Time-frequency representation with variant array of frequency-domain Prony estimators.

The frequency-domain Prony method (FDPM) [Ando, IEEE Trans. Signal Process. 68, 3461-3470 (2020)] provides a novel and exact short-time, frequency-decomposed scheme for autoregressive model identification and sinusoidal parameter estimation with a superior statistical performance. By using it as localized estimation elements, we construct the time-frequency representation (TFR) of signals as the frequency-reassigned map of the damped sinusoidal parameters of their components. The FDPM for both single and multiple sinusoids is based on a small number of windowless Fourier coefficients of sampled sequence. Thus, a unified and flexible construction of resolution and decomposition structures including linear and log-linear frequency arrays and their combination is possible, and dense analysis along the time axis can be implemented without a significant increase in computational cost. Conditions for constructing the frequency-variant arrays are formulated. Two cooperative behaviors in the TFR are considered to find stable traces of frequencies and rapidly time-varying incidences and components. Several experiments are shown to confirm extended features and performances of the proposed TFR using musical, speech, and natural sound signals.

Healing of bisphosphonate-associated atypical femoral fractures in patients with osteoporosis: a comparison between treatment with and without teriparatide.

Atypical femoral fracture (AFF) often appears with bisphosphonate use. Teriparatide (TPTD) treatment may promote AFF healing, but few controlled or comparative studies have examined the effects of TPTD on healing of bisphosphonate-associated AFF. We retrospectively reviewed the medical records of 45 consecutive AFFs in 34 Japanese patients who had received oral bisphosphonates (alendronate or risedronate) for osteoporosis before AFF and had been followed for ≥12 months (range, 12-90 months). Thirty-seven complete or incomplete AFFs (82 %) were treated surgically and eight incomplete AFFs (18 %) were treated conservatively. Bisphosphonates were stopped at diagnosis. Based on TPTD use after fracture, AFFs were divided into non-TPTD (n = 24) and TPTD (n = 21) groups. Time to fracture-healing and frequency of delayed healing or non-union were compared between groups. Because fracture type (complete or incomplete) differed significantly between groups, only subanalyses for all surgically treated AFFs (complete and incomplete), surgically treated complete AFFs, and conservatively treated incomplete AFFs were performed. In subanalyses for all AFFs treated surgically, mean (± standard deviation) time to fracture healing was significantly better in the TPTD group (5.4 ± 1.5 months) than in the non-TPTD group (8.6 ± 4.7 months; P = 0.012), and the frequency of delayed healing or non-union was significantly lower in the TPTD group than in the non-TPTD group (P = 0.014). Subanalyses for surgically treated complete AFFs yielded similar results, but subanalyses for incomplete AFFs treated conservatively showed no significant differences between groups. TPTD treatment appears to significantly shorten the postoperative time to fracture healing and reduce rates of delayed healing or non-union after bisphosphonate-associated AFF.

A unique hinge binder of extremely selective aminopyridine-based Mps1 (TTK) kinase inhibitors with cellular activity.

Mps1, also known as TTK, is a dual-specificity kinase that regulates the spindle assembly check point. Increased expression levels of Mps1 are observed in cancer cells, and the expression levels correlate well with tumor grade. Such evidence points to selective inhibition of Mps1 as an attractive strategy for cancer therapeutics. Starting from an aminopyridine-based lead 3a that binds to a flipped-peptide conformation at the hinge region in Mps1, elaboration of the aminopyridine scaffold at the 2- and 6-positions led to the discovery of 19c that exhibited no significant inhibition for 287 kinases as well as improved cellular Mps1 and antiproliferative activities in A549 lung carcinoma cells (cellular Mps1 IC50=5.3 nM, A549 IC50=26 nM). A clear correlation between cellular Mps1 and antiproliferative IC50 values indicated that the antiproliferative activity observed in A549 cells would be responsible for the cellular inhibition of Mps1. The X-ray structure of 19c in complex with Mps1 revealed that this compound retains the ability to bind to the peptide flip conformation. Finally, comparative analysis of the X-ray structures of 19c, a deamino analogue 33, and a known Mps1 inhibitor bound to Mps1 provided insights into the unique binding mode at the hinge region.

