Unimolecular Chemiexcited Oxygenation of Pathogenic Amyloids.

Pathogenic protein aggregates, called amyloids, are etiologically relevant to various diseases, including neurodegenerative Alzheimer disease. Catalytic photooxygenation of amyloids, such as amyloid-ß (Aß), reduces their toxicity; however, the requirement for light irradiation may limit its utility in large animals, including humans, due to the low tissue permeability of light. Here, we report that Cypridina luciferin analogs, dmCLA-Cl and dmCLA-Br, promoted selective oxygenation of amyloids through chemiexcitation without external light irradiation. Further structural optimization of dmCLA-Cl led to the identification of a derivative with a polar carboxylate functional group and low cellular toxicity: dmCLA-Cl-acid. dmCLA-Cl-acid promoted oxygenation of Aß amyloid and reduced its cellular toxicity without photoirradiation. The chemiexcited oxygenation developed in this study may be an effective approach to neutralizing the toxicity of amyloids, which can accumulate deep inside the body, and treating amyloidosis.

Impact of Surgical Timing on Functional Outcomes after Anterior Cruciate Ligament Reconstruction.

Objectives: Although acute anterior cruciate ligament reconstruction (ACLR) is often avoided because of postoperative joint stiffness, delayed ACLR can lead to a longer recovery time and can have a negative impact on physical function due to detraining. This study aimed to determine the effects of acute ACLR on postoperative outcomes, including muscle strength, performance, and return to sports. Methods: A total of 110 patients who underwent anatomical ACLR using hamstring autografts were included in this study and were divided into three groups: acute (ACLR performed within 2 weeks after ACL injury), 2-6 weeks (ACLR performed between 2 and 6 weeks after injury), and 6-12 weeks (ACLR performed between 6 and 12 weeks after injury). Several parameters were evaluated, including range of motion, knee joint stability, isokinetic knee strength, performance, and return to sports. Results: No significant differences were found in the range of motion or knee joint stability between the groups. The acute group exhibited significantly greater quadriceps strength at 3 months postoperatively than the other groups (p < 0.05). The single-leg hop test showed that 66.7%, 38.7%, and 33.3% of the patients in the acute, 2-6 weeks, and 6-12 weeks groups, respectively, recovered to an LSI of 90% or greater (p = 0.09, Cramer's V = 0.27). All patients in the acute group were able to return to sports (p = 0.14; Cramer's V = 0.28). Conclusions: Acute ACLR is advantageous for the early recovery of strength and performance without adverse events. Acute ACLR may shorten the time spent away from sports activities.

Risk factors for contralateral total knee arthroplasty after unilateral total knee arthroplasty.

BACKGROUND: Little attention has been focused on risk factors for undergoing bilateral total knee arthroplasty (TKA) after primary unilateral TKA among patients with knee osteoarthritis (OA). This study investigated the differences in characteristics between groups with and without additional TKA for the contralateral knee among patients with knee OA who underwent primary unilateral TKA. METHODS: Seventy-six patients who underwent primary unilateral TKA were included in this study. We defined patients who underwent additional TKA for the contralateral knee within one year of the primary TKA as a bilateral TKA group, and patients who did not undergo bilateral TKA as a unilateral TKA group. Femorotibial angle (FTA), percentage of mechanical axis (%MA), Kellgren-Lawrence (KL) grade, range of motion, Japan Orthopaedic Association (JOA) score, 10 m-walking time, C-reactive protein, estimated glomerular filtration rate, and serum albumin levels were selected as independent variables including covariates of age, sex, and body mass index for predicting bilateral TKA. We compared differences in variables between the two groups using the t-test or Mann-Whitney U-test and general linear models. A multivariate stepwise logistic regression model was also used to determine which variables correlated with bailateral TKA. RESULTS: In pairwise comparisons, the KL grade, FTA, %MA, JOA score, and knee flexion angle in the contralateral knee were significantly worse in the bilateral TKA group than in the unilateral TKA group after controlling for covariates (P < 0.01, respectively). A stepwise logistic regression revealed that significant contributors to undergoing the contralateral TKA were FTA (OR = 1.47, P < 0.001) and knee flexion angle (OR = 0.96, P = 0.022) of the contralateral knee. CONCLUSIONS: Severe varus deformity and limitations of flexion in the contralateral knee were found to be risk factors for undergoing additional TKA within one year of primary unilateral TKA among patients with knee OA.

Superconducting quantum circuit of NOR in quantum annealing.

The applicability of quantum annealing to various problems can be improved by expressing the Hamiltonian using a circuit satisfiability problem. We investigate the detailed characteristics of the NOR/NAND functions of a superconducting quantum circuit, which are the basic building blocks to implementing various types of problem Hamiltonians. The circuit is composed of superconducting flux qubits with all-to-all connectivity, where direct magnetic couplers are utilized instead of the variable couplers in the conventional superconducting quantum circuit. This configuration provides efficient scalability because the problem Hamiltonian is implemented using fewer qubits. We present an experiment with a complete logic operation of NOR/NAND, in which the circuit produces results with a high probability of success for arbitrary combinations of inputs. The features of the quantum circuit agree qualitatively with the theory, especially the mechanism for an operation under external flux modulation. Moreover, by calibrating the bias conditions to compensate for the offset flux from the surrounding circuit, the quantum circuit quantitatively agrees with the theory. To achieve true quantum annealing, we discuss the effects of the reduction in electric noise in quantum annealing.

