DJ-1 depletion prevents immunoaging in T-cell compartments.

Decline in immune function during aging increases susceptibility to different aging-related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T-cell subpopulations, still remain largely elusive. Here, we show that loss of DJ-1 encoded by PARK7/DJ-1, causing early-onset familial Parkinson's disease (PD), unexpectedly diminished signs of immunoaging in T-cell compartments of both human and mice. Compared with two gender-matched unaffected siblings of similar ages, the index PD patient with DJ-1 deficiency showed a decline in many critical immunoaging features, including almost doubled non-senescent T cells. The observation was further consolidated by the results in 45-week-old DJ-1 knockout mice. Our data demonstrated that DJ-1 regulates several immunoaging features via hematopoietic-intrinsic and naïve-CD8-intrinsic mechanisms. Mechanistically, DJ-1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T-cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ-1 in regulating immunoaging, discovering a potent target to interfere with immunoaging- and aging-associated diseases.

Radiomics-based prediction of nonalcoholic fatty liver disease following pancreatoduodenectomy.

PURPOSE: Predicting nonalcoholic fatty liver disease (NAFLD) following pancreaticoduodenectomy (PD) is challenging, which delays therapeutic intervention and makes its prevention difficult. We conducted this study to assess the potential application of preoperative computed tomography (CT) radiomics for predicting NAFLD. METHODS: The subjects of this retrospective study were 186 patients with PD from a single institution. We extracted the predictors of NAFLD after PD statistically from conventional clinical and radiomic features of the estimated remnant pancreas and whole liver region on preoperative nonenhanced CT images. Based on these predictors, we developed a machine-learning predictive model, which integrated clinical and radiomic features. A comparative model used only clinical features as predictors. RESULTS: The incidence of NAFLD after PD was 43.5%. The variables of the clinicoradiomic model included one shape feature of the pancreas, two texture features of the liver, and sex; the variables of the clinical model were age, sex, and chemoradiotherapy. The accuracy%, precision%, recall%, F1 score, and area under the curve of the two models were 75.0, 72.7, 66.7, 69.6, and 0.80; and 69.6, 68.4, 54.2, 60.5, and 0.69, respectively. CONCLUSIONS: Preoperative CT-derived radiomic features from the pancreatic and liver regions are promising for the prediction of NAFLD post-PD. Using these features enhances the predictive model, enabling earlier intervention for high-risk patients.

Effects of Conservative Interventions on Static and Dynamic Balance in Individuals With Chronic Ankle Instability: A Systematic Review and Meta-analysis.

OBJECTIVE: To determine which conservative interventions are effective for static and dynamic balance in patients with chronic ankle instability (CAI). DATA SOURCES: PubMed, Cochrane Library, Web of Sciences, and CINAHL databases were searched up to March 20, 2022. STUDY SELECTION: Randomized controlled trials investigating the effects of conservative interventions on static and/or dynamic balance in patients with CAI compared with those of different conservative interventions or controls were included. DATA EXTRACTION: Two independent reviewers extracted the data. Certainty of the evidence was assessed using the GRADE approach. DATA SYNTHESIS: Forty-eight studies (1906 participants) were included. Whole-body vibration training (WBVT) was significantly more effective than controls for both static (standardized mean difference, 1.13; 95% confidence interval [CI], 0.58-1.68; moderate-certainty evidence) and dynamic balance (0.56; CI, 0.24-0.88; low-certainty evidence). Balance training (BT) and joint mobilization were significantly more effective than controls for dynamic balance (0.77; CI, 0.41-1.14; and 0.75; CI, 0.35-1.14, respectively), but not for static balance (very low to low-certainty evidence). Adding other interventions to BT had no significant effect on either type of balance compared with that of BT alone (moderate to low-certainty evidence). Strength training (ST) and taping had no significant effect on either type of balance (very low- to low-certainty evidence). Multimodal interventions were significantly effective in improving dynamic balance (0.76; CI, 0.32-1.20; low-certainty evidence). Adding transcranial direct current stimulation to ST was significantly more effective for dynamic balance than ST (0.81; CI, 0.08-1.53; moderate-certainty evidence). The effects on balance were not significantly different among BT, ST, and WBVT (very low- to low-certainty evidence). CONCLUSIONS: The significantly effective interventions reviewed may be treatment options for balance impairments associated with CAI. However, interventions should be chosen carefully, as much of the certainty of evidence is very low to low.

Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment.

Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Eµ-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrial membrane potential and IFN-γ production. Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.