Robust sensing of approaching vehicles relying on acoustic cues.

The latest developments in automobile design have allowed them to be equipped with various sensing devices. Multiple sensors such as cameras and radar systems can be simultaneously used for active safety systems in order to overcome blind spots of individual sensors. This paper proposes a novel sensing technique for catching up and tracking an approaching vehicle relying on an acoustic cue. First, it is necessary to extract a robust spatial feature from noisy acoustical observations. In this paper, the spatio-temporal gradient method is employed for the feature extraction. Then, the spatial feature is filtered out through sequential state estimation. A particle filter is employed to cope with a highly non-linear problem. Feasibility of the proposed method has been confirmed with real acoustical observations, which are obtained by microphones outside a cruising vehicle.

[Development of a staging classification for leisure activities and social communication in dependent elderly persons].

AIM: The aim of this study was to develop a simple staging classification to measure leisure activity and social communication among the elderly at geriatric health care facilities. METHODS: In order to construct a staging scale for measuring the participation of the elderly subjects, we developed a list of 28 items for three domains: leisure activities, social participation and communication. Data were obtained from users of institutional and day care services at geriatric health service facilities. The Rasch model was applied to test the degree of item fit and difficulty. Simple staging scales were constructed based on 12 leisure activity and nine social communication items. The validity and reliability were tested using these newly developed scales according to the Rasch model and assessments of the test-retest reliability. RESULTS: The participants were 3,458 elderly persons, of whom 1,560 were currently using institutional services and 1,898 were using day care services. Among the 28 items, "traveling" was identified as the most difficult and "watching television" was identified as the easiest. Because items related to "social participation," such as volunteer activities, exhibited a low frequency, they were not used in the further analyses. Simple staging scales were constructed by analyzing the remaining items of leisure activities and social communication according to the Rasch model. The thresholds within the scales were determined in order of item difficulty. Cohen's kappa, as assessed by two different evaluators, was 0.75 for leisure activities and 0.77 for social communication. CONCLUSIONS: In this study, we developed staging scales for leisure activity and social communication. The construct validity and test-retest reliability were adequate for both scales. Service providers can improve service quality by using these scales for individual case management of elderly persons in conjunction with existing scales of activities of daily living.

Partial differential equation-based localization of a monopole source from a circular array.

Wave source localization from a sensor array has long been the most active research topics in both theory and application. In this paper, an explicit and time-domain inversion method for the direction and distance of a monopole source from a circular array is proposed. The approach is based on a mathematical technique, the weighted integral method, for signal/source parameter estimation. It begins with an exact form of the source-constraint partial differential equation that describes the unilateral propagation of wide-band waves from a single source, and leads to exact algebraic equations that include circular Fourier coefficients (phase mode measurements) as their coefficients. From them, nearly closed-form, single-shot and multishot algorithms are obtained that is suitable for use with band-pass/differential filter banks. Numerical evaluation and several experimental results obtained using a 16-element circular microphone array are presented to verify the validity of the proposed method.

Formation of Hemihydrate Crystal form Overcomes Milling Issue Induced by Exposed Functional Groups on Cleavage Plane for a Y5 Receptor Antagonist of Neuropeptide Y.

This study aimed to investigate the crystal forms of an originally designed Y5 receptor antagonist of neuropeptide Y. Polymorphic screening was performed via solvent evaporation and slurry conversion using various solvents. The obtained crystal forms α, ß, and γ were characterized by X-ray powder diffraction analysis. Thermal analysis determined that forms α, ß, and γ were hemihydrate, metastable and stable forms, respectively; the hemihydrate and the stable forms were candidates. To arrange the particle size, forms α and γ were subjected to jet milling. However, form γ could not be milled because of powder stiction to the apparatus, whereas form α could be. To investigate this mechanism, single-crystal X-ray diffraction analysis was performed. The crystal structure of form γ was characterized by two-dimensional hydrogen bonding between neighboring molecules. This revealed that the functional groups forming hydrogen bonds were exposed on the cleavage plane of form γ. The three-dimensional hydrogen-bonding network with water stabilized the hemihydrate form, α. These results indicate that the hydrogen bondable groups exposed on the cleavage plane of form γ should result in stiction of the powder and adherence to the apparatus. It was concluded that crystal conversion is a method to overcome the milling issue.

Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor could be a potential oral agent for treating COVID-19.

Structure-Based Approaches to Improving Selectivity through Utilizing Explicit Water Molecules: Discovery of Selective ß-Secretase (BACE1) Inhibitors over BACE2.

BACE1 is an attractive target for disease-modifying treatment of Alzheimer's disease. BACE2, having high homology around the catalytic site, poses a critical challenge to identifying selective BACE1 inhibitors. Recent evidence indicated that BACE2 has various roles in peripheral tissues and the brain, and therefore, the chronic use of nonselective inhibitors may cause side effects derived from BACE2 inhibition. Crystallographic analysis of the nonselective inhibitor verubecestat identified explicit water molecules with different levels of free energy in the S2' pocket. Structure-based design targeting them enabled the identification of propynyl oxazine 3 with improved selectivity. Further optimization efforts led to the discovery of compound 6 with high selectivity. The cocrystal structures of 7, a close analogue of 6, bound to BACE1 and BACE2 confirmed that one of the explicit water molecules is displaced by the propynyl group, suggesting that the difference in the relative water displacement cost may contribute to the improved selectivity.

Trifluoromethyl Dihydrothiazine-Based ß-Secretase (BACE1) Inhibitors with Robust Central ß-Amyloid Reduction and Minimal Covalent Binding Burden.

The ß-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as ß-secretase) is a promising target for the treatment of Alzheimer's disease. A pKa lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF3 dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability. Oral administration of 8 elicited robust Aß reduction in dog even at 0.16 mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [14 C]-KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1 mg/day. However, hepatotoxicity was observed when 15 was subjected to a two-week tolerance study in dog, which prevented further evaluation of this compound.

Discovery of an Extremely Potent Thiazine-Based ß-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose.

Genetic evidence points to deposition of amyloid-ß (Aß) as a causal factor for Alzheimer's disease. Aß generation is initiated when ß-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5 with robust Aß reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Aß reduction of 80% at trough level.

Rational Design of Novel 1,3-Oxazine Based ß-Secretase (BACE1) Inhibitors: Incorporation of a Double Bond To Reduce P-gp Efflux Leading to Robust Aß Reduction in the Brain.

Accumulation of Aß peptides is a hallmark of Alzheimer's disease (AD) and is considered a causal factor in the pathogenesis of AD. ß-Secretase (BACE1) is a key enzyme responsible for producing Aß peptides, and thus agents that inhibit BACE1 should be beneficial for disease-modifying treatment of AD. Here we describe the discovery and optimization of novel oxazine-based BACE1 inhibitors by lowering amidine basicity with the incorporation of a double bond to improve brain penetration. Starting from a 1,3-dihydrooxazine lead 6 identified by a hit-to-lead SAR following HTS, we adopted a p Ka lowering strategy to reduce the P-gp efflux and the high hERG potential leading to the discovery of 15 that produced significant Aß reduction with long duration in pharmacodynamic models and exhibited wide safety margins in cardiovascular safety models. This compound improved the brain-to-plasma ratio relative to 6 by reducing P-gp recognition, which was demonstrated by a P-gp knockout mouse model.

Discovery of Potent and Centrally Active 6-Substituted 5-Fluoro-1,3-dihydro-oxazine ß-Secretase (BACE1) Inhibitors via Active Conformation Stabilization.

ß-Secretase (BACE1) has an essential role in the production of amyloid ß peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux. The close analogue of 5-fluoro-oxazine 8 reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition. Changing to a pyrazine followed by optimization of substituents on both the oxazine and the pyrazine culminated in 24 with robust Aß reduction in vivo at low doses as well as reduced CYP2D6 inhibition. On the basis of the X-ray analysis and the QM calculation of given dihydro-oxazines, we reasoned that the substituents at the 6-position as well as the 5-fluorine on the oxazine would stabilize a bioactive conformation to increase potency.

Direct reconstruction algorithm of current dipoles for vector magnetoencephalography and electroencephalography.