Factorization by quantum annealing using superconducting flux qubits implementing a multiplier Hamiltonian.

Prime factorization (P = M × N) is a promising application for quantum computing. Shor's algorithm is a key concept for breaking the limit for analyzing P, which cannot be effectively solved by classical computation; however, the algorithm requires error-correctable logical qubits. Here, we describe a quantum annealing method for solving prime factorization. A superconducting quantum circuit with native implementation of the multiplier Hamiltonian provides combinations of M and N as a solution for number P after annealing. This circuit is robust and can be expanded easily to scale up the analysis. We present an experimental and theoretical exploration of the multiplier unit. We demonstrate the 2-bit factorization in a circuit simulation and experimentally at 10 mK. We also explain how the current conditions can be used to obtain high success probability and all candidate factorized elements.

Meniscal Repair Using Fibrin Clots Made From Bone Marrow Blood Wrapped in a Polyglycolic Acid Sheet.

Meniscal repair is one of the most common procedures for meniscal tears; however, a previous systematic review showed meniscal repairs have a greater reoperation rate compared with partial meniscectomies. Therefore, an improvement of existing meniscal repair techniques is warranted. Clinical results of polyglycolic acid (PGA) sheets have been reported for rotator cuff repairs. In recent years, we have performed meniscal repairs using wrapped fibrin clots in PGA sheet. We considered the use of wrapped fibrin clots with a PGA sheet to treat meniscus tears. The purpose of this paper is to introduce a step-by-step guide to our new delivery technique using fibrin clots.

The Cut-off Value of Physical Activity for Undergoing Total Knee Arthroplasty in Patients with Knee Osteoarthritis.

BACKGROUND: We aimed to determine a cut-off value for physical activity (PA), measured using an accelerometer, between patients with knee osteoarthritis (OA) who decided to undergo total knee arthroplasty (TKA) and those who continued conservative treatment. METHODS: Forty-two participants were assigned to either a TKA group or a non-TKA group (21 per group). They were instructed to wear an accelerometer throughout the day. Average daily steps (steps/day), average daily time of light PA (LPA) (min/day), and average daily time of moderate-to-vigorous PA (MVPA) (min/day) were measured for seven days. Variables between the two groups were compared using univariate analyses, and then a stepwise logistic regression was conducted to determine which variables best correlated with undergoing TKA. The PA cut-offs were analysed using the receiver operating characteristic curve. RESULTS: Pain severity (p = 0.002), KL grade (p = 0.001), and MVPA (p = 0.012) differed significantly between the groups. The most useful cut-off value was 5.84 (min/day) for MVPA (AUC = 0.773), although only pain severity and KL grade were found to be significant contributors to undergoing TKA. CONCLUSIONS: Our results revealed there was a significant decrease in PA levels (MVPA cut-off, 5-6 min/day) in the TKA group compared with the non-TKA group.

Efficacy of Methotrexate on Rat Knee Osteoarthritis Induced by Monosodium Iodoacetate.

OBJECTIVE: To explore whether methotrexate (MTX) prevents joint destruction and improves pain-related behaviors in the acute phase of knee osteoarthritis (OA) induced by monosodium iodoacetate (MIA) in a rat model. METHODS: Twenty of 25 male Wistar rats (10-14 weeks old) received 3 mg MIA via intra-articular injection into their right knee and were then administered a vehicle control (n=10) or 3 mg/kg MTX orally weekly (n=10). We assessed differences in pain-related behavior, spontaneous lifting behavior, micro-computed tomography (CT), histopathology, and expression of pain- and inflammatory-related genes using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) between the two groups for 4 weeks. Five rats were used as untreated controls to assess pain- and inflammatory-related mRNA expression in the dorsal root ganglia (DRG) and knee joints using RT-qPCR. RESULTS: Joint destruction and mechanical hyperalgesia were observed in the vehicle group. Decreases in mechanical pain thresholds for the knee joint and calf muscles were improved after MTX administration; however, joint damage assessed by micro-CT and histopathology was not significantly inhibited by MTX administration, while upregulation levels of transient receptor potential cation channel, subfamily V, member 1 (TRPV-1) (P<0.01) and brain-derived neurotrophic factor (BDNF) (P=0.02) mRNA in the DRG and nerve growth factor NGF mRNA (P=0.03) in the affected knee joints were significantly suppressed in the MTX group compared with the vehicle group at week 4. CONCLUSION: Our results imply that MTX administration improves pain-related behaviors and suppresses expression of pain-related mRNAs in the DRG and knee joint; however, MTX is not expected to prevent cartilage degeneration in MIA-induced OA in rat knee.

