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The genus Macaca is widely distributed, occupies a variety of habitats, shows diverse phenotypic characteristics, and is one of the best-studied genera of nonhuman primates. Here, we reported five re-sequencing Macaca genomes, including one M. cyclopis, one M. fuscata, one M. thibetana, one M. silenus, and one M. sylvanus. Together with published genomes of other macaque species, we combined 20 genome sequences of 10 macaque species to investigate the gene introgression and genetic differences among the species. The network analysis of the SNV-fragment trees indicates a reticular phylogeny of macaque species. Combining the results from various analytical methods, we identified extensive ancient introgression events among macaque species. The multiple introgression signals between different species groups were also observed, such as between fascicularis group species and silenus group species. However, gene flow signals between fascicularis and sinica group were not as strong as those between fascicularis group and silenus group. On the other hand, the unidirect gene flow in M. arctoides probably occurred between the progenitor of M. arctoides and the common ancestor of fascicularis group. Our study also shows that the genetic backgrounds and genetic diversity of different macaques vary dramatically among species, even among populations of the same species. In conclusion, using whole genome sequences and multiple methods, we have studied the evolutionary history of the genus Macaca and provided evidence for extensive introgression among the species., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The house mouse ( Mus musculus ), which is commensal to humans, has spread globally via human activities, leading to secondary contact between genetically divergent subspecies. This pattern of genetic admixture can provide insights into the selective forces at play in this well-studied model organism. Our analysis of 163 house mouse genomes, with a particular focus on East Asia, revealed substantial admixture between the subspecies castaneus and musculus , particularly in Japan and southern China. We revealed, despite the different level of autosomal admixture among regions, that all Y Chromosomes in the East Asian samples belonged to the musculus -type haplogroup, potentially explained by genomic conflict under sex-ratio distortion owing to varying copy numbers of ampliconic genes on sex chromosomes, Slx and Sly Our computer simulations, designed to replicate the observed scenario, show that the preferential fixation of musculus -type Y Chromosomes can be achieved with a slight increase in the male-to-female birth ratio. We also investigated the influence of selection on the posthybridization of the subspecies castaneus and musculus in Japan. Even though the genetic background of most Japanese samples closely resembles the subspecies musculus , certain genomic regions overrepresented the castaneus -like genetic components, particularly in immune-related genes. Furthermore, a large genomic block (∼2 Mbp) containing a vomeronasal/olfactory receptor gene cluster predominantly harbored castaneus -type haplotypes in the Japanese samples, highlighting the crucial role of olfaction-based recognition in shaping hybrid genomes., (© 2024 Fujiwara et al.; Published by Cold Spring Harbor Laboratory Press.)

The house shrew ( Suncus murinus-S . montanus species complex) colonized regions across southern Asia and the Indian Ocean following human activity. The house shrew is distributed on islands of the Ryukyu Archipelago, the southernmost part of Japan, but the evolutionary history of the shrew on those islands and possible associations between these populations and humans remain unknown. In this study, we conducted phylogenetic and population genetic analyses based on both nuclear and mitochondrial genome sequences of house shrews. Phylogenetic analyses based on mitochondrial cytochrome b ( cytb ) sequences revealed that shrews from the Ryukyu Archipelago showed strong genetic affinity to Vietnamese and southern Chinese shrews. Demographic analyses of cytb sequences indicated a rapid population expansion event affecting the haplotype group in Vietnam, southern China, and the Ryukyu Archipelago 3300-7900 years ago. Furthermore, gene flow between Ryukyu (Yonaguni Island) and Taiwan and between Ryukyu and Vietnam inferred from f 4 statistics of the nuclear genomes suggested repeated immigration to Ryukyu in recent years. The present study demonstrates that the Nagasaki population has a different origin from the Ryukyu population. These findings elucidate the complex pattern of genetic admixture in house shrews and provide insights into their evolutionary history.

Background: Real-world utilization data for evolocumab, the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to be introduced in Japan in 2016, to date are limited. This study aimed to clarify the current real-world patient user profiles of evolocumab based on large-scale health claims data.Methods and Results: This retrospective database study examined patients from a health administrative database (MDV database) who initiated evolocumab between April 2016 (baseline) and November 2021. Characteristics and clinical profiles of this patient population are described. In all, 4,022 patients were included in the final analysis. Most evolocumab prescriptions occurred in the outpatient setting (3,170; 78.82%), and 940 patients (23.37%) had a recent diagnosis of familial hypercholesterolemia. Common recent atherosclerotic cardiovascular disease events at baseline included myocardial infarction (1,633; 40.60%), unstable angina (561; 13.95%), and ischemic stroke (408; 10.14%). Comorbidity diseases included hypertension (2,504; 62.26%), heart failure (1,750; 43.51%), diabetes (1,199; 29.81%), and chronic kidney disease (297; 7.38%). Among the lipid-lowering regimens concomitant with evolocumab, ezetimibe+statin was used most frequently (1,281; 31.85%), followed by no concomitant lipid-lowering regimen (1,190; 29.59%), statin (950; 23.62%), and ezetimibe (601; 14.94%). The median evolocumab treatment duration for all patients was 260 days (interquartile range 57-575 days)., Conclusions: This study provides real-world insights into evolocumab utilization in Japan for optimizing patient care and adherence to guideline-based therapies to better address hypercholesterolemia in Japan.