Search for Ultralight Dark Matter from Long-Term Frequency Comparisons of Optical and Microwave Atomic Clocks.

We search for ultralight scalar dark matter candidates that induce oscillations of the fine structure constant, the electron and quark masses, and the quantum chromodynamics energy scale with frequency comparison data between a ^{171}Yb optical lattice clock and a ^{133}Cs fountain microwave clock that span 298 days with an uptime of 15.4%. New limits on the couplings of the scalar dark matter to electrons and gluons in the mass range from 10^{-22} to 10^{-20} eV/c^{2} are set, assuming that each of these couplings is the dominant source of the modulation in the frequency ratio. The absolute frequency of the ^{171}Yb clock transition is also determined as 518 295 836 590 863.69(28) Hz, which is one of the important contributions toward a redefinition of the second in the International System of Units.

Protocols of rehabilitation and return to sport, and clinical outcomes after medial patellofemoral ligament reconstruction with and without tibial tuberosity osteotomy: a systematic review.

PURPOSE: No consensus exists on rehabilitation programmes after medial patellofemoral ligament reconstruction (MPFLR) with or without tibial tuberosity osteotomy (TTO). This systematic review examined the content and timeline of rehabilitation (weightbearing, range of motion [ROM] and exercise therapy) and return to sport (RTS), as well as patient-reported outcomes after MPFLR with or without TTO. METHODS: The PubMed, Cochrane Library, Web of Sciences, CINAHL and SPORTDiscus databases were searched from inception to December 2021. Studies that reported postoperative rehabilitation programmes and patient-reported outcomes for patients aged ≥ 18 years who underwent MPFLR with or without concomitant TTO were included. RESULTS: Eighty-five studies were included, 57 of which were case series and only one randomised controlled trial on rehabilitation programmes. Non-weightbearing was set within one week post-operatively in approximately 80% of weightbearing programmes for MPFLR without and with TTO. Joint immobilisation was set within one week post-operatively in 65.3% and 93.8% of programmes for MPFLR without and with TTO, respectively. Weightbearing and ROM (≤ 90°) restriction were within three weeks post-operatively for > 50% of the programmes. Quadriceps strengthening was the most cited exercise therapy (33 programmes), most often initiated within two weeks post-operatively. However, few other exercise programmes were cited (only nine programmes). RTS was mostly noted at six months post-operatively (35 programmes). The weighted mean Kujala score was 87.4 points. CONCLUSION: Regardless of TTO addition to MPFLR, most studies restricted weightbearing and ROM only in the early post-operative period, with seemingly favourable clinical results. Limited information was available on post-operative exercise therapy.

The Reliability and Validity of a Novel Ankle Isometric Plantar Flexion Strength Test.

CONTEXT: Strengthening of ankle plantar flexor muscles is one of the important components in the rehabilitation of many lower limb injuries and disorders. However, there are few simple methods to evaluate ankle plantar flexor strength in clinical situations without using equipment. The purpose of this study was to verify the intraexaminer and interexaminer reliability and the concurrent validity of a novel ankle isometric plantar flexion (PF) strength test (PF break test [PFBT]). DESIGN: Case-control study. METHODS: The intraexaminer and interexaminer reliabilities of the PFBT were evaluated in 57 orthopedic patients and 30 healthy adults. The range of motion of the ankle joint and the number of heel raises were compared between positive and negative PFBT cases. Then, isometric ankle PF torque (ankle PF of 0°, 15°, and 30°) was compared in knee extension and in the 50° flexion position between positive and negative PFBT cases in 30 healthy adults. RESULTS: The intraexaminer reliability (κ) of the PFBT was .81 to .94, and the interexaminer reliability (κ) was .37 to .74. The PFBT positive group had a significantly smaller range of motion in the ankle joint (P < .05) and a significantly lower number of heel raises (P < .001) than the PFBT negative group in orthopedic patients, but no significant differences in healthy adults. The PFBT positive group had less ankle PF torque than the PFBT negative group at all ankle PF angles (P < .01). The isometric PF torque in the end range of ankle PF in knee extension could predict the results of the PFBT and correctly classified 90.0% of cases (P < .001). CONCLUSION: The PFBT is considered a simple and valid method to evaluate isometric ankle PF strength in the clinical setting.

Abnormalities of foot and ankle alignment in individuals with chronic ankle instability: a systematic review.

