TGF-ß3 from fibroblasts promotes necrotising sialometaplasia by suppressing salivary gland cell proliferation and inducing squamous metaplasia.

Necrotising sialometaplasia (NSM) is a non-neoplastic lesion mainly arising in the minor salivary glands of the oral cavity. In the clinical features, NSM shows swelling with or without ulceration, and can mimic a malignant disease such as squamous cell carcinoma. Histopathologically, NSM usually shows the lobular architecture that is observed in the salivary glands. Additionally, acinar infarction and squamous metaplasia of salivary ducts and acini are observable. The aetiology of this lesion remains unknown, although it has a characteristic feature that sometimes requires clinical and histopathological differentiation from malignancy. In this study, we investigated upregulated genes in NSM compared with normal salivary glands, and focused on the TGF-ß3 (TGFB3) gene. The results of the histopathological studies clarified that fibroblasts surrounding the lesion express TGF-ß3. Moreover, in vitro studies using mouse salivary gland organoids revealed that TGF-ß3 suppressed salivary gland cell proliferation and induced squamous metaplasia. We demonstrated a possible aetiology of NSM by concluding that increased TGF-ß3 expression during wound healing or tissue regeneration played a critical role in cell proliferation and metaplasia. © 2024 The Pathological Society of Great Britain and Ireland.

Multicenter retrospective study of nivolumab for recurrent/metastatic oral squamous cell carcinoma.

OBJECTIVES: Immunotherapy with nivolumab for patients with recurrent/metastatic oral squamous cell carcinoma has not been evaluated. Here, we aimed to examine the efficacy, safety, and prognostic factors of nivolumab in these patients. MATERIALS AND METHODS: This multicenter retrospective observational study involved patients who received nivolumab between April 2017 and June 2019. The patient characteristics were evaluated for association with progression-free and overall survival. Progression-free and overall survival rates were calculated; parameters that were significant in the univariate analysis were used as explanatory variables. Independent factors for progression-free and overall survival were identified using multivariate analysis. RESULTS: Totally, 143 patients were included. The overall response and disease control rates were 27.3% and 46.2%, respectively. The median, 1- and 2-year progression-free survival rates were 2.7 months, 25.4%, and 19.2%, respectively; those for overall survival were 11.2 months, 47.3%, and 33.6%, respectively. The independent factors affecting progression-free survival were performance status and immune-related adverse event occurrence, whereas those affecting overall survival were performance status, target disease, and number of previous lines of systemic cancer therapy. Eight patients reported grade ≥3 immune-related adverse events. CONCLUSION: Nivolumab was effective for recurrent/metastatic oral squamous cell carcinoma treatment and was well tolerated by patients.

Suicide Attitudes Among Suicide Loss Survivors and Their Adaptation to Loss: A Cross-Cultural Study in Japan and the United States.

Survivors' adaptation to a suicide loss is likely influenced by their attitudes toward suicide and their respective sociocultural contexts. Our study aimed to compare suicide attitudes and their association with depressive symptoms and sense of community safety in Japanese and American suicide loss survivors. A total of 193 Japanese survivors and 232 American survivors completed online surveys. The results show that Japanese survivors tended not to consider suicide as an illness or to recognize that others understood their experience but were more likely than American survivors to consider suicide as justifiable. Regression analyses indicated that taking suicide as a right was associated with depressive symptoms. Further, their sense of being understood by others was positively correlated with perceived community safety in both samples, but justifying suicide and considering it to be an illness was positively related to perceived community safety only among Japanese survivors.

Macaque monkeys show reversed ocular following responses to two-frame-motion stimulus presented with inter-stimulus intervals.

When two-frame apparent motion stimuli are presented with an appropriate inter-stimulus interval (ISI), motion is perceived in the direction opposite to the actual image shift. Herein, we measured a simple eye movement, ocular following responses (OFRs), in macaque monkeys to examine the ISI reversal effect on oculomotor. Two-frame movies with an ISI induced reversed OFRs. Without ISI, the OFRs to the two-frame movie were induced in the direction of the stimulus shift. However, with ISIs ≥10 ms, OFRs in the direction opposite to the phase shift were observed. This directional reversal persisted for ISIs up to 160 ms; for longer ISIs virtually no ocular response was observed. Furthermore, longer exposure to the initial image (Motion onset delay: MOD) reduced OFRs. We show that these dependences on ISIs/MODs can be explained by the motion energy model. Furthermore, we examined the dependence on ISI reversal using various spatial frequencies. To account for our findings, the optimal frequency of the temporal filters of the energy model must decrease between 0.5 and 1 cycles/°, suggesting that there are at least two channels with different temporal characteristics. These results are consistent with those from humans, suggesting that the temporal filters embedded in human and macaque visual systems are similar. Thus, the macaque monkey is a good animal model for the early visual processing of humans to understand the neural substrates underlying the visual motion detectors that elicit OFRs.