Background and Objectives : This study aims to identify the minor allele of the single nucleotide polymorphisms (SNPs) DAB2IP rs7025486, IL6R rs2228145, CDKN2BAS rs10757278, LPA rs3798220, LRP1 rs1466535, and SORT1 rs599839 in order to assess the risk of abdominal aortic aneurysm (AAA) formation and define the linkage among these SNPs. Materials and Methods : A case-control study with AAA patients (AAA group) and non-AAA controls (control group) was carried out in a study population. DNA was isolated from whole blood samples; the SNPs were amplified using PCR and sequenced. Results: In the AAA group of 148 patients, 87.2% of the patients were male, 64.2% had a history of smoking, and 18.2% had relatives with AAA. The mean ± SD of age, BMI, and aneurysmal diameter in the AAA group were 74.8 ± 8.3 years, 27.6 ± 4.6 kg/m 2 , and 56.2 ± 11.8 mm, respectively. In comparison with 50 non-AAA patients, there was a significantly elevated presence of the SNPs DAB2IP rs7025486[A], CDKN2BAS rs10757278[G], and SORT1 rs599839[G] in the AAA group ( p -values 0.040, 0.024, 0.035, respectively), while LPA rs3798220[C] was significantly higher in the control group ( p = 0.049). A haplotype investigation showed that the SNPs DAB2IP , CDKN2BAS , and IL6R rs2228145[C] were significantly elevated in the AAA group ( p = 0.037, 0.037, and 0.046) with minor allele frequencies (MAF) of 25.5%, 10.6%, and 15.4%, respectively. Only DAB2IP and CDKN2BAS showed significantly higher occurrences of a mutation ( p = 0.028 and 0.047). Except for LPA , all SNPs were associated with a large aortic diameter in AAA ( p < 0.001). Linkage disequilibrium detection showed that LPA to DAB2IP , to IL6R , to CDKN2BAS , and to LRP1 rs1466535[T] had D' values of 70.9%, 80.4%, 100%, and 100%, respectively. IL6R to LRP1 and to SORT1 had values for the coefficient of determination ( r 2 ) of 3.9% and 2.2%, respectively. Conclusions : In the investigated study population, the SNPs CDKN2BAS rs10757278, LPA rs3798220, SORT1 rs599839, DAB2IP rs7025486, and IL6R rs2228145 were associated with the development of abdominal aortic aneurysms. Individuals with risk factors for atherosclerosis and/or a family history of AAA should be evaluated using genetic analysis.

We analyzed 196 haplotype sequences from a gene-rich region (250 kb) that includes Mc1r, a gene involved in coat color regulation, to gain insight into the evolution of coat color variation in subspecies of the house mouse Mus musculus. Phylogenetic networks revealed haplotype groups from the major subspecies of M. m. castaneus (CAS), M. m. domesticus (DOM), and M. m. musculus (MUS). Using haplotype sequences assigned to each of CAS and MUS through phylogenetic analysis, we proposed migration routes associated with prehistoric humans from west to east across Eurasia. Comparing nucleotide diversity among subspecies-specific haplotypes in different geographic areas showed a marked reduction during migration, particularly in MUS-derived haplotypes from Korea and Japan, suggesting intensive population bottlenecks during migration. We found that a C>T polymorphism at site 302 (c.302C>T) in the Mc1r coding region correlated with a darkening of dorsal fur color in both CAS and MUS. However, C/C homozygous mice in MUS showed marked variation in lightness, indicating the possibility of another genetic determinant that affects the lightness of dorsal fur color. Detailed sequence comparisons of haplotypes revealed that short fragments assigned to DOM were embedded in CAS-assigned fragments, indicating ancient introgression between subspecies. The estimated age of c.302C>T also supports the hypothesis that genetic interaction between subspecies occurred in ancient times. This suggests that the genome of M. musculus evolved through gene flow between subspecies over an extended period before the movement of the species in conjunction with prehistoric humans.