BACKGROUND: To prevent recurrent ankle sprain, it is important to clarify the pathology of chronic ankle instability (CAI). An association has been reported between CAI and abnormalities of foot posture and ankle alignment. There is no consensus on the types of these abnormalities that occur in individuals with CAI. The objective of this systematic review is to clarify the relevance of abnormality of foot posture and ankle alignment for CAI. METHODS: A systematic computerized literature search was performed of the PubMed, CINAHL, SPORTDiscus, Web of Science, and the Cochrane Register of Clinical Trials databases. The selected studies either compared CAI patients with a control group or CAI ankles with contralateral healthy ankles and specifically reported foot posture and alignment of the ankle in the outcomes. They were written in English and published prior to June 2021. The methodological quality of the included studies was evaluated using a 16-question index. Data were extracted independently by two reviewers, and the certainty of evidence was assessed using GRADE approach. RESULTS: Sixteen studies including 872 patients of high to low methodological quality were included. These showed there was significant anterior displacement and internal rotation of the talus in CAI ankles (low evidence), but there was no consensus on fibular alignment or foot posture. CONCLUSIONS: This review showed there was significant anterior displacement and internal rotation of the talus in CAI ankles but found no consensus on the characteristics of fibular and foot alignment. Further investigations are required to clarify the characteristic foot and ankle malalignment in CAI to facilitate the development of efficient interventions.

Synthesis and biological activities of simplified aplysiatoxin analogs focused on the CH/π interaction.

Debromoaplysiatoxin (DAT) is a potent protein kinase C (PKC) activator with tumor-promoting and pro-inflammatory activities. Irie and colleagues have found that 10-methyl-aplog-1 (1), a simplified analog of DAT, has strong anti-proliferative activity against several cancer cell lines with few adverse effects. Therefore, 1 is a potential lead compound for cancer therapy. We synthesized a new derivative 2 which has a naphthalene ring at the side chain terminal position instead of a benzene ring, to increase CH/π interactions with Pro-241 of the PKCδ-C1B domain. Based on the synthetic route of 1, 2 was convergently synthesized in 26 linear steps from 6-hydroxy-1-naphthoic acid with an overall yield of 0.18%. Although the anti-proliferative activity of 2 was more potent than that of 1, the binding potency of 2 to the PKCδ-C1B domain did not exceed that of 1. Molecular dynamics simulation indicated the capability of 2 to simultaneously form hydrogen bonds and CH/π interactions with the PKCδ-C1B domain. Focusing on the hydrogen bonds, their geometry in the binding modes involving the CH/π interactions seemed to be sub-optimal, which may explain the slightly lower affinity of 2 compared to 1. This study could be of help in optimizing such interactions and synthesizing a promising lead cancer compound.

Morphological characteristics of the lateral ankle ligament complex.

PURPOSE: The relevance of each ligament comprising the lateral ankle ligament complex, including the anterior talofibular ligament (ATFL), calcaneofibular ligament (CFL), and posterior talofibular ligament (PTFL), has not been sufficiently elucidated; therefore, we aimed to clarify the morphological characteristics and relevance of these ligaments. METHODS: Total 152 legs from 152 Japanese cadavers were investigated. The lengths and widths of the ATFL, CFL, and PTFL were measured using a caliper. The ATFL was classified according to the number of fiber bundles (Types I, II, and III corresponded to one, two, and three fiber bundles, respectively), and the lengths and widths of the three ligaments were compared between the Type groups. In addition, the ratio of each ligament's length and width to the tibial length was calculated, and the correlation of the ratio of ligament length and width between the ATFL, CFL, and PTFL was examined about 34 legs. RESULTS: The ATFL, CFL, and PTFL were found to connect at the anterior/inferior tip of the lateral malleolus each other. The Type II group of the ATFL was most common (54.6%) in our investigated specimens. However, there were no significant inter-group differences in the lengths and widths of the CFL and PTFL. CONCLUSIONS: This study demonstrates that the lateral ankle ligaments may stabilize the ankle joint through interconnections.

Development of 8-branch Er:fiber frequency comb for Sr and Yb optical lattice clocks.

We demonstrate an 8-branch Er:fiber frequency comb with seven application ports, which can be individually optimized for applications with different wavelengths. The beat between the comb and a cw laser has a signal-to-noise ratio exceeding 30 dB at a resolution bandwidth of 300 kHz. The 8-branch frequency comb is used to perform frequency locking for four repumping and lattice lasers, and the frequency measurement of two clock lasers of strontium and ytterbium optical lattice clocks. We have achieved reliable optical lattice clock operation, thanks to the stable frequency locking and measurement obtained by using the 8-branch frequency comb. The developed frequency comb is a powerful experimental tool for various applications, including not only optical lattice clocks, but also research on quantum optics that use many frequency-stabilized lasers.

