Living organisms adapt to changing light environments via mechanisms that enhance photosensitivity under darkness and attenuate photosensitivity under bright light conditions. In hypocotyl ...phototropism, phototropin1 (phot1) blue light photoreceptors mediate both the pulse light-induced, first positive phototropism and the continuous light-induced, second positive phototropism, suggesting the existence of a mechanism that alters their photosensitivity. Here, we show that light induction of ROOT PHOTOTROPISM2 (RPT2) underlies photosensory adaptation in hypocotyl phototropism of Arabidopsis thaliana. rpt2 loss-offunction mutants exhibited increased photosensitivity to very low fluence blue light butwere insensitive to lowfluence blue light. Expression of RPT2 prior to phototropic stimulation in etiolated seedlings reduced photosensitivity during first positive phototropism and accelerated second positive phototropism. Our microscopy and biochemical analyses indicated that blue light irradiation causes dephosphorylation of NONPHOTOTROPIC HYPOCOTYL3 (NPH3) proteins andmediates their release from the plasma membrane. These phenomena correlate closely with the desensitization of phot1 signaling during the transition period from first positive phototropism to second positive phototropism. RPT2 modulated the phosphorylation of NPH3 and promoted reconstruction of the phot1-NPH3 complex on the plasma membrane. We conclude that photosensitivity is increased in the absence of RPT2 and that this results in the desensitization of phot1. Light-mediated induction of RPT2 then reduces the photosensitivity of phot1, which is required for second positive phototropism under bright light conditions.
Although ample evidence supports the notion that an acute bout of endurance exercise performed at or greater than 70% of maximum oxygen uptake suppresses appetite partly through changes in ...appetite-regulating hormones, no study has directly compared the influence between the phases of the menstrual cycle in women. This study compared the effects of an acute bout of exercise on orexigenic hormone (acylated ghrelin) and anorexigenic hormones (peptide YY and cholecystokinin) between the early follicular phase (FP) and the mid luteal phase (LP) of the menstrual cycle in physically active women. Ten healthy women (age, 20.6 ± 0.7 yr) completed two 3.5-h trials in each menstrual phase. In both trials, participants performed cycling exercises at 70% of heart rate reserve (at a corresponding intensity to 70% of maximum oxygen uptake) for 60 min followed by 90 min of rest. Following 90 min of rest, participants were provided with an ad libitum meal for a fixed duration of 30 min. Blood samples and subjective appetite were collected and assessed before exercise, during exercise, immediately postexercise, 45 min postexercise, and 90 min postexercise. The exercise increased estradiol (327%) and progesterone (681%) in the LP more than the FP, respectively (
< 0.001,
= 1.33;
< 0.001,
= 1.20). There were no between-trial differences in appetite-regulating hormones, subjective appetite, or energy intake of ad libitum meal. These findings indicate that exercise-induced increases in ovarian hormones in the LP may not influence appetite-regulating hormones in physically active women.
To our knowledge, this is the first study to compare how different phases of the menstrual cycle influence appetite-regulating hormones after acute exercise in healthy women. There were no differences in appetite-regulating hormones between the early follicular and mid luteal phases, whereas ovarian hormones were remarkably increased by cycling exercise in the mid luteal phase. These results highlight that appetite-regulating hormones in response to exercise do not appear to be influenced by the menstrual cycle.
Current immunotherapies aim to modulate the balance among different immune cell populations, thereby controlling immune reactions. However, they often cause immune overactivation or over-suppression, ...which makes them difficult to control. Thus, it would be ideal to manipulate immune cells at a local site without disturbing homeostasis elsewhere in the body. Recent technological developments have enabled the selective targeting of cells and tissues in the body. Photo-targeted specific cell therapy has recently emerged among these. Near-infrared photoimmunotherapy (NIR-PIT) has surfaced as a new modality for cancer treatment, which combines antibodies and a photoabsorber, IR700DX. NIR-PIT is in testing as an international phase III clinical trial for locoregional recurrent head and neck squamous cell carcinoma (HNSCC) patients (LUZERA-301, NCT03769506), with a fast-track designation by the United States Food and Drug Administration (US-FDA). In Japan, NIR-PIT for patients with recurrent head and neck cancer was conditionally approved in 2020. Although NIR-PIT is commonly used for cancer therapy, it could also be exploited to locally eliminate certain immune cells with antibodies for a specific immune cell marker. This strategy can be utilized for anti-allergic therapy. Herein, we discuss the recent technological advances in local immunomodulation technology. We introduce immunomodulation technology with NIR-PIT and demonstrate an example of the knockdown of regulatory T cells (Tregs) to enhance local anti-tumor immune reactions.