Introduction: Bone defects are often observed after surgery for fractures and bone tumors. Their treatment is technically difficult and sometimes results in negative clinical and economic outcomes. To repair bone defects, a bone graft is implanted by selecting a transplant material from an autologous or artificial bone. Each method has its advantages and disadvantages. Compared to the gold standard of autologous bone graft, bone graft substitutes are not limited by the amount of harvested graft and avoid complications at the donor site. ORB-03 is a new cotton-like bone graft substitute composed of beta-tricalcium phosphate (β-TCP) and a bioabsorbable polymer, polylactic-co-glycolic acid (PLGA). ORB-03 is easy to mold and can fill various bone defect shapes, and its three-dimensional microfiber scaffold can enhance the differentiation of osteoblasts and promote osteogenesis. We investigated the efficacy, ease of handling, and safety of ORB-03 as a bone graft substitute. A multicenter, open-label, single-group study was conducted at six institutions., Methods: Between July 2018 and August 2019, 60 patients with bone defects caused by fracture, benign tumors, or an iliac donor site from bone harvesting were enrolled in this study; 54 patients were finally included for the safety analysis and 48 patients for the image analysis. During surgery, ORB-03 was mixed with the patient's blood and molded into a bone defect. To evaluate the efficacy of ORB-03, radiography and computed tomography (CT) were performed at intervals until 24 weeks after surgery., Results: The effective rate and its accurate bilateral 95% confidence interval (CI) were calculated based on the efficacy criteria at 24 weeks postoperatively. The ease with which ORB-03 could be handled in surgery was evaluated. Adverse events that occurred after surgery were evaluated, and those associated with ORB-03 were examined. Bone fusion was good in all cases, and the radiography and CT effective rates were 100.0% and 91.5%, respectively. Handling was easy in all cases. There were four adverse events, none of which were clinically problematic., Conclusions: ORB-03 was found to be easy to handle, safe, and effective as a bone graft substitute for bone defects., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Tokeshi et al.)

Background: The immunomodulatory drug lenalidomide, which is now widely used for the treatment of multiple myeloma (MM), exerts pharmacological action through the ubiquitin-dependent degradation of IKZF1 and subsequent down-regulation of interferon regulatory factor 4 (IRF4), a critical factor for the survival of MM cells. IKZF1 acts principally as a tumour suppressor via transcriptional repression of oncogenes in normal lymphoid lineages. In contrast, IKZF1 activates IRF4 and other oncogenes in MM cells, suggesting the involvement of unknown co-factors in switching the IKZF1 complex from a transcriptional repressor to an activator. The transactivating components of the IKZF1 complex might promote lenalidomide resistance by residing on regulatory regions of the IRF4 gene to maintain its transcription after IKZF1 degradation., Methods: To identify unknown components of the IKZF1 complex, we analyzed the genome-wide binding of IKZF1 in MM cells using chromatin immunoprecipitation-sequencing (ChIP-seq) and screened for the co-occupancy of IKZF1 with other DNA-binding factors on the myeloma genome using the ChIP-Atlas platform., Results: We found that c-FOS, a member of the activator protein-1 (AP-1) family, is an integral component of the IKZF1 complex and is primarily responsible for the activator function of the complex in MM cells. The genome-wide screening revealed the co-occupancy of c-FOS with IKZF1 on the regulatory regions of IKZF1-target genes, including IRF4 and SLAMF7, in MM cells but not normal bone marrow progenitors, pre-B cells or mature T-lymphocytes. c-FOS and IKZF1 bound to the same consensus sequence as the IKZF1 complex through direct protein-protein interactions. The complex also includes c-JUN and IKZF3 but not IRF4. Treatment of MM cells with short-hairpin RNA against FOS or a selective AP-1 inhibitor significantly enhanced the anti-MM activity of lenalidomide in vitro and in two murine MM models. Furthermore, an AP-1 inhibitor mitigated the lenalidomide resistance of MM cells., Conclusions: C-FOS determines lenalidomide sensitivity and mediates drug resistance in MM cells as a co-factor of IKZF1 and thus, could be a novel therapeutic target for further improvement of the prognosis of MM patients., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Objectives: The prevalence of chronic pain increases with age. It has been reported that chronic pain is associated with sarcopenia and obesity. Age-related skeletal muscle loss and fat gain are known to occur due to chronic inflammation. The aim of this study was to analyze how skeletal muscle and fat, caused by chronic inflammation due to aging, regulate the development of geriatric chronic pain. Methods: The results of skeletal muscle and fat mass, 412 participants aged ≥65 years with non-specific chronic pain lasting ≥6 months, including low back, neck, and knee pain, was compared with the control without chronic pain. Body composition threshold regulating chronic pain was calculated. Results: A significantly lower skeletal muscle mass index and higher body fat percentage were observed in patients with chronic pain than that in the control. The muscle fat ratio (MFR) was significantly lower in the chronic pain group than in the control group. When the MFR threshold related to chronic pain was calculated by sex, it was 2.984 for men and 1.867 for women. Conclusions: Evaluation of the body composition of elderly patients with non-specific chronic pain revealed that the MFR was useful as an index related to chronic pain., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Institutional funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript., (© The Author(s) 2023.)

