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Age‐related central neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are a rising public health concern and have been plagued by repeated drug development failures. The complex nature and poor mechanistic understanding of the etiology of neurodegenerative diseases has hindered the discovery and development of effective disease‐modifying therapeutics. Quantitative systems pharmacology models of neurodegeneration diseases may be useful tools to enhance the understanding of pharmacological intervention strategies and to reduce drug attrition rates. Due to the similarities in pathophysiological mechanisms across neurodegenerative diseases, especially at the cellular and molecular levels, we envision the possibility of structural components that are conserved across models of neurodegenerative diseases. Conserved structural submodels can be viewed as building blocks that are pieced together alongside unique disease components to construct quantitative systems pharmacology (QSP) models of neurodegenerative diseases. Model parameterization would likely be different between the different types of neurodegenerative diseases as well as individual patients. Formulating our mechanistic understanding of neurodegenerative pathophysiology as a mathematical model could aid in the identification and prioritization of drug targets and combinatorial treatment strategies, evaluate the role of patient characteristics on disease progression and therapeutic response, and serve as a central repository of knowledge. Here, we provide a background on neurodegenerative diseases, highlight hallmarks of neurodegeneration, and summarize previous QSP models of neurodegenerative diseases.

Ground-state and finite-temperature properties of \\(S=1/2\\) Heisenberg ladders with a ferromagnetic leg, an antiferromagnetic leg, and antiferromagnetic rungs are studied. It is shown that a partial ferrimagnetic phase extends over a wide parameter range in the ground state. The numerical results are supported by an analytical calculation based on a mapping onto the nonlinear \\(\\) model and a perturbation calculation from the strong-rung limit. It is shown that the partial ferrimagnetic state is a spontaneously magnetized Tomonaga--Luttinger liquid with incommensurate magnetic correlation, which is confirmed by a DMRG calculation. The finite-temperature magnetic susceptibility is calculated using the thermal pure quantum state method. It is suggested that the susceptibility diverges as \\(T^-2\\) in the ferrimagnetic phases as in the case of ferromagnetic Heisenberg chains.

Pain-related sensory input is processed in the spinal dorsal horn (SDH) before being relayed to the brain. That processing profoundly influences whether stimuli are correctly or incorrectly perceived as painful. Significant advances have been made in identifying the types of excitatory and inhibitory neurons that comprise the SDH, and there is some information about how neuron types are connected, but it remains unclear how the overall circuit processes sensory input or how that processing is disrupted under chronic pain conditions. To explore SDH function, we developed a computational model of the circuit that is tightly constrained by experimental data. Our model comprises conductance-based neuron models that reproduce the characteristic firing patterns of spinal neurons. Excitatory and inhibitory neuron populations, defined by their expression of genetic markers, spiking pattern, or morphology, were synaptically connected according to available qualitative data. Using a genetic algorithm, synaptic weights were tuned to reproduce projection neuron firing rates (model output) based on primary afferent firing rates (model input) across a range of mechanical stimulus intensities. Disparate synaptic weight combinations could produce equivalent circuit function, revealing degeneracy that may underlie heterogeneous responses of different circuits to perturbations or pathological insults. To validate our model, we verified that it responded to reduction of inhibition (i.e. disinhibition) and ablation of specific neuron types in a manner consistent with experiments. Thus validated, our model offers a valuable resource for interpreting experimental results and testing hypotheses in silico to plan experiments for examining normal and pathological SDH circuit function. We developed a multiscale computer model of the posterior part of spinal cord gray matter (spinal dorsal horn), involved in perception of touch and pain. The model reproduces several experimental observations and makes predictions about how specific types of spinal neurons and synapses influence projection neurons that send information to the brain. Misfiring of these projection neurons can produce anomalous sensations associated with chronic pain. Our computer model will not only assist in planning future experiments, but will also be useful for developing new pharmacotherapy for chronic pain disorders, connecting the effect of drugs acting at the molecular scale with emergent properties of neurons and circuits that shape the pain experience.

