Synthesis of bioengineered heparin chemically and biologically similar to porcine-derived products and convertible to low MW heparin.

Heparins have been invaluable therapeutic anticoagulant polysaccharides for over a century, whether used as unfractionated heparin or as low molecular weight heparin (LMWH) derivatives. However, heparin production by extraction from animal tissues presents multiple challenges, including the risk of adulteration, contamination, prion and viral impurities, limited supply, insecure supply chain, and significant batch-to-batch variability. The use of animal-derived heparin also raises ethical and religious concerns, as well as carries the risk of transmitting zoonotic diseases. Chemoenzymatic synthesis of animal-free heparin products would offer several advantages, including reliable and scalable production processes, improved purity and consistency, and the ability to produce heparin polysaccharides with molecular weight, structural, and functional properties equivalent to those of the United States Pharmacopeia (USP) heparin, currently only sourced from porcine intestinal mucosa. We report a scalable process for the production of bioengineered heparin that is biologically and compositionally similar to USP heparin. This process relies on enzymes from the heparin biosynthetic pathway, immobilized on an inert support and requires a tailored N-sulfoheparosan with N-sulfo levels similar to those of porcine heparins. We also report the conversion of our bioengineered heparin into a LMWH that is biologically and compositionally similar to USP enoxaparin. Ultimately, we demonstrate major advances to a process to provide a potential clinical and sustainable alternative to porcine-derived heparin products.

Tunnel-Structured Phosphate Exhibiting High Proton Conductivity and Thermal Stability over a Wide Intermediate Temperature Range.

For the practical application of fuel cells in vehicles, it is a challenge to develop a proton solid electrolyte that coexhibits thermal stability and high proton conductivity at wide intermediate temperatures. Here, we report on the tunnel structured phosphate KNi1-xH2x(PO3)3·yH2O, which exhibits high proton conductivity at room temperature up to 500 °C, with the conductivity value reaching 1.7 × 10-2 S cm-1 at 275 °C for x = 0.18. This material, composed of the smallest cations that form the tunnel framework with face-shared (KO6) and (NiO6) chains and PO4 tetrahedral chains, retained the rigid framework up to 600 °C. Two oxygen sites of water molecules located adjacent to each other along the PO4 tetrahedral chains in the tunnel provided the proton conduction pathway. The sample maintained a conductivity of 5.0 × 10-3 S cm-1 for 10 h at 150 °C while changing the measurement atmosphere to a N2 gas flow, a 4% H2-96% Ar gas flow, and an O2 gas flow. The conductivity value at x = 0.18 obtained from the DC measurement was in the order of 10-6 S cm-1, close to the instrument's measurement limit. These results demonstrate that tunnel phosphate has potential as a proton solid electrolyte for next-generation fuel cells.

Effect of single-administration of D-sorbitol pretreatment on the bitterness and continued willingness to take asenapine: a randomized, single-blind, placebo-controlled, crossover trial.

BACKGROUND: Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of D-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia. METHODS: Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of D-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point). RESULTS: D-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste. CONCLUSION: Our findings indicate that single-administration of D-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.

Seabuckthorn (Hippophae rhamnoides, L.) pulp oil prevents ultraviolet-induced damage in human fibroblasts.

Seabuckthorn pulp oil (SBO) is used in beauty products because of its rich lipophilic substances with high nutraceutical and cosmeceutical potential. However, the mechanism through which SBO enhances skin elasticity remains unclear. Therefore, in this study, we examined the anti-photoaging activity of SBO in normal human dermal fibroblasts (NHDF) under ultraviolet (UV) irradiation. Pretreatment with SBO significantly suppressed UV-B-induced cell toxicity and collagen degradation, suggesting that SBO contains anti-photoaging substances. Further, palmitoleic acid, the main component of SBO, maintained cell viability and collagen levels in UV-B-irradiated NHDF by suppressing the expression of matrix metalloproteinase 1 and acted on the inhibition of p38 and JNK phosphorylation and nuclear translocation of nuclear factor-kappa B. These findings suggest the utility of SBO as an anti-photoaging agent.

Coracoclavicular and acromioclavicular ligament reconstruction with a double-bundle semitendinosus autograft and cortical buttons for chronic acromioclavicular joint dislocations: clinical and imaging outcomes.