Aims: The aim of this study was to clarify whether worsening of independence in activities of daily living (ADL) and also difficulties in ADL are triggered by hospitalization in older patients with heart failure (HF) and whether difficulties in ADL can predict readmission for HF regardless of independence in ADL in these patients., Methods and Results: We enrolled 241 HF patients in the present multi-institutional, prospective, observational study. The patients were divided according to age into the non-older patient group (<75 years, n = 137) and the older patient group (≥75 years, n = 104). The Katz index and the Performance Measure for Activities of Daily Living-8 (PMADL-8) were used to evaluate independence and difficulties in ADL, respectively. The endpoint of this study was rehospitalization for HF. Independence as indicated by the Katz index at discharge was significantly lower than that before admission only in the older patient group, and the value of the PMADL-8 at discharge was significantly higher than that before admission (P < 0.001). In all patients, after adjusting for the Katz index and other variables, PMADL-8 score was a significant predictor of rehospitalization for HF (hazard ratio 1.50; 95% confidence interval 1.07-2.13; P = 0.021)., Conclusions: Worsening of both independence and difficulties in ADL was triggered by hospitalization in older HF patients, and difficulties in ADL were relevant factors for risk of rehospitalization regardless of independence in ADL. These findings indicate the importance of preventing not only decreased independence but also increased difficulties in ADL during and after hospitalization., Competing Interests: Conflict of interest: The authors certify that there are no conflicts of interest with any financial organizations regarding the material discussed in this manuscript., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Covalent triazine networks are interesting candidates for organic electrocatalytic materials due to their tunable, durable and sustainable nature. However, the limited availability of molecular designs that ensure both two-dimensionality and functional groups in the π-conjugated plane has hindered their development. In this work, a layered triazine network composed of thiophene and pyridine ring was synthesized by the novel mild liquid phase condition. The resulting network showed layered nature since its intramolecular interaction stabilized its planar conformation. The connection on the 2-position of the heteroaromatic ring prevents steric hindrance. The simple acid treatment method could be used to exfoliate the networks, resulting in high yields of nanosheets. The planar triazine network showed superior electrocatalytic properties for the oxygen reduction reaction in the structure-defined covalent organic networks., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Purpose: To investigate the prevalence and risk factors and influence of pseudoarthrosis on activities of daily living (ADL) of patients with osteoporotic vertebral fracture (OVF)., Methods: Spinal pseudoarthrosis is defined as the presence of a cleft in the vertebral body on a lateral X-ray image in the sitting position at 1 year after admission. Of the total 684 patients treated for OVF between January 2012 and February 2019 at our institution, 551 patients (mean age, 81.9 years; a male-to-female ratio, 152:399) who could be followed up to 1 year were included in this study. Prevalence, risk factors, and influence of pseudoarthrosis on the ADL of patients as well as fracture type and location were investigated. Pseudoarthrosis was set as the objective variable. Total bone mineral density, skeletal muscle mass index, sex, age, history of osteoporosis treatment, presence of dementia, vertebral kyphosis angle, fracture type (presence of posterior wall injury), degree of independence before admission, history of steroid use, albumin level, renal function, presence of diabetes, and diffuse idiopathic skeletal hyperostosis were set as explanatory variables for multivariate analysis of the influence of pseudoarthrosis on the walking ability and ADL independence before and 1 year after OVF., Results: In total, 54 (9.8%) patients were diagnosed with pseudarthrosis 1 year after injury (mean age, 81.3 ± 6.5 years; male-to-female ratio, 18:36). BKP was performed in nine patients who did not develop pseudoarthrosis after 1 year. In the multivariate analysis, only the presence of posterior wall injury was significantly correlated with the presence of pseudoarthrosis (OR = 2.059, p = 0.039). No significant difference was found between the pseudarthrosis group and the non-pseudarthrosis group in terms of walking ability and ADL independence at 1 year., Conclusions: The prevalence of pseudoarthrosis following OVF was 9.8%, and its risk factor was posterior wall injury. The BKP group was not included in the pseudoarthrosis group, which may have led to an underestimation of the prevalence of pseudoarthrosis. The prevalence, risk factors, and influence of spinal pseudoarthrosis on patients' ADL following osteoporotic vertebral fracture (OVF) were investigated. Pseudoarthrosis occurs in 9.8% 1 year after the injury in patients with OVF. Posterior wall injury was the risk factor of pseudoarthrosis., (© 2023. The Author(s).)

