A study of criteria for grading follicular lymphoma using a cell type classifier from pathology images based on complementary-label learning.

We propose a criterion for grading follicular lymphoma that is consistent with the intuitive evaluation, which is conducted by experienced pathologists. A criterion for grading follicular lymphoma is defined by the World Health Organization (WHO) based on the number of centroblasts and centrocytes within the field of view. However, the WHO criterion is not often used in clinical practice because it is impractical for pathologists to visually identify the cell type of each cell and count the number of centroblasts and centrocytes. Hence, based on the widespread use of digital pathology, we make it practical to identify and count the cell type by using image processing and then construct a criterion for grading based on the number of cells. Here, the problem is that labeling the cell type is not easy even for experienced pathologists. To alleviate this problem, we build a new dataset for cell type classification, which contains the pathologists' confusion records during labeling, and we construct the cell type classifier using complementary-label learning from this dataset. Then we propose a criterion based on the composition ratio of cell types that is consistent with the pathologists' grading. Our experiments demonstrate that the classifier can accurately identify cell types and the proposed criterion is more consistent with the pathologists' grading than the current WHO criterion.

Immediate curative effects of exercise therapy in patients with myalgia of the masticatory muscles.

BACKGROUND: Exercise therapy is occasionally considered as an initial treatment for temporomandibular disorders. However, pain can be exacerbated during exercise therapy. OBJECTIVE: To investigate the immediate curative effects of exercise therapy in patients with masticatory muscle myalgia. METHODS: Fifty-nine patients with masticatory muscle myalgia were included. Therapists performed exercise therapy (stretched the painful masseter and/or cervical muscles along the direction of muscle contraction) in 10 rounds of traction, each lasting 10 s. The patient's pain-free maximum mouth opening distance and degree of pain (VAS value) before and immediately after exercise therapy were compared using the Wilcoxon signed-rank test. The Mann-Whitney U test was used for the subgroup comparisons. RESULTS: Mouth opening increased from 41 (IQR 38-43) to 46 (IQR 43-48) mm and pain alleviation from 48 (IQR 31-56) to 21 (IQR 10-56) immediately following exercise therapy (p < .001 for both). None of the patients experienced pain exacerbation or reduction in mouth opening post-exercise. No difference in mouth opening distance changes according to sex, painful side, painful site and therapist were observed (p > .05 for all). Pain reduction was greater in patients with unilateral pain (26, IQR 12-39) than those with bilateral (13, IQR 5-25) (p = .019). There were no differences in the change in the degree of pain according to sex, painful site and therapist (p > .05 for all). CONCLUSION: Exercise therapy immediately enlarged the mouth opening distance and reduced myalgia; therefore, it could be helpful in managing masticatory muscle myalgia.

Effects of flurbiprofen on the functional regulation of serotonin transporter and its misfolded mutant.

Flurbiprofen, a nonsteroidal anti-inflammatory drug, reportedly exhibits chemical chaperone activity. Herein, we investigated the role of flurbiprofen in regulating serotonin transporter (SERT) function via membrane trafficking. We used COS-7 cells transiently expressing wild-type (WT) SERT or a C-terminus-deleted mutant of SERT (SERTΔCT), a misfolded protein. Flurbiprofen treatment reduced the expression of immaturely glycosylated SERT and enhanced the expression of maturely glycosylated SERT. In addition, we observed increased serotonin uptake in SERT-expressing cells. These results suggest that flurbiprofen modulates SERT function by promoting membrane trafficking. In SERTΔCT-expressing cells, flurbiprofen reduced the protein expression and uptake activity of SERTΔCT. Furthermore, flurbiprofen inhibited the formation of SERTΔCT aggregates. Studies using flurbiprofen enantiomers suggested that these effects of flurbiprofen on SERT were not mediated via cyclooxygenase inhibition. The levels of GRP78/BiP, an endoplasmic reticulum (ER) stress marker, were assessed to elucidate whether flurbiprofen can ameliorate SERTΔCT-induced ER stress. Interestingly, flurbiprofen induced GRP78/BiP expression only under ER stress conditions and not under steady-state conditions. In HRD1 E3 ubiquitin ligase knockdown cells, flurbiprofen affected the ER-associated degradation system. Collectively, the findings suggest that flurbiprofen may function as an inducer of molecular chaperones, in addition to functioning as a chemical chaperone.

A Novel Microcontroller-Based System for the Wheel-Running Activity in Mice.

Voluntary wheel-running activity is a way to assess rodents' circadian rhythm and motivation for exercise. Deficits in these behaviors are implicated in the pathophysiology of sleep and psychiatric disorders. Limited space in animal facilities can hamper long-term monitoring of running wheel activity outside of the home cage. To address this issue, we provide a stand-alone solution to monitor the wheel-running activity of mice in their home cage. This system, named the wheel-running activity acquisition (WRAQ) system, is based on a microcontroller driven by a lithium polymer battery. With the WRAQ, we can record the wheel-running activity and illumination data for at least 30 d. Applying the WRAQ to an endotoxemia mouse model robustly detected the altered wheel-running activity and its recovery. With wireless data transfer capability extension, the system also allows for online monitoring and reporting of the circadian time (CT). We used the online monitoring of wheel-running activity with this extended WRAQ system and observed a significant shift of the active period in the circadian rhythm following a temporal chemogenetic activation of the suprachiasmatic nucleus (SCN)-subparaventricular zone (SPZ). Together, these findings indicate that the WRAQ system is a novel and cost-effective solution for the analysis of wheel-running activity in mice.