This paper presents a novel algorithm to reconstruct parameters of a sufficient number of current dipoles that describe data (equivalent current dipoles, ECDs, hereafter) from radial/vector magnetoencephalography (MEG) with and without electroencephalography (EEG). We assume a three-compartment head model and arbitrary surfaces on which the MEG sensors and EEG electrodes are placed. Via the multipole expansion of the magnetic field, we obtain algebraic equations relating the dipole parameters to the vector MEG/EEG data. By solving them directly, without providing initial parameter guesses and computing forward solutions iteratively, the dipole positions and moments projected onto the xy-plane (equatorial plane) are reconstructed from a single time shot of the data. In addition, when the head layers and the sensor surfaces are spherically symmetric, we show that the required data reduce to radial MEG only. This clarifies the advantage of vector MEG/EEG measurements and algorithms for a generally-shaped head and sensor surfaces. In the numerical simulations, the centroids of the patch sources are well localized using vector/radial MEG measured on the upper hemisphere. By assuming the model order to be larger than the actual dipole number, the resultant spurious dipole is shown to have a much smaller strength magnetic moment (about 0.05 times smaller when the SNR = 16 dB), so that the number of ECDs is reasonably estimated. We consider that our direct method with greatly reduced computational cost can also be used to provide a good initial guess for conventional dipolar/multipolar fitting algorithms.

Giant cell tumor of fifth lumbar vertebrae: two case reports and review of the literature.

BACKGROUND CONTEXT: complete or total en bloc spondylectomy has been recommended for giant cell tumors of the spine. Wide local resection of the fifth lumbar vertebra carries potential risks of major complications because of its anatomical features. Only nine cases of the giant cell tumors involving the fifth lumbar vertebra have been reported in the literature. PURPOSE: to present two cases of giant cell tumor of the fifth lumbar vertebra treated by single-stage combined anterior and posterior tumor resection over 7 years of follow-up. STUDY DESIGN: Case report and a review of literature. METHODS: A 33-year-old female and a 20-year-old female, each diagnosed with giant cell tumor of fifth lumbar vertebra, underwent single-stage tumor resection through a combined posterior and retroperitoneal anterior approach. RESULTS: The resection of the fifth lumbar vertebra was completed in the first case without major perioperative complications. In the second case, massive bleeding during the anterior procedure for resection of the vertebral body interrupted the total resection of the tumor, resulting in possible residual tumor which required adjuvant radiotherapy. The patients recovered both clinically and neurologically after the operation. Spinal reconstruction was maintained, and no recurrence of the tumor was evident at the 7-year and 8-year follow-up, respectively. CONCLUSION: There was no recurrence of the tumor after the combined single-stage anterior and posterior tumor resection and adjuvant radiotherapy for the second case for over 7 years follow-up. However, complete resection of the vertebra and tumor at the fifth lumbar vertebra is still challenging to accomplish.

Progressive myelopathy due to idiopathic intraspinal tumoral calcinosis of the cervical spine. Case report.

Tumoral calcinosis is a rare disorder that most often occurs in periarticular regions of the extremities. Here, the authors report on an extremely rare case of idiopathic intraspinal tumoral calcinosis of the cervical spine. This 54-year-old man presented with a 2-week history of progressive cervical myelopathy. Results of magnetic resonance imaging and computed tomography myelography of the cervical spine revealed an intraspinal calcified mass lesion posterior to the spinal cord at the C3-4 level, resulting in marked spinal cord compression. Spinal cord decompression and en bloc resection of the mass lesion were performed via a C-2 laminoplasty and C3-4 laminectomy. The mass was localized in the dura mater. Histologically, the lesion consisted of numerous nodules with amorphous calcified materials and a florid proliferation of multinucleated giant cells; that is, its histological characteristics were identical to those of tumoral calcinosis. The symptoms disappeared completely after surgery. In all previously reported cases of cervical tumoral calcinosis, the lesion was located in the paraspinal soft tissue, with bone and facet joint involvement. The present case is the first reported instance of cervical tumoral calcinosis localized only in the spinal canal.

Spondylolisthesis of the thoracic spine. Case report.