BACKGROUND: There are few clinical and radiographic studies of coracoclavicular (CC) ligament reconstruction in chronic acromioclavicular (AC) joint dislocation. Additionally, reported AC joint reduction rates vary. HYPOTHESIS: Arthroscopically assisted double-bundle semitendinosus tendon autografts with CC and AC ligament reconstruction for AC joint reconstruction provide AC joint stability and improved function at the final visit. METHODS: In this retrospective study of prospectively collected data, 21 patients surgically treated for chronic AC joint dislocation (Rockwood III-V) were assessed clinically and radiographically preoperatively, and at day 1, 3 months, 12 months, and at a final visit (>24 months) postoperatively. Clinical assessments included Constant and American Shoulder and Elbow Surgeons scores. The CC vertical distance (CCD) on the affected and unaffected sides [CCD ratio (%)] on the anterosuperior view were measured. AC joint vertical reduction loss was defined as an increase in the CCD ratio of >25%. Horizontal AC joint instability was evaluated on axillary views. Pearsons' correlation coefficients were generated to examine the relationships among postoperative clinical scores, CCD ratio, interval from injury to surgery, and age at the time of surgery. RESULTS: Twenty-one shoulders in 21 patients (mean age, 40.0 years at the time of surgery; 16 men, 5 women) were evaluated with a mean 31.7-month follow-up period. The mean Constant scores, American Shoulder and Elbow Surgeons scores, and CCD ratios significantly improved from preoperatively to the final visit (57.4 ± 10.1, 49.1 ± 12.1, 101.6 ± 64.1 preoperatively; 89.6 ± 5.3, 96.5 ± 4.2, 9.9 ± 34.5 at the final visit, respectively [P < .001 for all]). Vertical AC and horizontal AC joint instability were observed in 4 shoulders (19.0%) and in 1 shoulder (4.8%), respectively. However, there was no significant correlation between the increase in CCD and clinical scores at the final visit (Constant score; r = 0.179, P = .438: American Shoulder and Elbow Surgeons score; r = -0.260, P = .256) or the interval from injury to surgery (r = 0.099, P = .669) or age at the time of surgery (r = 0.019, P = .935). No clinical complications were associated with clinical symptoms. CONCLUSIONS: Patients who underwent the index procedure achieved significant improvement in shoulder function without complications related clinical symptom after a mean follow-up interval of 31.7 months. In contrast, the rates of total ACJ instability in the vertical and horizontal planes were unsatisfactory but compatible with those in previous studies.

Inhibition of Rho-kinase ameliorates decreased spine density in the medial prefrontal cortex and methamphetamine-induced cognitive dysfunction in mice carrying schizophrenia-associated mutations of the Arhgap10 gene.

Copy-number variations in the ARHGAP10 gene encoding Rho GTPase-activating protein 10 are associated with schizophrenia. Model mice (Arhgap10 S490P/NHEJ mice) that carry "double-hit" mutations in the Arhgap10 gene mimic the schizophrenia in a Japanese patient, exhibiting altered spine density, methamphetamine-induced cognitive dysfunction, and activation of RhoA/Rho-kinase signaling. However, it remains unclear whether the activation of RhoA/Rho-kinase signaling due to schizophrenia-associated Arhgap10 mutations causes the phenotypes of these model mice. Here, we investigated the effects of fasudil, a brain permeable Rho-kinase inhibitor, on altered spine density in the medial prefrontal cortex (mPFC) and on methamphetamine-induced cognitive impairment in a touchscreen­based visual discrimination task in Arhgap10 S490P/NHEJ mice. Fasudil (20 mg/kg, intraperitoneal) suppressed the increased phosphorylation of myosin phosphatase-targeting subunit 1, a substrate of Rho-kinase, in the striatum and mPFC of Arhgap10 S490P/NHEJ mice. In addition, daily oral administration of fasudil (20 mg/kg/day) for 7 days ameliorated the reduced spine density of layer 2/3 pyramidal neurons in the mPFC. Moreover, fasudil (3-20 mg/kg, intraperitoneal) rescued the methamphetamine (0.3 mg/kg)-induced cognitive impairment of visual discrimination in Arhgap10 S490P/NHEJ mice. Our results suggest that Rho-kinase plays significant roles in the neuropathological changes in spine morphology and in the vulnerability of cognition to methamphetamine in mice with schizophrenia-associated Arhgap10 mutations.

