Accurate structure prediction of biomolecular interactions with AlphaFold 3.

The introduction of AlphaFold 21 has spurred a revolution in modelling the structure of proteins and their interactions, enabling a huge range of applications in protein modelling and design2-6. In this paper, we describe our AlphaFold 3 model with a substantially updated diffusion-based architecture, which is capable of joint structure prediction of complexes including proteins, nucleic acids, small molecules, ions, and modified residues. The new AlphaFold model demonstrates significantly improved accuracy over many previous specialised tools: far greater accuracy on protein-ligand interactions than state of the art docking tools, much higher accuracy on protein-nucleic acid interactions than nucleic-acid-specific predictors, and significantly higher antibody-antigen prediction accuracy than AlphaFold-Multimer v2.37,8. Together these results show that high accuracy modelling across biomolecular space is possible within a single unified deep learning framework.

Prescription Drug Prices: An AAN Position Statement.

This position statement serves to establish the AAN's stance on the methods to address the cost of prescription drugs being considered by state and federal policymakers so that the AAN can continue to advocate effectively for its members. Neurologists seek to provide high-value care for patients with neurologic diseases at the lowest cost possible. However, many therapies for neurologic diseases are among the most expensive in the United States. The 3 major cost challenges include (1) unjustified increases in the pricing for drugs used to treat neurologic disorders, (2) the high cost of medications used to treat rare diseases where there are limited or no therapeutic options available, and (3) the high cost of noninnovative (already FDA-approved) therapies that used accelerated FDA approval pathways or Orphan Drug Act designated to expedite approvals in neurologic disorders. In each of these cases, AAN is concerned that the high cost does not deliver sufficient value to patients or society. The AAN's position is that action must be taken to ensure that effective prescription medications are accessible for patients with complex, chronic neurologic conditions. Potential solutions should be affordable, simple, and transparent. Cost-containment efforts must also address the burden on the entire healthcare system because high prescription drug prices may be shifted and absorbed in ways that negatively affect patient and prescriber access to important medications. AAN supports price negotiations, the cost saving potential of generics and biosimilars, development of novel therapeutics, price transparency, and importation.

The Brain Health Imperative in the 21st Century-A Call to Action: The AAN Brain Health Platform and Position Statement.

Brain health is crucial to optimizing both the function and well-being of every person at each stage of life and is key to both individual and social progress. As a concept, brain health is complex and requires a multidisciplinary collaborative approach between many professional and public organizations to bring into effect meaningful change. Neurologists are uniquely positioned to serve as specialists in brain health and to advance the newly evolving field of preventive neurology, which aims to identify individuals at high risk of brain disorders and other neurologic conditions and offer strategies to mitigate disease emergence or progression. For decades, the American Academy of Neurology (AAN) has demonstrated a commitment to brain health through its public outreach and advocacy. The AAN's Brain Health Initiative launched in 2022 with a strategic plan prioritizing brain health as a key aspect of public engagement and positioning the AAN and neurologists as champions of brain health in collaboration with a broad range of other brain health providers. In this study, we present (1) the new definition of brain health developed by the AAN for neurologists, patients, partners in health care, and the public; (2) the strategic objectives of the AAN Brain Health Initiative; and (3) the AAN Brain Health Platform and Action Plan framework, including key positions on brain health, its 3 ambitious goals, and a national brain health vision. The top-line priorities of the AAN Brain Health Action Plan highlight the need for research, education, public policy, and direct-to-public messaging across the individual's life span and will serve as a catalyst for future cross-disciplinary collaborations within each epoch and longitudinally. The AAN Brain Health Platform is designed to communicate the AAN's vision for brain health and provide a blueprint toward achieving the future of optimal brain health across the life span for all. Through this position statement, we call upon neurologists and other stakeholders in brain health to join our collective efforts to accomplish the ultimate goal of transforming the current trajectory of public health of an increasing burden of neurologic disorders-from both illness and injury-to achieving optimal brain health for all.

Total Synthesis of Aflastatin A.