The thoracic spine is stabilized in the anteroposterior direction by the rib cage and the facet joints. Spondylolisthesis of the thoracic spine is less common than that of the lumbar spine. The authors describe a rare case of thoracic spondylolisthesis in which the patient suffered back pain and myelopathy. The patient was a 44-year-old woman. Plain radiography revealed Grade I T11-12 spondylolisthesis. The pedicle-facet joint angle at T-11 was 118 degrees, greater than that of T-10 or T-12. Postmyelography computerized tomography scanning revealed posterior compression of the dural sac as well as enlargement of and degenerative changes in the facet joint at T-11. Magnetic resonance imaging showed anterior and posterior compression of the spinal cord at the level of the spondylolisthesis. To achieve posterior T10-12 decompression, the surgeons performed a laminectomy and posterolateral fusion in which a pedicle screw fixation system was placed. The patient's back pain disappeared immediately after the operation. The authors conclude that the enlargement of the pedicle-facet joint angle and the degenerative changes of the facet joint caused the thoracolumbar spondylolisthesis.

Ligamentum flavum hematoma in the cervical spine - case report.

A 67-year-old man presented with a rare case of ligamentum flavum hematoma manifesting as progressive tetraplegia following cervical traction therapy. Magnetic resonance imaging of the cervical spine showed a posterior mass that was continuous with the ligamentum flavum at the C3-4 levels. Complete resection of the mass that contained brownish hemorrhage was performed, resulting in excellent symptom relief. We speculate that repeated trivial trauma to the degenerative ligamentum flavum was the main predisposing factor in the present case. Ligamentum flavum hematoma is a rare cause of spinal root or cord compression which typically occurs in the lower thoracic or lumbar spine, but may also appear in the cervical spine.

Molecular-Level Understanding of the Encapsulation and Dissolution of Poorly Water-Soluble Ibuprofen by Functionalized Organic Nanotubes Using Solid-State NMR Spectroscopy.

A comprehensive study of the encapsulation and dissolution of the poorly water-soluble drug ibuprofen (IBU) using two types of organic nanotubes (ONT-1 and ONT-2) was conducted. ONT-1 and ONT-2 had similar inner and outer diameters, but these surfaces were functionalized with different groups. IBU was encapsulated by each ONT via solvent evaporation. The amount of IBU in the ONTs was 9.1 and 29.2 wt % for ONT-1 and ONT-2, respectively. Dissolution of IBU from ONT-1 was very rapid, while from ONT-2 it was slower after the initial burst release. One-dimensional (1D) (1)H, (13)C, and two-dimensional (2D) (1)H-(13)C solid-state NMR measurements using fast magic-angle spinning (MAS) at a rate of 40 kHz revealed the molecular state of the encapsulated IBU in each ONT. Extremely mobile IBU was observed inside the hollow nanosapce of both ONT-1 and ONT-2 using (13)C MAS NMR with a single pulse (SP) method. Interestingly, (13)C cross-polarization (CP) MAS NMR demonstrated that IBU also existed on the outer surface of both ONTs. The encapsulation ratios of IBU inside the hollow nanospaces versus on the outer surfaces were calculated by waveform separation to be approximately 1:1 for ONT-1 and 2:1 for ONT-2. Changes in (13)C chemical shifts showed the intermolecular interactions between the carboxyl group of IBU and the amino group on the ONT-2 inner surface. The cationic ONT-2 could form the stronger electrostatic interactions with IBU in the hollow nanosapce than anionic ONT-1. On the other hand, 2D (1)H-(13)C NMR indicated that the hydroxyl groups of the glucose unit on the outer surface of the ONTs interacted with the carboxyl group of IBU in both ONT-1 and ONT-2. The changes in peak shape and chemical shift of the ONT glucose group after IBU encapsulation were larger in ONT-2 than in ONT-1, indicating a stronger interaction between IBU and the outer surface of ONT-2. The smaller amount of IBU encapsulation and rapid IBU dissolution from ONT-1 could be due to the weak interactions both at the outer and inner surfaces. Meanwhile, the stronger interaction between IBU and the inner surface of ONT-2 could suppress IBU dissolution, although the IBU on the outer surface of ONT-2 was released soon after dispersal in water. This study demonstrates that the encapsulation amount and the dissolution rates of poorly water-soluble drugs, a class which makes up the majority of new drug candidates, can be controlled using the functional groups on the surfaces of ONTs by considering the host-guest interactions.