Live-cell epigenome manipulation by synthetic histone acetylation catalyst system.

Chemical modifications of histones, such as lysine acetylation and ubiquitination, play pivotal roles in epigenetic regulation of gene expression. Methods to alter the epigenome thus hold promise as tools for elucidating epigenetic mechanisms and as therapeutics. However, an entirely chemical method to introduce histone modifications in living cells without genetic manipulation is unprecedented. Here, we developed a chemical catalyst, PEG-LANA-DSSMe 11, that binds with nucleosome's acidic patch and promotes regioselective, synthetic histone acetylation at H2BK120 in living cells. The size of polyethylene glycol in the catalyst was a critical determinant for its in-cell metabolic stability, binding affinity to histones, and high activity. The synthetic acetylation promoted by 11 without genetic manipulation competed with and suppressed physiological H2B ubiquitination, a mark regulating chromatin functions, such as transcription and DNA damage response. Thus, the chemical catalyst will be a useful tool to manipulate epigenome for unraveling epigenetic mechanisms in living cells.

Atypical Sarcoidosis Diagnosed by Massive Splenomegaly.

We examined a 22-year-old woman who was admitted to our hospital with abdominal distention. At 19 years of age, the patient presented with hepatosplenomegaly. She was examined several times in another hospital; however, the cause was unidentified. Our evaluation showed severe pancytopenia and a spleen 13×24 cm in size. The serum levels of angiotensin-converting enzyme and lysozyme were elevated. She was diagnosed with liver sarcoidosis based on non-caseating epithelioid granuloma in liver biopsy tissue. To improve the symptoms, splenectomy was performed, and her pancytopenia and symptoms improved. Sarcoidosis should be considered in cases of massive splenomegaly.

Failure risks in anatomic single-bundle anterior cruciate ligament reconstruction via the outside-in tunnel technique using a hamstring autograft.

PURPOSE: To retrospectively evaluate the failure risk factors in anatomic single-bundle anterior cruciate ligament (ACL) reconstruction via outside-in tunnel technique using a hamstring autograft, and investigate the relationship between each risk factor. METHODS: The patients who underwent the ACL reconstruction with a minimum 1-year follow-up were included. We divided the patients into two groups - those who experienced graft failure (the failure group) and those who did not experience graft failure (the no failure group) - and compared their age, height, weight, sports activity level, graft size, and muscle strength. We defined graft failure as patients who underwent revision ACL reconstruction or had a second injurious ACL episode and those with a graft grade of C or D based on the International Knee Documentation Committee score. RESULTS: The study included 232 patients (101 male, 131 female; mean age at operation was 26.1 ±â€¯11.9 years). The failure rate was 11.6% (failure group: 27 patients; no failure group: 205 patients). The patients in the failure group were younger and had higher sports activity level than those in the no failure group. (p < 0.001 and p < 0.001, respectively). Patient body weight in the failure group was lower than that in the no failure group (p = 0.047). Regarding the graft size of the tibial side, the failure group had smaller graft sizes than the no failure group (p = 0.030). With respect to muscle strength, quadriceps strength 6 months after surgery in the failure group was stronger than that in the no failure group (p = 0.001). In addition, the hamstring/quadriceps strength (H/Q) ratios 3 and 6 months after surgery were lower in the failure group than that in the no failure group (p = 0.041 and p = 0.001, respectively). There was an association between the age and the body weight, between the body weight and the graft size of the tibial side, and between lower age and high sports activity. Moreover, the high quadriceps strength at 6 months and the low H/Q ratio at 3 months were related to the low H/Q ratio at 6 months. CONCLUSION: Young age, high activity sports level, low body weight, small graft diameter of the tibial side, high quadriceps strength at 6 months, and low H/Q ratio at 3 and 6 months can be failure risk factors in anatomic single-bundle ACL reconstruction via the outside-in tunnel technique using a hamstring autograft.

Reversibility and energy dissipation in adiabatic superconductor logic.

Reversible computing is considered to be a key technology to achieve an extremely high energy efficiency in future computers. In this study, we investigated the relationship between reversibility and energy dissipation in adiabatic superconductor logic. We analyzed the evolution of phase differences of Josephson junctions in the reversible quantum-flux-parametron (RQFP) gate and confirmed that the phase differences can change time reversibly, which indicates that the RQFP gate is physically, as well as logically, reversible. We calculated energy dissipation required for the RQFP gate to perform a logic operation and numerically demonstrated that the energy dissipation can fall below the thermal limit, or the Landauer bound, by lowering operation frequencies. We also investigated the 1-bit-erasure gate as a logically irreversible gate and the quasi-RQFP gate as a physically irreversible gate. We calculated the energy dissipation of these irreversible gates and showed that the energy dissipation of these gate is dominated by non-adiabatic state changes, which are induced by unwanted interactions between gates due to logical or physical irreversibility. Our results show that, in reversible computing using adiabatic superconductor logic, logical and physical reversibility are required to achieve energy dissipation smaller than the Landauer bound without non-adiabatic processes caused by gate interactions.