedented direct access to C4 amination products. The resulting N-heterocyclic pyridinium salts can be isolated via simple trituration. The free amine can be liberated under mild Zincke aminolysis, or the amination and cleavage can be telescoped to a one-pot process. The scope of the method is broad; the conditions are mild and operationally simple, and the aminated products are produced in good to excellent yields. Computational studies provide insights into the mechanism of activation, which involves an unusual direct nucleophilic functionalization of an I(III) ligand, as well as a kinetic basis for the observed C2 and C4 amination products.

Mono- and Bis-Phosphine Promoted Incorporation of Boron, Nitrogen, and Phosphorus into Heterocycles via Staudinger Reactions of Borafluorene Azides.

We report the synthesis and characterization of a series of BNP-incorporated borafluorenate heterocycles formed via thermolysis reactions of pyridylphosphine and bis(phosphine)-coordinated borafluorene azides. The use of diphenyl-2-pyridylphosphine (PyPh2P), trans-1,2-bis(diphenylphosphino)ethylene (Ph2P(H)C═C(H)PPh2), and bis(diphenylphosphino)methane (Ph2PC(H2)PPh2) as stabilizing ligands resulted in Staudinger reactions to form complex heterocycles with four- (BN2P, BNPC, P2N2) and five-membered (BNP2C and BN2PC) rings, which were successfully isolated and fully characterized by multinuclear NMR and X-ray crystallography. However, when bis(diphenylphosphino)benzene (Ph2P-Ph-PPh2) was used as the ligand in a reaction with 9-bromo-9-borafluorene (BF-Br), due to the close proximity of the donor P atoms, the diphosphine-stabilized borafluoronium ion with an unusual borafluorene dibromide anion was formed. Reaction of the borafluoronium ion with trimethylsilyl azide left the cation intact, and the dibromide anion was substituted by a diazide. Density functional theory calculations were used to provide mechanistic insight into the formation of these new boracyclic compounds. This work highlights a new method in which donor phosphine ligands may be used to promote dimerization, cyclization, and ring contraction reactions to produce boracycles via Staudinger reactions.

Development and multi-center validation of a fully automated digital immunoassay for neurofilament light chain: toward a clinical blood test for neuronal injury.

OBJECTIVES: Neurofilament light chain (NfL) has emerged as a promising biomarker for detecting and monitoring axonal injury. Until recently, NfL could only be reliably measured in cerebrospinal fluid, but digital single molecule array (Simoa) technology has enabled its precise measurement in blood samples where it is typically 50-100 times less abundant. We report development and multi-center validation of a novel fully automated digital immunoassay for NfL in serum for informing axonal injury status. METHODS: A 45-min immunoassay for serum NfL was developed for use on an automated digital analyzer based on Simoa technology. The analytical performance (sensitivity, precision, reproducibility, linearity, sample type) was characterized and then cross validated across 17 laboratories in 10 countries. Analytical performance for clinical NfL measurement was examined in individual patients with relapsing remitting multiple sclerosis (RRMS) after 3 months of disease modifying treatment (DMT) with fingolimod. RESULTS: The assay exhibited a lower limit of detection (LLoD) of 0.05 ng/L, a lower limit of quantification (LLoQ) of 0.8 ng/L, and between-laboratory imprecision <10 % across 17 validation sites. All tested samples had measurable NfL concentrations well above the LLoQ. In matched pre-post treatment samples, decreases in NfL were observed in 26/29 RRMS patients three months after DMT start, with significant decreases detected in a majority of patients. CONCLUSIONS: The sensitivity characteristics and reproducible performance across laboratories combined with full automation make this assay suitable for clinical use for NfL assessment, monitoring in individual patients, and cross-comparisons of results across multiple sites.

Ice loss from the East Antarctic Ice Sheet during late Pleistocene interglacials.

Understanding ice sheet behaviour in the geological past is essential for evaluating the role of the cryosphere in the climate system and for projecting rates and magnitudes of sea level rise in future warming scenarios1-4. Although both geological data5-7 and ice sheet models3,8 indicate that marine-based sectors of the East Antarctic Ice Sheet were unstable during Pliocene warm intervals, the ice sheet dynamics during late Pleistocene interglacial intervals are highly uncertain3,9,10. Here we provide evidence from marine sedimentological and geochemical records for ice margin retreat or thinning in the vicinity of the Wilkes Subglacial Basin of East Antarctica during warm late Pleistocene interglacial intervals. The most extreme changes in sediment provenance, recording changes in the locus of glacial erosion, occurred during marine isotope stages 5, 9, and 11, when Antarctic air temperatures11 were at least two degrees Celsius warmer than pre-industrial temperatures for 2,500 years or more. Hence, our study indicates a close link between extended Antarctic warmth and ice loss from the Wilkes Subglacial Basin, providing ice-proximal data to support a contribution to sea level from a reduced East Antarctic Ice Sheet during warm interglacial intervals. While the behaviour of other regions of the East Antarctic Ice Sheet remains to be assessed, it appears that modest future warming may be sufficient to cause ice loss from the Wilkes Subglacial Basin.