Increase in rotavirus prevalence with the emergence of genotype G9P[8] in replacement of genotype G12P[6] in Sabah, Malaysia.

Rotaviruses are major causative agents of acute diarrhea in children under 5 years of age in Malaysia. However, a rotavirus vaccine has not been included in the national vaccination program. To date, only two studies have been carried out in the state of Sabah, Malaysia, although children in this state are at risk of diarrheal diseases. Previous studies showed that 16%-17% of cases of diarrhea were caused by rotaviruses and that equine-like G3 rotavirus strains are predominant. Because the prevalence of rotaviruses and their genotype distribution vary over time, this study was conducted at four government healthcare facilities from September 2019 through February 2020. Our study revealed that the proportion of rotavirus diarrhea increased significantly to 37.2% (51/137) after the emergence of the G9P[8] genotype in replacement of the G12P[8] genotype. Although equine-like G3P[8] strains remain the predominant rotaviruses circulating among children, the Sabahan G9P[8] strain belonged to lineage VI and was phylogenetically related to strains from other countries. A comparison of the Sabahan G9 strains with the G9 vaccine strains used in the RotaSiil and Rotavac vaccines revealed several mismatches in neutralizing epitopes, indicating that these vaccines might not be effective in Sabahan children. However, a vaccine trial may be necessary to understand the precise effects of vaccination.

Sensory evaluation of the bitterness of asenapine using D-sorbitol pretreatment: single-blind, placebo-controlled, crossover trial.

BACKGROUND: Antipsychotics are essential in the acute treatment of and maintenance therapy for schizophrenia, but medication adherence and long-term treatment continuity are needed to maximize their effectiveness. Each antipsychotic has various side effects, which may affect adherence. Some patients with schizophrenia are reluctant to take asenapine because of its unique oral-related side effects, such as the bitter taste caused by sublingual administration. Our previous basic research found that D-sorbitol lowered the bitterness parameters of the taste sensors. However, whether D-sorbitol has the same effect in patients remains unclear. Therefore, using a D-sorbitol solution, we aim to evaluate changes in the bitterness of asenapine among patients with schizophrenia. METHODS: In this single-blind, placebo-controlled, crossover trial, we plan to recruit 20 adult patients with schizophrenia spectrum disorder who take sublingual asenapine tablets. The participants will be divided into two groups (n = 10 each). Each group will be given a D-sorbitol or placebo solution on the first day for rinsing before taking the sublingual asenapine tablets. After a 1-day interval, the participants will rinse their mouths again with a different liquid. Questionnaires regarding changes in taste and the willingness to continue asenapine will be conducted before the start of the study and after each rinse. The primary and secondary end points will be a taste evaluation of bitterness, and the willingness to continue asenapine, respectively. Differences in questionnaire scores between the D-sorbitol and placebo solutions will be calculated and analyzed using a McNemar test. DISCUSSION: This study aims to determine the efficacy of D-sorbitol in masking the bitter taste of asenapine. To our knowledge, it is the first intervention study using D-sorbitol for bitter taste of asenapine in patients with schizophrenia. Evidence of the efficacy of D-sorbitol could result in D-sorbitol pretreatment being an easy and inexpensive means of improving adherence to asenapine. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials jRCTs041210019, on May 14, 2021. Ethics approval was obtained from the Nagoya University Clinical Research Review Board.

Prognostic Implications of Urinary Potassium to Creatinine Ratio in Patients With Predialysis Chronic Kidney Disease: A Cohort Study.