PIM447, a pan-proviral integration site for Moloney leukemia (PIM) kinase inhibitor, has shown preclinical activity in multiple myeloma (MM). This phase I, open-label, multicenter, dose-escalation study aimed to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of PIM447 in Japanese patients with relapsed and/or refractory (R/R) MM. The study included 13 patients (250 mg once daily (QD), [n = 7]; 300 mg QD, [n = 6]). The sole dose-limiting toxicity observed was grade 3 QTc prolongation in one patient from the 300 mg group, and the MTD and RDE was not determined. The most common suspected PIM447-related adverse events (AEs) included thrombocytopenia (76.9%), anemia (53.8%), and leukopenia (53.8%). All patients experienced at least one grade 3 or 4 AE, most frequently thrombocytopenia or leukopenia (61.5% each). The overall response rate was 15.4%, disease control rate 69.2%, clinical benefit rate 23.1%, and two patients had a partial response (one in each dose group). Two patients treated with 250 mg QD had a progression-free survival > 6 months. PIM447 250 mg or 300 mg QD was tolerated in Japanese patients with R/R MM. Further studies are required to evaluate clinical outcomes of PIM447 in combination with other drugs for the treatment of MM.Trial registration: clinicaltrials.gov: (NCT02160951).

Background Brugada syndrome (BrS) is an inherited cardiac channelopathy associated with a high risk of sudden cardiac death (SCD) due to ventricular fibrillation (VF). Although implantable cardioverter‐defibrillators (ICDs) are the primary therapy for SCD prevention, the risk stratification of elderly patients with BrS remains unclear. This study aimed to evaluate the incidence and risk factors of life‐threatening arrhythmias in elderly patients with BrS. Methods We analyzed 523 patients with BrS (mean age 51 ± 13 years, 497 men) enrolled in the multicenter prospective Japan Idiopathic Ventricular Fibrillation Study. Patients were categorized into the elderly (>60 years, n = 150) and nonelderly (≤60 years, n = 373) groups. Clinical characteristics, programmed electrical stimulation (PES) results, and outcomes, including cardiac events (CEs: VF, fast ventricular tachycardia, or SCD), were compared. Statistical analyses were performed using Kaplan–Meier curves and Cox proportional hazard models. Results During a mean follow‐up of 106 ± 62 months, 59 patients (11%) experienced CE. The annual CE incidence was lower in the elderly group than in the nonelderly group (0.7% vs. 1.5%, p = 0.016). History of VF independently predicted CE occurrence in elderly patients (hazard ratio: 23.5, p < 0.001). Asymptomatic elderly patients exhibited a negligible risk of CE. PES did not predict CE occurrence in the elderly group. Conclusions Elderly patients with BrS have a better prognosis than nonelderly patients, particularly if they are asymptomatic. A history of VF is a key risk factor for life‐threatening arrhythmias in elderly patients with BrS. This study suggests that asymptomatic elderly patients with Brugada syndrome may be at a very low risk of developing life‐threatening arrhythmias.

Asteroids fall to Earth in the form of meteorites, but these provide little information about their origins. The Japanese mission Hayabusa2 is designed to collect samples directly from the surface of an asteroid and return them to Earth for laboratory analysis. Three papers in this issue describe the Hayabusa2 team's study of the near-Earth carbonaceous asteroid 162173 Ryugu, at which the spacecraft arrived in June 2018 (see the Perspective by Wurm). Watanabe et al. measured the asteroid's mass, shape, and density, showing that it is a “rubble pile” of loose rocks, formed into a spinning-top shape during a prior period of rapid spin. They also identified suitable landing sites for sample collection. Kitazato et al. used near-infrared spectroscopy to find ubiquitous hydrated minerals on the surface and compared Ryugu with known types of carbonaceous meteorite. Sugita et al. describe Ryugu's geological features and surface colors and combined results from all three papers to constrain the asteroid's formation process. Ryugu probably formed by reaccumulation of rubble ejected by impact from a larger asteroid. These results provide necessary context to understand the samples collected by Hayabusa2, which are expected to arrive on Earth in December 2020. Science , this issue p. 268 , p. 272 , p. eaaw0422 ; see also p. 230 The near-Earth asteroid Ryugu probably formed by reaccumulation of rubble from an impact on a larger parent asteroid. The near-Earth carbonaceous asteroid 162173 Ryugu is thought to have been produced from a parent body that contained water ice and organic molecules. The Hayabusa2 spacecraft has obtained global multicolor images of Ryugu. Geomorphological features present include a circum-equatorial ridge, east-west dichotomy, high boulder abundances across the entire surface, and impact craters. Age estimates from the craters indicate a resurfacing age of ≲ 10 6 years for the top 1-meter layer. Ryugu is among the darkest known bodies in the Solar System. The high abundance and spectral properties of boulders are consistent with moderately dehydrated materials, analogous to thermally metamorphosed meteorites found on Earth. The general uniformity in color across Ryugu’s surface supports partial dehydration due to internal heating of the asteroid’s parent body.