Extramedullary disease (EMD) is known to be associated with chemoresistance and poor prognosis in multiple myeloma (MM); however, the mechanisms of its development are not fully understood. Elucidating the mechanism of EMD development and its therapeutic targeting would greatly contribute to further improvement of treatment outcome in patients with MM. Here, we show that bone marrow stroma cell-derived hyaluronan (HA) elicits homophilic interactions of MM cells by binding to surface CD44, especially long-stretch variants, under physiological shear stress and generates cell clusters that might develop into EMD. We recapitulated the development of EMD via administration of HA in a syngeneic murine MM model in a CD44-dependent manner. HA-induced MM cell clusters exhibited the specific resistance to proteasome inhibitors (PIs) in vitro and in murine models via γ-secretase-mediated cleavage of the intracellular domains of CD44, which in turn transactivated PI resistance-inducible genes. Treatment of HA-injected mice with anti-CD44 antibody or γ-secretase inhibitors readily suppressed the development of EMD from transplanted MM cells and significantly prolonged the survival of recipients by overcoming PI resistance. The HA-CD44 axis represents a novel pathway to trigger EMD development and could be a target of the prediction, prevention, and treatment of EMD in patients with MM., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In Madagascar, the house mouse (Mus musculus) is widely believed to have colonized with human activities and is now one of the most abundant rodents on the island. However, its genetic background at the genomic level remains unclear, and clarifying this would help us to infer the timing of introduction and route of migration. In this study, we determined the whole-genome sequences of five Madagascar house mice captured from an inland location in Madagascar. We examined the genetic background of samples by analyzing the mitochondrial and autosomal genomes. We confirmed that the mitochondrial genome lineages of collected samples formed a single clade placed at one of the most basal positions in the Mus musculus species. Autosomal genomic sequences revealed that these samples are most closely related to the subspecies M. m. castaneus (CAS), but also contain a genetic component of the subspecies M. m. domesticus (DOM). The signature of a strong population bottleneck 1,000-3,000 years ago was observed in both mitochondrial and autosomal genomic data. In a comparison with global samples of M. musculus, the Madagascar samples showed strong genetic affinity to many CAS samples across a wide range of Indian Ocean coastal and insular regions, with divergence time estimated as around 4,000 years ago. These findings support the proposition that the ancestors of these animals started to colonize the island with human agricultural activity and experienced a complex history during their establishment.

Background: Lower leg strength at hospital discharge is strongly associated with poor prognosis in older patients with acute decompensated heart failure (ADHF). Improving leg strength is important in acute-phase cardiac rehabilitation (CR)., Aims: This study aimed to clarify whether a change in leg strength occurs during hospitalization of older ADHF patients receiving CR and whether it affects leg strength at discharge., Methods and Results: We enrolled 247 ADHF patients who underwent CR during hospitalization. They were divided into the non-older patient group (&lt;75 years; n = 142) and older patient group (≥75 years; n = 105). Quadriceps isometric strength (QIS), body mass-corrected QIS (%BM QIS), and change in QIS during hospitalization (QIS ratio) were evaluated in all patients. Physical function in the stable phase was measured by the Performance Measure for Activities of Daily Living-8 (PMADL-8). The QIS value increased during hospitalization in the non-older patient group (30.0 ± 11.1 vs. 31.6 ± 10.9 kgf, P &lt; 0.001) but did not increase in the older patient group (19.1 ± 6.3 vs. 19.5 ± 6.1 kgf, P = 0.275). Multiple regression analysis revealed that PMADL-8 significantly predicted %BM QIS at discharge in the non-older patient group (β = -0.254, P = 0.004), whereas in the older patient group, QIS ratio and PMADL-8 significantly predicted %BM QIS at discharge (β = 0.264, P = 0.008 for QIS ratio and β = -0.307, P = 0.003 for PMADL-8)., Conclusions: Leg strength was not improved in older ADHF patients during hospitalization even if they received CR, and this affected leg strength at discharge, suggesting that careful skeletal muscle intervention should be provided during hospitalization, and patients need to continue exercise after discharge., Competing Interests: Conflicts of interest: The authors declare that there is no conflict of interest., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Introduction: Although thoracic spondylotic myelopathy (TSM) without ossification or disc disorder has been associated with some dynamic factors in the thoracolumbar area, a detailed investigation is yet to be published. Thus, in this study, we investigated the segmental motion and sagittal alignment of the thoracolumbar area in patients with and without TSM., Methods: Patients with TSM who were treated from 2013 to 2020 were enrolled in this study. The non-TSM group consisted of sex- and age-matched patients with spinal disorders other than TSM. Segmental mobility from T10-L2 during passive maximum flexion and extension following myelography and the sagittal cobb angles of T10-L1 and L1-L5 in the standing position were measured using multidetector computed tomography (CT). The mobility of each segment was set as the difference in the angles between the two positions., Results: In total, 10 patients (8 males and 2 females, mean age 65.8 years) with TSM and 20 without TSM were enrolled. The most stenotic level was observed at T10-T11 in four cases and T11-T12 in six. The average mobility at this segment in the TSM group (5.8°) was significantly greater than that in the non-TSM group (2.1°) (p<0.001). In the TSM group, the cobb angles of T10-L1 and L1-L5 were 2.3° and 17.4° of lordosis, respectively, which differed significantly from those in the non-TSM group, which were 8° of kyphosis and 32.2° of lordosis, respectively (p<0.001 and p=0.001, respectively)., Conclusions: Compared with those without TSM, patients with TSM were found to have greater segmental mobility at the most stenotic level, thoracolumbar lordosis, and decreased lumbar lordosis., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest. The manuscript submitted does not contain information about medical device(s)/drug(s)., (Copyright © 2023 The Japanese Society for Spine Surgery and Related Research.)