The total syntheses of aflastatin A and its C3-C48 degradation fragment (6a, R = H) have been accomplished. The syntheses feature several complex diastereoselective fragment couplings, including a Felkin-selective trityl-catalyzed Mukaiyama aldol reaction, a chelate-controlled aldol reaction involving soft enolization with magnesium, and an anti-Felkin-selective boron-mediated oxygenated aldol reaction. Careful comparison of the spectroscopic data for the synthetic C3-C48 degradation fragment to that reported by the isolation group revealed a structural misassignment in the lactol region of the naturally derived degradation product. Ultimately, the data reported for the naturally derived aflastatin A C3-C48 degradation lactol (6a, R = H) were attributed to its derivative lactol trideuteriomethyl ether (6c, R = CD3). Additionally, the revised absolute configurations of six stereogenic centers (C8, C9, and C28-C31) were confirmed.

Gender Discrepancies in Neurologist Compensation.

BACKGROUND AND OBJECTIVES: Previous studies have shown gender disparities in physician pay in various specialties. This retrospective, cross-sectional study evaluated data from the American Academy of Neurology (AAN) Compensation and Productivity Survey for differences in neurologist compensation by gender. METHODS: Of the 3,268 completed surveys submitted, 2,719 were from neurologists and 1,466 had sufficient data for analysis (551 women, 951 men respondents). We calculated an hourly wage from full-time equivalent (FTE) status and weeks worked per year. We evaluated differences in men and women neurologist compensation with multivariable generalized linear models adjusting for race, ethnicity, geographic region, practice setting, years in practice, call status, leadership role, straight salary, and subspecialty. RESULTS: Baseline characteristics for men and women neurologists were similar with the exception of subspecialty distribution. More men were practicing in higher-wage subspecialties compared to women (p < 0.05). Mean FTE annual salary for all neurologists was $280,315, and mean standardized hourly compensation was $131. Estimated annual salary for women was 10.7% less (p ≤ 0.001, 95% confidence interval -4% to -16%) after controlling for race, region, years of practice, practice setting, call status, leadership role, and subspecialty-wage category. FTE annual salary for women neurologists in high-compensation specialties ($281,838) was lower than the mean annual salary for men neurologists in both high-compensation ($365,751) and low-compensation subspecialties ($282,813). When broken down by years of practice, the highest earning women neurologists' mean hourly wage (11-20 years of practice, $128/h) was less than that of all men neurologists except those with 0 to 5 years of practice ($125/h). DISCUSSION: This study, using convenience sample data, adds to the existing body of evidence demonstrating that, despite adjustment for multiple confounding variables, ongoing disparities exist in physician compensation. Despite efforts by professional societies such as the AAN, ongoing systemic issues and barriers exist. Further research into underlying causes and mitigation strategies is recommended; use of probability sampling methods in future research will be important to decrease potential bias and to increase generalizability.

A Late Cretaceous true polar wander oscillation.

True polar wander (TPW), or planetary reorientation, is well documented for other planets and moons and for Earth at present day with satellites, but testing its prevalence in Earth's past is complicated by simultaneous motions due to plate tectonics. Debate has surrounded the existence of Late Cretaceous TPW ca. 84 million years ago (Ma). Classic palaeomagnetic data from the Scaglia Rossa limestone of Italy are the primary argument against the existence of ca. 84 Ma TPW. Here we present a new high-resolution palaeomagnetic record from two overlapping stratigraphic sections in Italy that provides evidence for a ~12° TPW oscillation from 86 to 78 Ma. This observation represents the most recent large-scale TPW documented and challenges the notion that the spin axis has been largely stable over the past 100 million years.

Side chain virtual screening of matched molecular pairs: a PDB-wide and ChEMBL-wide analysis.

Optimization in medicinal chemistry often involves designing replacements for a section of a molecule which aim to retain potency while improving other properties of the compound. In this study, we perform a retrospective analysis using a number of computational methods to identify active side chains amongst a pool of random decoy side chains, mimicking a similar procedure that might be undertaken in a real medicinal chemistry project. We constructed a dataset derived from public ChEMBL and PDB data by identifying all ChEMBL assays where at least one of the compounds tested has also been co-crystallized in the PDB. Additionally, we required that there be at least ten active compounds tested in the same ChEMBL assay that are matched molecular pairs to the crystallized ligand. Using the compiled dataset consisting of sets of compounds from 402 assays, we have tested a number of methods for scoring side chains including Spark, a bioisostere replacement tool from Cresset, molecular docking using Glide from Schrodinger, docking with Smina, as well as other methods. In this work, we present a comparison of the performance of these methods in discriminating active side chains from decoys as well as recommendations for circumstances when different methods should be used.

Paleomagnetic evidence for modern-like plate motion velocities at 3.2 Ga.