PurposeAntral pulmonary vein isolation (PVI) using a radiofrequency hot balloon catheter (RHB) is a feasible therapeutic option for treating atrial fibrillation (AF). Lesion durability after antral RHB-PVI remains unknown. This study aimed to evaluate lesion durability and the associations between procedural characteristics after antral RHB-PVI.MethodsA total of 200 patients received antral RHB-PVI using the single-shot technique between April 2016 and March 2018. Antral RHB-PVI was performed following a pre-specified protocol and RHB energy application was performed for a maximum of two times for each PV. Consecutive patients who underwent repeated procedures for recurrence of any type of atrial tachyarrhythmia were enrolled.ResultsTwenty-six (13%) patients underwent repeated ablation and 20 patient documented AF recurrence (AF group) and 6 patients documented non-AF recurrence (non-AF group). Repeated ablation was performed at a median (25th, 75th percentiles) of 378 days (217, 487) after the initial procedure and durable PVI was observed in 86 (83.5%) PVs. Durability reached 89.7% when PVI was achieved only using an RHB. In the AF group (79 PVs), durable PVI was observed in 62 (78.5%) PVs, whereas all 24 PVs were still isolated in the non-AF group. The majority of reconnection sites were around the superior PVs.ConclusionsAntral RHB-PVI shows high lesion durability, especially with both inferior PVs.

A previously healthy 49-year-old Japanese woman presented with cervical lymph node swelling and tenderness. Lymph node biopsy revealed reactive lymphadenitis without granulomas. No malignant cells were found, and no acid-fast positive bacilli were identified by Ziehl–Neelsen staining. She was treated unsuccessfully with various antibiotics, and it was very challenging to reach a diagnosis. 18F-Fluorodeoxyglucose (18F-FDG) uptake in bones was evaluated using positron emission tomography-computed tomography (PET-CT), and disseminated mycobacterial infection was suspected. The interferon-gamma (IFN-γ) release assays QuantiFERON (QFT) and T-SPOT were used to diagnose tuberculosis infection. On testing, a difference in mitogen response was found between these assays. The response was low for QFT but adequate for T-SPOT, suggesting the presence of anti-IFN-γ antibodies. This difference depended on whether the patient’s plasma (including anti-IFN-γ antibodies) was used within the assay system. Mycobacterium abscessus was isolated from lymph node cultures, and plasma anti-IFN-γ antibodies were confirmed. The patient was diagnosed with disseminated M. abscessus infection with underlying adult-onset immunodeficiency caused by anti-IFN-γ antibodies. Granulomas are a pathological hallmark of mycobacterial infection, but may not fully form in immunodeficient patients. Clinicians should be aware of the possibility of mycobacterial infection without granuloma formation due to anti-IFN-γ antibodies.

Renal dysfunction results in the accumulation of various uremic toxins, including indoxyl sulphate (IS), and is a major risk factor for atrial fibrillation (AF). Experimental studies have demonstrated that IS exacerbates atrial remodelling via oxidative stress, inflammation, and fibrosis. However, its clinical impact on AF-promoting cardiac remodelling has not been described. Therefore, the purpose of this study was to clarify the relationship between basal IS levels and the 1-year outcomes after catheter ablation for the treatment of AF. Our prospective observational study included data from 125 patients with AF who underwent catheter ablation. Over a 1-year follow-up period, AF recurrence was identified in 21 patients. The 1-year AF-free survival was significantly lower in patients with high serum IS levels (≥0.65 μg/mL) than in those with low IS levels (60.1 ± 10.4% versus 85.2 ± 3.9%, P  = 0.007). Univariable analysis identified that an IS concentration ≥ 0.65 μg/mL was associated with AF recurrence (hazard ratio [HR] = 3.10 [1.26–7.32], P  = 0.015), and this association was maintained in multivariate analysis (HR = 3.67 [1.13–11.7], P  = 0.031). Thus, in patients undergoing AF ablation, serum IS levels at baseline independently predict the recurrence of arrhythmia.