The N-glycans attached to proteins contain various GlcNAc branches, the aberrant formation of which correlates with various diseases. N-Acetylglucosaminyltransferase-IVa (GnT-IVa or MGAT4A) and Gnt-IVb (or MGAT4B) are isoenzymes that catalyze the formation of the β1,4-GlcNAc branch in N-glycans. However, the functional differences between these isozymes remain unresolved. Here, using cellular and UDP-Glo enzyme assays, we discovered that GnT-IVa and GnT-IVb have distinct glycoprotein preferences both in cells and in vitro. Notably, we show that GnT-IVb acted efficiently on glycoproteins bearing an N-glycan premodified by GnT-IV. To further understand the mechanism of this reaction, we focused on the noncatalytic C-terminal lectin domain, which selectively recognizes the product glycans. Replacement of a nonconserved amino acid in the GnT-IVb lectin domain with the corresponding residue in GnT-IVa altered the glycoprotein preference of GnT-IVb to resemble that of GnT-IVa. Our findings demonstrate that the C-terminal lectin domain regulates differential substrate selectivity of GnT-IVa and GnT-IVb, highlighting a new mechanism by which N-glycan branches are formed on glycoproteins., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

N-Glycosylation is a common post-translational modification, and the number of GlcNAc branches in N-glycans impacts glycoprotein functions. N-Acetylglucosaminyltransferase-IVa (GnT-IVa, also designated as MGAT4A) forms a β1-4 GlcNAc branch on the α1-3 mannose arm in N-glycans. Downregulation or loss of GnT-IVa causes diabetic phenotypes by dysregulating glucose transporter-2 in pancreatic β-cells. Despite the physiological importance of GnT-IVa, its structure and catalytic mechanism are poorly understood. Here, we identify the lectin domain in mouse GnT-IVa's C-terminal region. The crystal structure of the lectin domain shows structural similarity to a bacterial GlcNAc-binding lectin. Comprehensive glycan binding assay using 157 glycans and solution NMR reveal that the GnT-IVa lectin domain selectively interacts with the product N-glycans having a β1-4 GlcNAc branch. Point mutation of the residue critical to sugar recognition impairs the enzymatic activity, suggesting that the lectin domain is a regulatory subunit for efficient catalytic reaction. Our findings provide insights into how branching structures of N-glycans are biosynthesized., (© 2022. The Author(s).)

Drug repurposing has broad importance in planetary health for therapeutics innovation in infectious diseases as well as common or rare chronic human diseases. Drug repurposing has also proved important to develop interventions against the COVID-19 pandemic. We propose a new approach for drug repurposing involving two-stage prediction and machine learning. First, diseases are clustered by gene expression on the premise that similar patterns of altered gene expression imply critical pathways shared in different disease conditions. Next, drug efficacy is assessed by the reversibility of abnormal gene expression, and results are clustered to identify repurposing targets. To cluster similar diseases, gene expression data from 262 cases of 31 diseases and 268 controls were analyzed by Uniform Manifold Approximation and Projection for Dimension Reduction followed by k -means to optimize the number of clusters. For evaluation, we examined disease-specific gene expression data for inclusion, body myositis, polymyositis, and dermatomyositis (DM), and used LINCS L1000 characteristic direction signatures search engine (L1000CDS 2 ) to obtain lists of small-molecule compounds that reversed the expression patterns of these specifically altered genes as candidates for drug repurposing. Finally, the functions of affected genes were analyzed by Gene Set Enrichment Analysis to examine consistency with expected drug efficacy. Consequently, we found disease-specific gene expression, and importantly, identified 20 drugs such as BMS-387032, phorbol-12-myristate-13-acetate, mitoxantrone, alvocidib, and vorinostat as candidates for repurposing. These were previously noted to be effective against two of the three diseases, and have a high probability of being effective against the other. That is, inclusion body myositis and DM. The two-stage prediction approach to drug repurposing presented here offers innovation to inform future drug discovery and clinical trials in a variety of human diseases.