OBJECTIVES: Although a low or high serum potassium level in chronic kidney disease (CKD) is associated with worsening renal function and increased cardiovascular disease (CVD) events, urinary potassium excretion has been found to predict adverse health outcomes with conflicting results. We conducted a cohort study to determine whether urinary potassium to creatinine (K/Cr) ratio is an independent risk for further deterioration in renal function or increased CVD events. METHODS: We identified 650 predialysis patients with CKD hospitalized for an educational program regarding CKD between January 2010 and December 2018. The study outcomes were CKD progression and incident CVD events, with baseline urinary K/Cr ratio categorized into quartiles-Q1, < 19.8; Q2, 19.9-27.7; Q3, 27.8-37.9; and Q4, > 38.0. RESULTS: During follow-up (median, 35 months), 509 CKD progressions and 129 incident CVD events were identified. Sixty two patients died during follow-up. Multivariate Cox proportional hazard model showed that after adjustment for demographic factors and laboratory data, patients in Q1 had a 2.02-fold higher risk of worsening renal function than those in Q4 (95% confidence interval, 1.50-2.71; P < .001), whereas urinary K/Cr ratio had no association with the incidence of CVD events. Similarly, inverse probability weighting analysis showed an increased risk of CKD progression in the lowest quartile. Furthermore, the association between low fractional excretion of potassium and worsening renal function was confirmed. CONCLUSION: A low urinary K/Cr ratio is independently associated with worsening renal function but not with a risk of incident CVD event in predialysis patients with CKD.

Functional connector hubs in the cerebellum.

Accumulating evidence from anatomical and neuroimaging studies suggests that the cerebellum is engaged in a variety of motor and cognitive tasks. Given its various functions, a key question is whether the cerebellum also plays an important role in the brain's integrative functions. Here, we hypothesize the existence of connector regions, also known as connector hubs, where multiple resting state networks converged in the cerebellum. To verify this, we employed a recently developed voxel-level network measure called functional connectivity overlap ratio (FCOR), which could be used to quantify the spatial extent of a region's connection to several large-scale cortical networks. Using resting state functional MRI data from 101 healthy participants, cerebellar FCOR maps were constructed and used to identify the locations of connector hubs in the cerebellum. Results showed that a number of cerebellar regions exhibited strong connectivity with multiple functional networks, verifying our hypothesis. These highly connected regions were located in the posterior cerebellum, especially in lobules VI, VII, and IX, and mainly connected to the core neurocognitive networks such as default mode and executive control networks. Regions associated with the sensorimotor network were also localized in lobule V, VI, and VIII, albeit in small clusters. These cerebellar connector hubs may play an essential role in the processing of information across the core neurocognitive networks.

Regulation of osteoarthritis development by ADAM17/Tace in articular cartilage.

INTRODUCTION: A disintegrin and metalloproteinase 17 (Adam17), also known as TNFα-converting enzyme (Tace), is a membrane-anchored protein involved in shedding of TNF, IL-6 receptor, ligands of epidermal growth factor receptor (EGFR), and Notch receptor. This study aimed to examine the role of Adam17 in adult articular cartilage and osteoarthritis (OA) pathophysiology. MATERIALS AND METHODS: Adam17 expression was examined in mouse knee joints during OA development. We analyzed OA development in tamoxifen-inducible chondrocyte-specific Adam17 knockout mice of a resection of the medial meniscus and medial collateral ligament (medial) model, destabilization of the medial meniscus (DMM) model, and aging model. We analyzed downstream pathways by in vitro experiments, and further performed intra-articular administration of an Adam17 inhibitor TAPI-0 for surgically induced mouse OA. RESULTS: Adam17 expression in mouse articular cartilage was increased by OA progression. In all models, Adam17 knockout mice showed ameliorated progression of articular cartilage degradation. Adam17 knockout decreased matrix metallopeptidase 13 (Mmp13) expression in both in vivo and in vitro experiments, whereas Adam17 activation by phorbol-12-myristate-13-acetate (PMA) increased Mmp13 and decreased aggrecan in mouse primary chondrocytes. Adam17 activation enhanced release of soluble TNF and transforming growth factor alpha, a representative EGF ligand, from mouse primary chondrocytes, while it did not change release of soluble IL-6 receptor or nuclear translocation of Notch1 intercellular domain. Intra-articular administration of the Adam17 inhibitor ameliorated OA progression. CONCLUSIONS: This study demonstrates regulation of OA development by Adam17, involvement of EGFR and TNF pathways, and the possibility of Adam17 as a therapeutic target for OA.

The effect of sodium zirconium cyclosilicate on acid-base balance in chronic kidney disease.