A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia.

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10-9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10-18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

Evaluation of laser frequency offset locking using an electrical delay line.

Frequency offset locking between two Nd:YAG lasers is performed using frequency locking with an electrical delay line. The relative frequency instability of the offset locking is measured to be 3.5×10-12 for an averaging time of 1 s, which is approximately 77 times smaller than that of the free-running case. The frequency instability of the frequency locking is compared to that of the phase locking between the two Nd:YAG lasers. Furthermore, a compact solid-state laser is frequency locked to an optical frequency comb with a frequency instability of 8.2×10-11 for an averaging time of 1 s, which is improved by approximately 20 times, with respect to the free-running case. The offset-locking scheme using a delay line is useful for various applications including a research on quantum optics, interferometric measurements, and experiments involving laser cooling, such as an optical lattice clock.

Computerized Hammer Sounding Interpretation for Concrete Assessment with Online Machine Learning.

Developing efficient Artificial Intelligence (AI)-enabled systems to substitute the human role in non-destructive testing is an emerging topic of considerable interest. In this study, we propose a novel hammering response analysis system using online machine learning, which aims at achieving near-human performance in assessment of concrete structures. Current computerized hammer sounding systems commonly employ lab-scale data to validate the models. In practice, however, the response signal patterns can be far more complicated due to varying geometric shapes and materials of structures. To deal with a large variety of unseen data, we propose a sequential treatment for response characterization. More specifically, the proposed system can adaptively update itself to approach human performance in hammering sounding data interpretation. To this end, a two-stage framework has been introduced, including feature extraction and the model updating scheme. Various state-of-the-art online learning algorithms have been reviewed and evaluated for the task. To conduct experimental validation, we collected 10,940 response instances from multiple inspection sites; each sample was annotated by human experts with healthy/defective condition labels. The results demonstrated that the proposed scheme achieved favorable assessment accuracy with high efficiency and low computation load.

Toe-in Landing Increases the Ankle Inversion Angle and Moment During Single-Leg Landing: Implications in the Prevention of Lateral Ankle Sprains.

CONTEXT: Identifying the foot positions that are vulnerable to lateral ankle sprains is important for injury prevention. The effects of foot position in the transverse plane on ankle biomechanics during landing are unknown. OBJECTIVE: To examine the effects of toe-in or toe-out positioning on ankle inversion motion and moment during single-leg landing. DESIGN: Repeated measures. SETTING: Motion analysis laboratory. PARTICIPANTS: 18 healthy participants (9 men and 9 women). INTERVENTIONS: Participants performed single-leg landing trials from a 30-cm high box under 3 conditions: natural landing, foot internally rotated (toe-in), and foot externally rotated (toe-out). MAIN OUTCOME MEASURES: 4 toe-in or toe-out angles were calculated against 4 reference coordinates (laboratory, pelvis, thigh, and shank) in the transverse plane. Ankle inversion angle, angular velocity, and external moment in the 200 ms after initial foot-to-ground contact were compared between the 3 landing conditions. RESULTS: All toe-in or toe-out angles other than those calculated against the shank were significantly different between each of the 3 landing conditions (P < .001). Ankle inversion angle, angular velocity, and moment were highest during toe-in landings (P < .01), while eversion angle and moment were highest during toe-out landings (P < .001). The effect sizes of these differences were large. Vertical ground reaction forces were not different between the 3 landing conditions (P = .290). CONCLUSIONS: Toe-in or toe-out positioning during single-leg landings impacts on ankle inversion and eversion motion and moment. Athletes could train not to land with the toe-in positioning to prevent lateral ankle sprains.

Control of B-cell lymphoma by therapeutic vaccination and acquisition of immune resistance is independent of direct tumour IFN-gamma signalling.