TLS (translocated in liposarcoma), also known as FUS (fused in sarcoma), is an RNA/DNA-binding protein that plays regulatory roles in transcription, pre-mRNA splicing and mRNA transport. Mutations in ...TLS are responsible for familial amyotrophic lateral sclerosis (ALS) type 6. Furthermore, TLS-containing intracellular inclusions are found in polyglutamine diseases, sporadic ALS, non-SOD1 familial ALS and a subset of frontotemporal lobar degeneration, indicating a pathological significance of TLS in a wide variety of neurodegenerative diseases. Here, we identified TLS domains that determine intracellular localization of the murine TLS. Among them, PY-NLS located in the C-terminus is a strong determinant of intracellular localization as well as splicing regulation of an E1A-derived minigene. Disruption of PY-NLS promoted the formation of cytoplasmic granules that were partially overlapped with stress granules and P-bodies. Some of the ALS-linked mutations altered both intracellular localization and splicing regulation of TLS, while most mutations alone did not affect splicing regulation. However, phospho-mimetic substitution of Ser505 (or Ser513 in human) could enhance the effects of ALS mutations, highlighting interplay between post-translational modification and ALS-linked mutations. These results demonstrate that ALS-linked mutations can variably cause loss of nuclear functions of TLS depending on the degree of impairment in nuclear localization.
The conventional treatment of thoracic tumors includes surgery, anticancer drugs, radiation, and cancer immunotherapy. Light therapy for thoracic tumors has long been used as an alternative; ...conventional light therapy also called photodynamic therapy (PDT) has been used mainly for early-stage lung cancer. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a completely different concept from conventional PDT, has been developed and approved in Japan for the treatment of recurrent and previously treated head and neck cancer because of its specificity and effectiveness. NIR-PIT can apply to any target by changing to different antigens. In recent years, it has become clear that various specific and promising targets are highly expressed in thoracic tumors. In combination with these various specific targets, NIR-PIT is expected to be an ideal therapeutic approach for thoracic tumors. Additionally, techniques are being developed to further develop NIR-PIT for clinical practice. In this review, NIR-PIT is introduced, and its potential therapeutic applications for thoracic cancers are described.
Huntington's Disease (HD) is a dominantly inherited pathology caused by the accumulation of mutant huntingtin protein (HTT) containing an expanded polyglutamine (polyQ) tract. As the polyglutamine ...binding peptide 1 (QBP1) is known to bind an expanded polyQ tract but not the polyQ motif found in normal HTT, we selectively targeted mutant HTT for degradation by expressing a fusion molecule comprising two copies of QBP1 and copies of two different heat shock cognate protein 70 (HSC70)-binding motifs in cellular and mouse models of HD. Chaperone-mediated autophagy contributed to the specific degradation of mutant HTT in cultured cells expressing the construct. Intrastriatal delivery of a virus expressing the fusion molecule ameliorated the disease phenotype in the R6/2 mouse model of HD. Similar adaptor molecules comprising HSC70-binding motifs fused to an appropriate structure-specific binding agent(s) may have therapeutic potential for treating diseases caused by misfolded proteins other than those with expanded polyQ tracts.
The present study investigated the effects of the menstrual cycle on muscle glycogen and circulating substrates during high-intensity intermittent exercise until exhaustion in healthy women who ...habitually exercised. In total, 11 women with regular menstrual cycles completed three tests, which comprised the early follicular phase (E-FP), late follicular phase (L-FP), and luteal phase (LP) of the menstrual cycle. High-intensity intermittent exercise until exhaustion was performed on each test day. Evaluation of muscle glycogen concentration by sup.13C-magnetic resonance spectroscopy and measurement of estradiol, progesterone, blood glucose, lactate, free fatty acids (FFA), and insulin concentrations were conducted before exercise (Pre) and immediately after exercise (Post). Muscle glycogen concentrations from thigh muscles at Pre and Post were not significantly different between menstrual cycle phases (P = 0.57). Muscle glycogen decreases by exercise were significantly greater in L-FP (59.0 + or - 12.4 mM) than in E-FP (48.3 + or - 14.4 mM, P < 0.05). Nonetheless, blood glucose, blood lactate, serum FFA, serum insulin concentrations, and exercise time until exhaustion in E-FP, L-FP, and LP were similar. The study results suggest that although exercise time does not change according to the menstrual cycle, the menstrual cycle influences muscle glycogen utilization during high-intensity intermittent exercise until exhaustion in women with habitual exercise activity. Novelty: * This study compared changes in muscle glycogen concentration across the menstrual cycle during high-intensity intermittent exercise until exhaustion using sup.13C-magnetic resonance spectroscopy. * Our results highlight the influence of the menstrual cycle on muscle glycogen during high-intensity intermittent exercise in healthy women. Key words: high-intensity intermittent exercise, late follicular phase, menstrual cycle, ovarian hormones, estrogen, muscle glycogen La presente etude a examine les effets du cycle menstruel sur le glycogene musculaire et les substrats circulants lors d'exercices intermittents de haute intensite jusqu'a epuisement chez des femmes en bonne sante qui faisaient habituellement de l'exercice. Au total, onze femmes ayant des cycles menstruels reguliers ont effectue trois tests qui comprenaient la phase folliculaire precoce (<< E-FP >>), la phase folliculaire tardive (<< L-FP >>) et la phase luteale (<< LP >>) du cycle menstruel. Des exercices intermittents de haute intensite jusqu'a epuisement ont ete effectues chaque jour de test. L'evaluation de la concentration de glycogene musculaire par spectroscopie par resonance magnetique sup.13C et la mesure des concentrations d'aestradiol, de progesterone, de glucose sanguin, de lactate, d'acides gras libres (<< FFA >>) et d'insuline ont ete effectuees avant l'exercice (pre) et immediatement apres l'exercice (post). Les concentrations de glycogene des muscles de la cuisse a pre et a post n'etaient pas significativement differentes entre les phases du cycle menstruel (p = 0,57). Les diminutions de glycogene musculaire par l'exercice etaient significativement plus importantes dans L-FP (59,0 + or - 12,4 mM) que dans E-FP (48,3 + or - 14,4 mM, p < 0,05). Neanmoins, la glycemie, le lactate sanguin, les FFA seriques, les concentrations seriques d'insuline et le temps d'exercice jusqu'a l'epuisement en E-FP, L-FP et LP etaient similaires. Les resultats de l'etude suggerent que, meme si le temps d'exercice ne change pas en fonction du cycle menstruel, ce dernier influence l'utilisation du glycogene musculaire pendant l'exercice intermittent de haute intensite jusqu'a l'epuisement chez les femmes ayant une activite physique habituelle. Traduit par la Redaction Les nouveautes: * En utilisant la spectroscopie par resonance magnetique sup.13C, cette etude a compare les changements de concentration de glycogene musculaire tout au long du cycle menstruel pendant un exercice intermittent de haute intensite jusqu'a l'epuisement. * Nos resultats mettent en evidence l'influence du cycle menstruel sur le glycogene musculaire lors d'exercices intermittents de haute intensite chez des femmes en bonne sante. Mots-cles : exercice intermittent de haute intensite, phase folliculaire tardive, cycle menstruel, hormones ovariennes, aestrogene, glycogene musculaire
We proposed an automatic procedure of identification of crystalline orientation of W tips observed by field ion microscopy by means of machine-learning-based objective detection and classification. ...The identification is performed with the geometrical position of {110} and {112} planes detected by YOLOv3, and the correct crystalline orientation was output for 85% of the total data by k-nearest neighbor algorithm, indicating the effectiveness of this method.
We investigated the influence of the menstrual cycle (MC) on leukocyte response after exercise-induced muscle damage (EIMD). During the early follicular (E-FP, n = 12) or mid-luteal phase (M-LP, n = ...12), 24 untrained females with eumenorrhea performed 60 eccentric exercises using nondominant arms. Blood samples were collected at pre- and 4, 48, and 96 h postexercise to analyze estradiol and progesterone concentrations, leukocyte count and fractionation, and creatine kinase (CK) activity. We also assessed the maximal voluntary isometric contraction torque of elbow flexion, range of motion in the elbow joint, upper-arm circumference, and muscle soreness as indirect muscle damage markers at pre-; immediately post-; and 4, 48, and 96 h postexercise. The percent change in neutrophil counts from pre- to 4 h postexercise was lower in M-LP than in E-FP (E-FP, 30.7% 15.9–65.7% vs. M-LP, 10.3% −2.3–30.0%; median interquartile range: 25–75%; p = 0.068). Progesterone concentration at pre-exercise was significantly negatively correlated with the percent change in neutrophil counts from pre- to 4 h postexercise in M-LP (r = −0.650, p = 0.022). MC did not affect CK activity or other muscle damage markers. Thus, progesterone concentration rather than MC may be related to neutrophil response following EIMD.
Moisture-activated dry granulation (MADG) is an eco-friendly granulation method that uses a small amount of water and insoluble excipients to absorb moisture. MADG is expected to improve productivity ...and reduce costs. Erythritol, an excipient used for preparing orally disintegrating tablets (ODTs), has poor tabletability and is difficult to form into tablets by conventional methods, such as high-shear granulation (HSG) and direct compression. In this study, we optimized the manufacturing conditions for ODTs to improve the tabletability of erythritol using MADG. The disintegration time of tablets made using the MADG method was approximately one-tenth that of those made using the HSG method, and the hardness was approximately 1.4 times higher. Moreover, MADG could delay disintegration and improve tabletability. We further attempted to optimize the manufacturing conditions using MADG, particularly in terms of the amount of water used. The disintegration time increased as the amount of added water increased. Moreover, water absorption tests revealed that capillary wetting decreased as the amount of water added increased, but the initial wetting did not change. These results suggested that the disintegration time was prolonged because of the increase in granule density and decrease in capillary wetting with the increase in the amount of added water. The hardness of the tablets increased because of the easy deformation of the granules after the addition of up to 3% water; however, when more than 3% water was added, the hardness decreased because of the aggregation of the granules with the excess water. Finally, two-dimensional maps of the effect of the amount of added water and water activity indicated that tablets with a hardness of ≥80 N and a disintegration time of ≤15 s could be produced by adjusting the amount of added water to within the range of 2.2–3.3% and water activity to 0.3–0.53. These results indicate that MADG can improve the tabletability of erythritol and be used for the granulation of ODTs. Tablets with appropriate hardness and disintegration properties can be produced by adjusting the water content to approximately 2.7% and the water activity to approximately 0.4 when producing ODTs with MADG.
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