Hyperkalemia is a common electrolyte abnormality in chronic kidney disease (CKD). Sodium zirconium cyclosilicate (SZC) is a novel selective cation exchanger that is used to treat hyperkalemia and may also capture ammonium, which is of a similar size to potassium. We investigated the effect of SZC on acid-base balance in CKD patients. This retrospective study surveyed 20 patients with CKD whose serum potassium levels were maintained within the normal range by treatment with polysulfonate resin, which was replaced with SZC during the clinical course. We compared clinical parameters before and after changing medications. Changing the potassium binder from polysulfonate resin to SZC increased serum bicarbonate (p = 0.016) and decreased blood urea nitrogen (p = 0.017). Serum potassium levels were maintained within the normal range. Urine pH, anion gap, and osmolality gap were unchanged during treatment. No gastrointestinal symptoms were noted during the observation period. Our data suggest that SZC may improve not only hyperkalemia but also metabolic acidosis by increasing the excretion of ammonium from the intestinal tract in patients with CKD. SZC could be a more suitable medication for CKD patients with hyperkalemia and metabolic acidosis.

Sequencing of selected chromatin remodelling genes reveals increased burden of rare missense variants in ASD patients from the Japanese population.

Chromatin remodelling is an important process in neural development and is related to autism spectrum disorder (ASD) and schizophrenia (SCZ) aetiology. To further elucidate the involvement of chromatin remodelling genes in the genetic aetiology of ASD and SCZ in the Japanese population, we performed a case-control study. Targeted sequencing was conducted on coding regions of four BAF chromatin remodelling complex genes: SMARCA2, SMARCA4, SMARCC2, and ARID1B in 185 ASD, 432 SCZ patients, and 517 controls. 27 rare non-synonymous variants were identified in ASD and SCZ patients, including 25 missense, one in-frame deletion in SMRACA4, and one frame-shift variant in SMARCC2. Association analysis was conducted to investigate the burden of rare variants in BAF genes in ASD and SCZ patients. Significant enrichment of rare missense variants in BAF genes, but not synonymous variants, was found in ASD compared to controls. Rare pathogenic variants indicated by in silico tools were significantly enriched in ASD, but not statistically significant in SCZ. Pathogenic-predicted variants were located in disordered binding regions and may confer risk for ASD and SCZ by disrupting protein-protein interactions. Our study supports the involvement of rare missense variants of BAF genes in ASD and SCZ susceptibility.

Long-term outcomes and duration of outdoor ambulation following primary total knee arthroplasty in patients with rheumatoid arthritis.

BACKGROUND: The medical treatment of rheumatoid arthritis (RA) has made remarkable progress with the introduction of methotrexate and biological agents. However, there have been few reports of long-term results of total knee arthroplasty (TKA) for RA since the introduction of these drugs. Ambulation is an important form of exercise for maintaining health. We investigated the long-term outcomes and the ability to walk outdoors following TKA in patients with RA. METHODS: We retrospectively reviewed 142 patients with RA (201 knees) who had undergone primary TKA. The mean follow-up was 10.6 years. RESULTS: Markers of RA disease activity all improved significantly postoperatively. Mean Japanese Orthopedic Association scores improved from 49.3 points before surgery to 81.8 at follow-up. The mean maximum flexion angle improved from 107.8° to 112.9°. The causes of TKA revision comprised 2 mechanical loosening, 1 late infection, and 1 fracture of the femoral condyle. The survival rate of TKA was 96.6% at 15 years. Fifty-five patients were not able to walk outdoors. The rate of inability to ambulate outdoors was 38.3 per 1000 person-years. The survival rate of ability to ambulate outdoors were 48.8% at 15 years. Preoperative advanced age, low body weight, steroid use and non-use of biologics were identified as risk factors for inability to ambulate outdoors. CONCLUSIONS: Although the cumulative survival rate of TKA implants was as good as 96.6% in 15 years, the cumulative rate of ability to ambulate outdoors was only 48.8%. The reason for the inability to walk outdoors was thought to be mainly due to deterioration of RA, comorbidity or muscular weakness associated with aging, rather than knee dysfunction.

Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial.

Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18-48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P < .001) but placebo also reduced the score (8.3 to 7.2; P < .001), no between-group difference was found (effect size -0.08; 95% CI, -0.46 to 0.31; P = .69); however, plasma oxytocin was only elevated from baseline to endpoint in the oxytocin-group compared with the placebo-group (effect size -1.12; -1.53 to -0.70; P < .0001). Among the secondary endpoints, oxytocin reduced ADOS repetitive behavior (2.0 to 1.5; P < .0001) compared with placebo (2.0 to 1.8; P = .43) (effect size 0.44; 0.05 to 0.83; P = .026). In addition, the duration of gaze fixation on socially relevant regions, another secondary endpoint, was increased by oxytocin (41.2 to 52.3; P = .03) compared with placebo (45.7 to 40.4; P = .25) (effect size 0.55; 0.10 to 1.0; P = .018). No significant effects were observed for the other secondary endpoints. No significant difference in the prevalence of adverse events was observed between groups, although one participant experienced temporary gynecomastia during oxytocin administration. Based on the present findings, we cannot recommend continuous intranasal oxytocin treatment alone at the current dose and duration for treatment of the core social symptoms of high-functioning ASD in adult men, although this large-scale trial suggests oxytocin's possibility to treat ASD repetitive behavior.

New cell delivery system CellSaic with adipose-derived stromal cells promotes functional angiogenesis in critical limb ischemia model mice.

Current therapies for patients with critical limb ischemia have not reduced amputation risk owing to poor cell engraftment. The recombinant peptide Cellnest increases the engraftment rate of administered cells by forming a complex with the cells (CellSaic). We hypothesized that CellSaic containing adipose-derived stromal cells (ADSCs) could improve lower limb blood flow better than ADSCs alone, resulting in better transplanted cell engraftment. ADSCs were extracted from 8-week-old C57BL/6N mice. Thirty-two critical limb ischemia model mice were established by ligating femoral arteries. They were divided into CellSaic (n = 11), ADSC (n = 10), saline (n = 9), and Cellnest (n = 9) groups. Blood flow rate (affected side blood flow / healthy side blood flow × 100%) was evaluated using a laser Doppler blood flow meter every week. Mice were euthanized on day 28 for histological evaluation. Compared with the ADSC group (54.5 ± 17.2%), treated side blood flow rate of the CellSaic group (78.0 ± 24.9%) showed significant improvement on day 28 after administration (p < 0.05). CD31 staining showed significantly higher number of capillary vessels in the CellSaic group (53.0 ± 8.9 cells/mm3) than in the ADSC group (43.0 ± 6.8 cells/mm3) (p < 0.05). Fluorescent staining showed significantly higher number of arterioles containing both CD31 and αSMA double-positive cells in the CellSaic group than in the ADSC group (p < 0.05). CellSaic containing ADSCs exhibited superiority to ADSC transplantation alone in promoting functional angiogenesis, suggesting its potential in improving clinical outcomes of angiogenic therapy for ischemic limbs.

Identifying the brain's connector hubs at the voxel level using functional connectivity overlap ratio.

Neuroimaging studies have shown that the brain is functionally organized into several large-scale brain networks. Within these networks are regions that are widely connected to several other regions within and/or outside the network. Regions that connect to several other networks, known as connector hubs, are believed to be crucial for information transfer and between-network communication within the brain. To identify regions with high between-network connectivity at the voxel level, we introduced a novel metric called functional connectivity overlap ratio (FCOR), which quantifies the spatial extent of a region's connection to a given network. Using resting state functional magnetic resonance imaging data, FCOR maps were generated for several well-known large-scale resting state networks (RSNs) and used to examine the relevant associations among different RSNs, identify connector hub regions in the cerebral cortex, and elucidate the hierarchical functional organization of the brain. Constructed FCOR maps revealed a strong association among the core neurocognitive networks (default mode, salience, and executive control) as well as among primary processing networks (sensorimotor, auditory, and visual). Prominent connector hubs were identified in the bilateral middle frontal gyrus, posterior cingulate, lateral parietal, middle temporal, dorsal anterior cingulate, and anterior insula, among others, regions mostly associated with the core neurocognitive networks. Finally, clustering the whole brain using FCOR features yielded a topological organization that arranges brain regions into a hierarchy of information processing systems with the primary processing systems at one end and the heteromodal systems comprising connector hubs at the other end.