The mode and rates of tectonic processes and lithospheric growth during the Archean [4.0 to 2.5 billion years (Ga) ago] are subjects of considerable debate. Paleomagnetism may contribute to the discussion by quantifying past plate velocities. We report a paleomagnetic pole for the ~3180 million year (Ma) old Honeyeater Basalt of the East Pilbara Craton, Western Australia, supported by a positive fold test and micromagnetic imaging. Comparison of the 44°±15° Honeyeater Basalt paleolatitude with previously reported paleolatitudes requires that the average latitudinal drift rate of the East Pilbara was ≥2.5 cm/year during the ~170 Ma preceding 3180 Ma ago, a velocity comparable with those of modern plates. This result is the earliest unambiguous evidence yet uncovered for long-range lithospheric motion. Assuming this motion is due primarily to plate motion instead of true polar wander, the result is consistent with uniformitarian or episodic tectonic processes in place by 3.2 Ga ago.

American Academy of Neurology members' preparedness to treat sexual and gender minorities.

OBJECTIVE: To measure the attitudes and knowledge of American Academy of Neurology (AAN) member neurologists in caring for sexual and gender minority (SGM) patients (e.g., those who identify in the lesbian, gay, bisexual, transgender, queer, or questioning [LGBTQ+] spectrum) to inform future educational offerings. METHODS: A questionnaire was created in an iterative process by the LGBTQ+ Survey Task Force, consisting of 21 questions examining self-reported knowledge, attitudes, and clinical preparedness in caring for SGM patients. Participants responded to each statement with a 5-point Likert scale ("strongly disagree" to "strongly agree"). The survey was distributed via electronic and conventional mail to a random, representative sample of 1,000 AAN members. RESULTS: The response rate was 13.5% (n = 135). Most respondents (60%-66%) were aware of local and national barriers that inhibit SGM individuals from using health care services; the majority (73%-91%) felt comfortable assessing SGM patients. Over half believed sexual orientation (SO) and gender identity (GI) to be social determinants of health (61% and 57%, respectively). Yet a third would not tailor neurologic care based on a patient's SGM identity, and 43% believed that SO/GI has no bearing on the management of neurologic illness. CONCLUSIONS: Most neurologists surveyed were aware of overarching barriers to care experienced by SGM individuals; however, a minority of respondents recognized the intersection of SGM identity with neurologic health. Our results highlight awareness gaps that could be addressed via targeted educational opportunities, ensuring that neurologists provide high-quality neurologic care to patients of all sexual orientations and gender identities.

α-Synuclein-Confocal Nanoscanning (ASYN-CONA), a Bead-Based Assay for Detecting Early-Stage α-Synuclein Aggregation.

α-Synuclein fibrils are considered a hallmark of Parkinson's disease and other synucleinopathies. However, small oligomers that formed during the early stages of α-synuclein aggregation are thought to be the main toxic species causing disease. The formation of α-synuclein oligomers has proven difficult to follow, because of the heterogeneity and transient nature of the species formed. Here, a novel bead-based aggregation assay for monitoring the earliest stages of α-synuclein oligomerization, α-Synuclein-Confocal Nanoscanning (ASYN-CONA), is presented. The α-synuclein A91C single cysteine mutant is modified with a trifunctional chemical tag, which allows simultaneous fluorescent labeling with a green dye (tetramethylrhodamine, TMR) and attachment to microbeads. Beads with bound TMR-labeled α-synuclein are then incubated with a red dye (Cy5)-labeled variant of α-synuclein A91C, and EtOH (20%) to induce aggregation. Aggregation is detected by confocal scanning imaging, below the equatorial plane of the beads, which is known as the CONA technique. On-bead TMR-labeled α-synuclein and aggregated Cy5-labeled α-synuclein from the solution are quantitatively monitored in parallel by detection of fluorescent halos or "rings". α-Synuclein on-bead oligomerization results in a linear increase of red bead ring fluorescence intensity over a period of 5 h. Total internal reflection fluorescence microscopy was performed on oligomers cleaved from the beads, and it revealed that (i) oligomers are sufficiently stable in solution to investigate their composition, consisting of 6 ± 1 monomer units, and (ii) oligomers containing a mean of 15 monomers bind Thioflavin-T. Various known inhibitors of α-synuclein aggregation were used to validate the ASYN-CONA assay for drug screening. Baicalein, curcumin, and rifampicin showed concentration-dependent inhibition of the α-synuclein aggregation and the IC50 (the concentration of the compound at which the maxiumum intensity was reduced by one-half) were calculated.

Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M1 receptors.

BACKGROUND AND PURPOSE: We aimed to identify and develop novel, selective muscarinic M1 receptor agonists as potential therapeutic agents for the symptomatic treatment of Alzheimer's disease. EXPERIMENTAL APPROACH: We developed and utilized a novel M1 receptor occupancy assay to drive a structure activity relationship in a relevant brain region while simultaneously tracking drug levels in plasma and brain to optimize for central penetration. Functional activity was tracked in relevant native in vitro assays allowing translational (rat-human) benchmarking of structure-activity relationship molecules to clinical comparators. KEY RESULTS: Using this paradigm, we identified a series of M1 receptor selective molecules displaying desirable in vitro and in vivo properties and optimized key features, such as central penetration while maintaining selectivity and a partial agonist profile. From these compounds, we selected spiropiperidine 1 (SPP1). In vitro, SPP1 is a potent, partial agonist of cortical and hippocampal M1 receptors with activity conserved across species. SPP1 displays high functional selectivity for M1 receptors over native M2 and M3 receptor anti-targets and over a panel of other targets. Assessment of central target engagement by receptor occupancy reveals SPP1 significantly and dose-dependently occupies rodent cortical M1 receptors. CONCLUSIONS AND IMPLICATIONS: We report the discovery of SPP1, a novel, functionally selective, brain penetrant partial orthosteric agonist at M1 receptors, identified by a novel receptor occupancy assay. SPP1 is amenable to in vitro and in vivo study and provides a valuable research tool to further probe the role of M1 receptors in physiology and disease.

Utilizing the Axon Registry® for quality improvement.

In 2015, the American Academy of Neurology began development of a clinical quality data registry now known as the Axon Registry®. The data collected by the Axon Registry and reported back to participants include performance on a number of quality measures relevant to neurology practice. While the Axon Registry may serve any number of needs for neurology practices, the essential function of the registry is to inform neurologists regarding the quality of their care and provide them with a tool to establish not only performance baselines but progress toward improved quality of care. This article includes 2 case studies of how the Axon Registry has been implemented in neurology practices to date. In the future, implementation of patient-reported outcome data and additional outcome measures will be necessary to expand the reach and effectiveness of the Axon Registry as a quality improvement tool.

Atomic Layer Deposition of Metal Oxide on Nanocellulose for Enabling Microscopic Characterization of Polymer Nanocomposites.

Analysis of cellulose nanocrystals (CNCs) at low volume fractions in polymer nanocomposites through conventional electron microscopy still remains a challenge due to insufficient contrast between CNCs and organic polymer matrices. Herein, a methodology for enhancing the contrast of CNC, through atomic layer deposition (ALD) of alumina (Al2 O3 ) on CNCs is demonstrated. The metal oxide coated CNC allows clear visualization by transmission electron microscopy, when they are dispersed in water and polyol. A coating of about 6 ± 1 nm thick alumina layer on the CNC is achieved after 50 ALD cycles. This also enables the characterization of CNC dispersion/orientation (at 0.2 wt% loading) in an amorphous cellular system rigid polyurethane foam (RPUF), using backscattered electron microscopy with energy-dispersive X-ray spectroscopy. Microscopic analysis of the RPUF with alumina-coated CNC confirms that the predominant alignment of CNC occurs in a direction parallel to the foam rise.

Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases.

The cholinergic signalling system has been an attractive pathway to seek targets for modulation of arousal, cognition, and attention which are compromised in neurodegenerative and neuropsychiatric diseases. The acetylcholine muscarinic receptor M1 and M4 subtypes which are highly expressed in the central nervous system, in cortex, hippocampus and striatum, key areas of cognitive and neuropsychiatric control, have received particular attention. Historical muscarinic drug development yielded first generation agonists with modest selectivity for these two receptor targets over M2 and M3 receptors, the major peripheral sub-types hypothesised to underlie the dose-limiting clinical side effects. More recent compound screening and medicinal chemistry optimization of orthosteric and allosteric agonists, and positive allosteric modulators binding to sites distinct from the highly homologous acetylcholine binding pocket have yielded a collection of highly selective tool compounds for preclinical validation studies. Several M1 selective ligands have progressed to early clinical development and in time will hopefully lead to useful therapeutics for treating symptoms of Alzheimer's disease and related disorders. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'.