Immunomodulatory therapies can effectively control haematological malignancies by promoting antitumour immunity. Previously, we reported transient growth of poorly immunogenic murine non-Hodgkin B-cell lymphomas (B-NHL) by targeting natural killer T (NKT) cells with a therapeutic vaccine approach. Therapeutic efficacy was highly dependent on the ability of the vaccine to provoke rapid interferon-gamma (IFNγ) production from NKT and NK cells. By manipulating the capacity of either host or lymphoma cells to signal through the IFNγ receptor (IFNγR), we investigated whether the therapeutic effect conferred by vaccine-induced IFNγ is a result of immune cell activation, lymphoma IFNγ sensitivity or a combination of both. We demonstrated that antitumour immunity elicited by vaccination requires IFNγ signalling within host cells but not tumour cells. IFNγR-deficient mice failed to mount an effective antitumour immune response following vaccination despite elevated IFNγ levels. With successive exposure to vaccination, lymphomas acquired an increasingly therapy-resistant phenotype and displayed a reduction in major histocompatibility complex I and CD1d surface expression, which is independent of tumour intrinsic IFNγ signalling. Our results suggest that immunotherapy-induced IFNγ production mainly exerts its therapeutic effect via signalling through host cells, rather than directly to tumour cells in B-NHL. This signifies that intact IFNγ signalling within patients' immune compartment rather than tumour cell sensitivity to IFNγ is more critical for successful treatment. Finally, tumour IFNγ signalling alone does not drive acquired tumour resistance to vaccination, implying that additional immunoediting pathways are responsible for tumour immune escape.

Second harmonic generation at 399 nm resonant on the 1S0-1P1 transition of ytterbium using a periodically poled LiNbO3 waveguide.

We demonstrate a compact and robust method for generating a 399-nm light resonant on the 1S0 - 1P1 transition in ytterbium using a single-pass periodically poled LiNbO3 waveguide for second harmonic generation (SHG). The obtained output power at 399 nm was 25 mW when a 798-nm fundamental power of 380 mW was coupled to the waveguide. We observed no degradation of the SHG power for 13 hours with a low power of 6 mW. The obtained SHG light has been used as a seed light for injection locking, which provides sufficient power for laser cooling ytterbium.

Total Synthesis of Aquayamycin.

An efficient and practical total synthesis of aquayamycin has been accomplished. The highly oxidized and stereochemically complex tetracyclic ring system was constructed using three key reactions: 1) highly diastereoselective 1,2-addition of C-glycosyl naphthyllithium to a cyclic ketone, 2) indium-mediated site-selective allylation-rearrangement sequence of naphthoquinone, and 3) diastereoselective intramolecular pinacol coupling. This synthetic strategy offers a novel and efficient pathway to prepare aquayamycin-type angucycline antibiotics.

Kinematics and muscle activities of the lower limb during a side-cutting task in subjects with chronic ankle instability.

PURPOSE: The purpose of the present study was to evaluate lower limb kinematics and muscular activities during walking, side-turning while walking, and side-cutting movement in athletes with chronic ankle instability and compare the results to those of athletes without chronic ankle instability. METHODS: Lower limb kinematics and muscular activities were evaluated in 10 athletes with chronic ankle instability and 10 healthy control athletes using a three-dimensional motion analysis system and surface electromyography during the 200-ms pre-initial contact (IC) and stance phases while walking, side-turning while walking, and side-cutting. RESULTS: During walking or side-turning while walking, there were no significant differences in kinematics or muscle activities between the subjects with and without chronic ankle instability. For the side-cutting task, however, ankle inversion angles during the 200-ms pre-IC and late stance phases [effect sizes (ESs) = 0.95-1.43], the hip flexion angle (ESs = 0.94-0.96) and muscular activities of the gastrocnemius medialis (ESs = 1.04-1.73) during the early stance phase were significantly greater in the athletes with chronic ankle instability than in the healthy control athletes. CONCLUSIONS: Alterations of kinematics in athletes with chronic ankle instability were found not only at the ankle but also at hip joints during the side-cutting movement. These alterations were not detected during walking or side-turning while walking. The findings of the present study indicate that clinicians should take into account the motion of the hip joint during the side-cutting movement in persons with chronic ankle instability. LEVEL OF EVIDENCE: III.

Compact iodine-stabilized laser operating at 531 nm with stability at the 10(-12) level and using a coin-sized laser module.

We demonstrate a compact iodine-stabilized laser operating at 531 nm using a coin-sized light source consisting of a 1062-nm distributed-feedback diode laser and a frequency-doubling element. A hyperfine transition of molecular iodine is observed using the light source with saturated absorption spectroscopy. The light source is frequency stabilized to the observed iodine transition and achieves frequency stability at the 10(-12) level. The absolute frequency of the compact laser stabilized to the a(1) hyperfine component of the R(36)32 - 0 transition is determined as 564074632419(8) kHz with a relative uncertainty of 1.4×10(-11). The iodine-stabilized laser can be used for various applications including interferometric measurements.