Changes in white matter fiber density and morphology across the adult lifespan: A cross-sectional fixel-based analysis.

White matter (WM) fiber bundles change dynamically with age. These changes could be driven by alterations in axonal diameter, axonal density, and myelin content. In this study, we applied a novel fixel-based analysis (FBA) framework to examine these changes throughout the adult lifespan. Using diffusion-weighted images from a cohort of 293 healthy volunteers (89 males/204 females) from ages 21 to 86 years old, we performed FBA to analyze age-related changes in microscopic fiber density (FD) and macroscopic fiber morphology (fiber cross section [FC]). Our results showed significant and widespread age-related alterations in FD and FC across the whole brain. Interestingly, some fiber bundles such as the anterior thalamic radiation, corpus callosum, and superior longitudinal fasciculus only showed significant negative relationship with age in FD values, but not in FC. On the other hand, some segments of the cerebello-thalamo-cortical pathway only showed significant negative relationship with age in FC, but not in FD. Analysis at the tract-level also showed that major fiber tract groups predominantly distributed in the frontal lobe (cingulum, forceps minor) exhibited greater vulnerability to the aging process than the others. Differences in FC and the combined measure of FD and cross section values observed between sexes were mostly driven by differences in brain sizes although male participants tended to exhibit steeper negative linear relationship with age in FD as compared to female participants. Overall, these findings provide further insights into the structural changes the brain's WM undergoes due to the aging process.

Prognostic value of hypochloremia versus hyponatremia among patients with chronic kidney disease-a retrospective cohort study.

BACKGROUND: Serum chloride (Cl) levels confer better prognostic value than serum sodium (Na) levels among patients with heart failure. Little is known about the relationship between serum Cl levels and clinical outcomes among patients with chronic kidney disease (CKD). METHODS: This was a retrospective cohort study enrolling patients with Stages G3-G5 CKD who visited the nephrology outpatient department of Osaka University Hospital from April 2005 to December 2014. The main exposure was time-varying serum Cl levels categorized as quartiles. The study outcome was a composite of all-cause death and cardiovascular events. RESULTS: A total of 2661 patients with CKD were included in the analysis. During a median follow-up of 4.0 years, 284 deaths and 416 cardiovascular events occurred. Compared with patients in the third Cl quartile, those in the first Cl quartile showed a significantly higher risk of the outcome after adjustment for demographics and clinical factors including time-varying serum Na, serum albumin and bicarbonate levels, and use of diuretics and sodium bicarbonate [hazard ratio (HR) 2.13; 95% confidence interval (CI) 1.20-3.81; P = 0.01] and, additionally, anion gap (HR 2.13; 95% CI 1.26-3.57; P = 0.004). Adding serum Cl levels, but not serum Na levels, to the multivariable model significantly improved net reclassification index (0.335; P < 0.001) and integrated discrimination improvement (0.0113; P = 0.01). CONCLUSIONS: Lower serum Cl levels are an independent predictor of death and cardiovascular events. The incremental prognostic value of Cl was superior to that of Na in patients with CKD.

Chemical stimulus-responsive supramolecular hydrogel formation and shrinkage of a hydrazone-containing short peptide derivative.

Artificial supramolecular nanostructures showing transient properties have attracted significant attention in recent years. New discoveries in this area may provide insights into a better understanding of the sophisticated organization of complex biomolecular systems. Nevertheless, research concerning such materials is still limited. Better knowledge of the chemical reactivity and corresponding molecular transformations of self-assembling molecules, which guide their assembly/disassembly, may provide an opportunity to construct transient supramolecular nanostructures capable of showing chemical stimulus responsiveness. Herein, we report a short peptide derivative containing a hydrazone bond, which shows transient hydrogel formation (no only sol-to-gel but also gel-to-shrunken gel phase transition) accompanied by continuous transformation and growth of supramolecular nanostructures triggered by hydrazone-oxime exchange reaction in response to hydroxylamine. Such controlled shrinkage behavior of supramolecular hydrogels in response to specific chemical stimuli has rarely been explored compared with conventional polymer hydrogel systems.