Lessons learned in induced fit docking and metadynamics in the Drug Design Data Resource Grand Challenge 2.

Two of the major ongoing challenges in computational drug discovery are predicting the binding pose and affinity of a compound to a protein. The Drug Design Data Resource Grand Challenge 2 was developed to address these problems and to drive development of new methods. The challenge provided the 2D structures of compounds for which the organizers help blinded data in the form of 35 X-ray crystal structures and 102 binding affinity measurements and challenged participants to predict the binding pose and affinity of the compounds. We tested a number of pose prediction methods as part of the challenge; we found that docking methods that incorporate protein flexibility (Induced Fit Docking) outperformed methods that treated the protein as rigid. We also found that using binding pose metadynamics, a molecular dynamics based method, to score docked poses provided the best predictions of our methods with an average RMSD of 2.01 Å. We tested both structure-based (e.g. docking) and ligand-based methods (e.g. QSAR) in the affinity prediction portion of the competition. We found that our structure-based methods based on docking with Smina (Spearman ρ = 0.614), performed slightly better than our ligand-based methods (ρ = 0.543), and had equivalent performance with the other top methods in the competition. Despite the overall good performance of our methods in comparison to other participants in the challenge, there exists significant room for improvement especially in cases such as these where protein flexibility plays such a large role.

Sharing notes with patients: A review of current practice and considerations for neurologists.

Improved patient engagement is a critical consideration in the new payment climate. Releasing progress notes for patients to view may improve patient involvement and engagement in their care. Patients perceive benefit from viewing physician progress notes. As initial studies involved only primary care physicians, specialist physicians may have specific considerations when releasing notes to patients. This article provides a framework for neurologists to implement a note release policy in their practice.

Sleep Medicine Coding and Coverage Guidelines.

Successful sleep billing and reimbursement is dependent on correct reporting of proper diagnostic codes for sleep disorders and associated testing. Recent changes in disease classification systems have affected the coding for sleep disorders. Guidelines set forth by the American Academy of Sleep Medicine and followed by third-party payers provide direction for the required techniques and indications for sleep procedures.

Advancing Precambrian palaeomagnetism with the PALEOMAGIA and PINT(QPI) databases.

State-of-the-art measurements of the direction and intensity of Earth's ancient magnetic field have made important contributions to our understanding of the geology and palaeogeography of Precambrian Earth. The PALEOMAGIA and PINT(QPI) databases provide thorough public collections of important palaeomagnetic data of this kind. They comprise more than 4,100 observations in total and have been essential in supporting our international collaborative efforts to understand Earth's magnetic history on a timescale far longer than that of the present Phanerozoic Eon. Here, we provide an overview of the technical structure and applications of both databases, paying particular attention to recent improvements and discoveries.

Polypharmacological in Silico Bioactivity Profiling and Experimental Validation Uncovers Sedative-Hypnotic Effects of Approved and Experimental Drugs in Rat.

In this work, we describe the computational ("in silico") mode-of-action analysis of CNS-active drugs, which is taking both multiple simultaneous hypotheses as well as sets of protein targets for each mode-of-action into account, and which was followed by successful prospective in vitro and in vivo validation. Using sleep-related phenotypic readouts describing both efficacy and side effects for 491 compounds tested in rat, we defined an "optimal" (desirable) sleeping pattern. Compounds were subjected to in silico target prediction (which was experimentally confirmed for 21 out of 28 cases), followed by the utilization of decision trees for deriving polypharmacological bioactivity profiles. We demonstrated that predicted bioactivities improved classification performance compared to using only structural information. Moreover, DrugBank molecules were processed via the same pipeline, and compounds in many cases not annotated as sedative-hypnotic (alcaftadine, benzatropine, palonosetron, ecopipam, cyproheptadine, sertindole, and clopenthixol) were prospectively validated in vivo. Alcaftadine, ecopipam cyproheptadine, and clopenthixol were found to promote sleep as predicted, benzatropine showed only a small increase in NREM sleep, whereas sertindole promoted wakefulness. To our knowledge, the sedative-hypnotic effects of alcaftadine and ecopipam have not been previously discussed in the literature. The method described extends previous single-target, single-mode-of-action models and is applicable across disease areas.