For more than 100 years, house mice (Mus musculus) have been used as a key animal model in biomedical research. House mice are genetically diverse, yet their genetic background at the global level has not been fully understood. Previous studies have suggested that they originated in South Asia and diverged into three major subspecies, almost simultaneously, approximately 110,000-500,000 years ago; however, they have spread across the world with the migration of modern humans in prehistoric and historic times (∼10,000 years ago to the present day) and have undergone secondary contact, which has complicated the genetic landscape of wild house mice. In this study, we sequenced the whole-genome sequences of 98 wild house mice collected from Eurasia, particularly East Asia, Southeast Asia, and South Asia. Although wild house mice were found to consist of three major genetic groups corresponding to the three major subspecies, individuals representing admixtures between subspecies were more prevalent in East Asia than has been previously recognized. Furthermore, several samples exhibited an incongruent pattern of genealogies between mitochondrial and autosomal genomes. Using samples that likely retained the original genetic components of subspecies with the least admixture, we estimated the pattern and timing of divergence among the subspecies. The estimated divergence time of the three subspecies was 187,000-226,000 years ago. These results will help us to understand the genetic diversity of wild mice on a global scale, and the findings will be particularly useful in future biomedical and evolutionary studies involving laboratory mice established from such wild mice., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

While the house mouse (Mus musculus), widely distributed in Eurasia, is known to have substantial coat color variation between and within local populations, in both primary and secondary distribution areas, including the Japanese archipelago, the evolutionary history of the color variation is poorly understood. To address the ventral fur color variation, we quantified the lightness of museum skin specimens, and found that the southern subspecies, M. m. castaneus (CAS), has high and low lightness in dry and rainy geographic regions, respectively. The northern subspecies, M. m. musculus (MUS), has low and high levels of lightness in the high and middle latitudes of northern Eurasia, respectively. We examined sequence variation of the agouti signaling protein gene (Asip), which is known to be responsible for the ventral fur color. We performed phylogenetic analyses with 196 haplotype sequences of Asip (~180 kb) generated by phasing the whole-genome data of 98 wild mice reported previously. Network and phylogenetic tree construction revealed clustering of haplotypes representing the two subspecies, MUS and CAS. A number of subclusters with geographic affinities appeared within the subspecies clusters, in which the essential results were consistent with those reconstructed with whole mitochondrial genome data, indicating that the phased haplotype genome sequences of the nuclear genome can be a useful tool for tracing the dispersal of geographical lineages. The results of phylogeographic analysis showed that CAS mice with darker ventral fur possessed similar Asip haplotypes across the geographic distribution, suggesting that these haplotypes are major causes of the historical introduction of Asip haplotypes for darker ventral fur in mice from northern India to the peripheral areas, including the Japanese archipelago. Similarly, MUS in East Asia, which has a white abdomen, formed an Asip haplogroup with that from northern Iran, also with a white abdomen.

Proprioception is a deep sensation that perceives the position of each part of the body, state of movement and muscle contraction, and resistance and mass applied to the body. Proprioceptive feedback influences movement and positional accuracy, resulting in key somatosensory functions for human postural control. Proprioception encompasses signals received from proprioceptors located in the skin, subcutaneous tissue, muscles, tendons, and joint capsules, commonly known as mechanoreceptors. The muscle spindle, a crucial proprioceptor, is stretched during eccentric contraction of muscle, thus generating an action potential on afferent fibers to convey a proprioceptive information to the sensorimotor cortex in the brain. For exercise therapy in patients with locomotor disease, proprioception serves an essential function for motor control; thus, this should be considered to obtain effective muscle output. As postural control is achieved by proprioceptive function according to the balance between the lower limb and trunk, relative proprioceptive weighting ratio can help clarify proprioceptive control using muscle response to mechanical vibration. The absence of proprioceptive information congruent with motor intention activates cortical center monitoring incongruence of sensation, leading to pathological pain. Therapeutic procedures may aim to restore the integrity of cortical information processing in musculoskeletal chronic pain. Poor proprioception is one of the main causes of decreased postural balance control in elderly patients with low back pain (LBP). It has been hypothesized that proprioception of the lower limbs deteriorates with age-related muscle mass loss (sarcopenia), which increases the proprioceptive burden on the lumbar spine. Accurate diagnosis of the proprioceptive function is important for establishing a treatment procedure for proprioceptive recovery, and further prospective research is required to clarify the relationship between proprioception and LBP improvement., Competing Interests: Conflicts of Interest: The device(s)/drug(s) is/are FDA approved or approved by the corresponding national agency for this indication., (Copyright © 2022 The Japanese Society for Spine Surgery and Related Research.)