Syntaxin 3 interacts with serotonin transporter and regulates its function.

Herein, we investigated the functional association of the serotonin transporter (SERT) with syntaxin-3 (STX3). We first overexpressed SERT and STX3 in various cells and examined their interaction, localization, and functional association. Immunoprecipitation studies revealed that STX3 interacted with SERT when expressed in COS-7 cells. Immunocytochemical studies revealed that SERT and STX3 were colocalized in the endoplasmic reticulum (ER) and Golgi apparatus. STX3 overexpression significantly reduced the uptake activity of SERT by attenuating its plasma membrane expression, suggesting that overexpressed STX3 anchors SERT in the ER and Golgi apparatus. STX3 knockdown did not affect the uptake activity of SERT but altered its glycosylation state. To elucidate the association of STX3 with SERT under physiological conditions, rather than overexpressing cells, we investigated this interaction in polarized Caco-2 cells, which endogenously express both proteins. Immunocytochemical studies revealed that SERT and STX3 were localized in microvilli-like structures at the apical plasma membrane. STX3 knockdown marginally but significantly decreased the serotonin uptake activity of Caco-2 cells, suggesting that STX3 positively regulates SERT function in Caco-2 cells, as opposed to SERT regulation by STX3 in overexpressing cells. Collectively, STX3 may colocalize with SERT during SERT membrane trafficking and regulate SERT function in an STX3-expressing lesion-dependent manner.

Short-term effects of range-of-motion exercise on temporomandibular joints of patients who undergo disc displacement with reduction of temporomandibular joint.

[Purpose] We investigated the short-term effects of an exercise therapy program that combined a range-of-motion exercise for the temporomandibular joint with self-traction therapy for patients with temporomandibular joint disorders who undergo disc displacement with reduction of the painful temporomandibular joint. [Participants and Methods] The program involved 31 patients with moderate or higher functional pain. The range-of-motion exercise for the temporomandibular joint was performed at the first visit by the therapist, and the patients were instructed to perform self-traction therapy in the morning and while bathing for the next 2 weeks, until their next visit. The maximum mouth opening distance and the visual analog scale scores at the first consultation and 2 weeks later were compared to assess the changes in pain on motion and mastication as well as the impact of the program on daily activities. [Results] All symptoms of the patients showed significant improvements after 2 weeks of starting the treatment. [Conclusion] The results of this study suggest that an exercise therapy program combining range-of-motion exercises for the temporomandibular joint and self-traction therapy may be an effective conservative therapy for reducing the pain and obstacles experienced by patients with temporomandibular joint disorders who undergo disc displacement with reduction of the painful temporomandibular joint.

Role of the E3 ubiquitin ligase HRD1 in the regulation of serotonin transporter function.

To elucidate the regulation of serotonin transporter (SERT) function via its membrane trafficking, we investigated the involvement of the ubiquitin E3 ligase HRD1 (HMG-CoA reductase degradation protein), which participates in endoplasmic reticulum (ER)-associated degradation (ERAD), in the functional regulation of SERT. Cells transiently expressing wild-type SERT or a SERT C-terminal deletion mutant (SERTΔCT), a SERT protein predicted to be misfolded, were used for experiments. Studies using HRD1-overexpressing or HRD1-knockdown cells demonstrated that HRD1 is involved in SERT proteolysis. Overexpression of HRD1 promoted SERT ubiquitination, the effect of which was augmented by treatment with the proteasome inhibitor MG132. Immunoprecipitation studies revealed that HRD1 interacts with SERT in the presence of MG132. In addition, HRD1 was intracellularly colocalized with SERT, especially with aggregates of SERTΔCT in the ER. HRD1 also affected SERT uptake activity in accordance with the expression levels of the SERT protein. These results suggest that HRD1 contributes to the membrane trafficking and functional regulation of SERT through its involvement in ERAD-mediated SERT degradation.

Suggestions on the applicability of visual instructions with see-through head mounted displays depending on the task.

Task instructions have traditionally been communicated orally in many fields. However, recently more and more wearable displays, such as the see-through head mounted displays (HMDs) have been developed, and some studies have provided ideas on applying visual instruction using these new interfaces to particular situations. However, in some cases, where instructions are communicated amongst the workers, the data is not sufficient for field workers to choose the best way of communicating instructions depending on the situation. Thus, this study aims to clarify the cases in which it is effective to apply visual instructions with HMDs, and to provide information that suggests the applicability of such visual instructions instead of or in addition to the traditional auditory instructions in different situations. These suggestions will be a useful reference for workers in safety-critical fields, helping them make better decisions about whether, when, and where to introduce the new method of instructions. It will also address some of the unsolved problems in the field, such as errors, low efficiency, and discomfort in communication.