The Vero cell line is an immortalized cell line established from kidney epithelial cells of the African green monkey. A variety of Vero sublines have been developed and can be classified into four major cell lineages. In this study, we determined the whole-genome sequence of Vero E6 (VERO C1008), which is one of the most widely used cell lines for the proliferation and isolation of severe acute respiratory syndrome coronaviruses (SARS-CoVs), and performed comparative analysis among Vero JCRB0111, Vero CCL-81, Vero 76, and Vero E6. Analysis of the copy number changes and loss of heterozygosity revealed that these four sublines share a large deletion and loss of heterozygosity on chromosome 12, which harbors type I interferon and CDKN2 gene clusters. We identified a substantial number of genetic differences among the sublines including single nucleotide variants, indels, and copy number variations. The spectrum of single nucleotide variants indicated a close genetic relationship between Vero JCRB0111 and Vero CCL-81, and between Vero 76 and Vero E6, and a considerable genetic gap between the former two and the latter two lines. In contrast, we confirmed the pattern of genomic integration sites of simian endogenous retroviral sequences, which was consistent among the sublines. We identified subline-specific/enriched loss of function and missense variants, which potentially contribute to the differences in response to viral infection among the Vero sublines. In particular, we identified four genes ( IL1RAP , TRIM25 , RB1CC1 , and ATG2A ) that contained missense variants specific or enriched in Vero E6. In addition, we found that V739I variants of ACE2, which functions as the receptor for SARS-CoVs, were heterozygous in Vero JCRB0111, Vero CCL-81, and Vero 76; however, Vero E6 harbored only the allele with isoleucine, resulting from the loss of one of the X chromosomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Konishi, Yamaji, Sakuma, Kasai, Endo, Kohara, Hanada and Osada.)

Purpose: The purposes of this in vitro study were to investigate whether the addition of dexamethasone can compensate for any cytotoxic effects of the amide-type local anesthetics (LA) bupivacaine and ropivacaine and whether morphine and morphine-6-glucuronide (M6G) may be a safe alternative for peritendinous application., Methods: Biopsies of human biceps tendons ( n  = 6) were dissected and cultivated. Cells were characterized by the expression for tenocyte markers, collagen I, biglycan, tenascin C, scleraxis, and RUNX via reverse transcriptase-polymerase chain reaction and immunohistochemistry. Tenocytes were incubated with bupivacaine, ropivacaine, morphine, M6G, or a saline control with and without addition of dexamethasone for 15, 60, or 240 min. Cell viability was determined by quantifying the presence of adenosine-triphosphate., Results: Significant time-dependent cytotoxic effects were observed for LA after all exposure times. After 15, 60, and 240 minutes, cell viability decreased to 81.1%, 49.4% and 0% ( P < .001) for bupivacaine and to 81.4%, 69.6%, and 9.3% ( P < .001) for ropivacaine compared to saline control. Dexamethasone did not compensate for these cytotoxic effects. Cell viability was not affected after 15, 60-min exposures to morphine and M6G but decreased significantly ( P < .001) after 240 minutes compared to saline control. However, in combination with dexamethasone, tenocyte viability was significantly increased at all times for morphine ( P < .01) and at 15 and 60 minutes for M6G ( P < .01)., Conclusions: The results showed that amide-type LA have a time-dependent cytotoxic effect on human tenocytes in vitro, which could not be compensated for by dexamethasone, whereas morphine and M6G had no cytotoxic effects on tenocytes after 15 and 60 minutes. The addition of dexamethasone to morphine and M6G had a positive effect on viability, which increased significantly compared to the opioids., Clinical Relevance: It is known that amide-type local anesthetics used for local joint analgesia have chondrotoxic side-effects. The combined application of morphine and dexamethasone may be a safe alternative., (© 2021 The Authors.)

Previous studies of the brown bear (Ursus arctos) on Hokkaido Island, Japan, have detected three geographically distinct subpopulations representing different mitochondrial lineages and shown that gene flow between subpopulations has occurred due to male-biased dispersal. In this study, we determined whole-genomic sequences for six Hokkaido brown bears and analyzed these data along with previously published genomic sequences of 17 brown bears from other parts of the world. We found that the Hokkaido population is genetically distinct from the other populations, keeping genetic diversity higher than the endangered populations in western Europe but lower than most populations on the continents. A reconstruction of historical demography showed no increase in population size for the Hokkaido population during the Eemian interglacial period (130,000-114,000 years ago). In a phylogenetic analysis of the autosomal data, the Hokkaido population formed a clade distinct from North American and European populations, showing that it has maintained genetic diversity independently from continental populations following geographical isolation on the island. This autosomal genetic similarity contrasts with the geographically separate mitochondrial lineages on Hokkaido and indicates the occurrence of male-driven gene flow between subpopulations., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)