Comparison of neuronal responses in primate inferior-temporal cortex and feed-forward deep neural network model with regard to information processing of faces.

Feed-forward deep neural networks have better performance in object categorization tasks than other models of computer vision. To understand the relationship between feed-forward deep networks and the primate brain, we investigated representations of upright and inverted faces in a convolutional deep neural network model and compared them with representations by neurons in the monkey anterior inferior-temporal cortex, area TE. We applied principal component analysis to feature vectors in each model layer to visualize the relationship between the vectors of the upright and inverted faces. The vectors of the upright and inverted monkey faces were more separated through the convolution layers. In the fully-connected layers, the separation among human individuals for upright faces was larger than for inverted faces. The Spearman correlation between each model layer and TE neurons reached a maximum at the fully-connected layers. These results indicate that the processing of faces in the fully-connected layers might resemble the asymmetric representation of upright and inverted faces by the TE neurons. The separation of upright and inverted faces might take place by feed-forward processing in the visual cortex, and separations among human individuals for upright faces, which were larger than those for inverted faces, might occur in area TE.

Aggregatibacter actinomycetemcomitans infection causes DNA double-strand breaks in host cells.

Periodontal disease, an inflammatory disease, is caused by infection with periodontal pathogens. Long-term periodontal disease increases the risk of oral carcinogenesis. Similar to other peptic cancers, oral carcinogenesis also requires multiple genome instabilities; however, the risk factors related to the accumulation of genome instabilities are poorly understood. Here, we suggested that specific periodontal pathogens may increase the risk of genome instability. Accordingly, we screened several periodontal pathogens based on the ability to induce DNA double-strand breaks (DSBs) in host cells. We found that Aggregatibacter actinomycetemcomitans Y4 infection induced DSB formation in host cells. To assess whether DSB formation induced by infection with A. actinomycetemcomitans occurred through apoptotic chromosome fragmentation, cells were treated with a caspase inhibitor, Z-VAD-FMK. DSB accumulation induced by infection with A. actinomycetemcomitans was observed, even in the presence of Z-VAD-FMK, suggesting that this breakage occurred independently of apoptosis. These results suggested that some periodontal pathogens can increase the risk of genome instabilities in host cells and subsequently increase the risk of carcinogenesis.

Parental Grief After Offspring Suicide and Adaptation to the Loss in Japan.

Several reports have indicated that grief and mental health outcomes of people bereaved by suicide vary by their relationship to the deceased. Parents who have lost offspring experience higher levels of distress than those with other relationships to the deceased. However, there are limited studies investigating the experience of parental bereavement by suicide, and further research is needed. The present study aimed to clarify the differences in grief reactions between bereaved parents and those with other relationships to the deceased in Japan and explore a statistical model of adaptation to the loss. In total, 105 bereaved participants completed a questionnaire covering grief reaction, meaning reconstruction, mental health, social context, and demographic variables. Parents scored higher on several grief reaction items and lower in sense-making than those with other relationships. In addition, path analysis showed that sense-making acted as a moderator in the experience of loss of offspring and grief reaction.

Autoimmune sialadenitis is associated with the upregulation of chemokine/chemokine receptor pairs in T cell-specific TRAF6-deficient mice.

Sialadenitis is an inflammatory condition affecting the salivary glands including the parotid, submandibular, and sublingual glands. There are several different types of sialadenitis, each with different sites of predilection. However, the pathogenic mechanism underlying the tissue specificity of sialadenitis is largely unknown. TRAF6 is a cytoplasmic adaptor protein that is necessary for the activation of dendritic cells in response to Toll-like receptor ligands, thereby regulating innate immune responses. We previously demonstrated that T cell-specific TRAF6-deficient mice (TRAF6ΔT mice) spontaneously develop systemic inflammatory disease. Here, we show that salivary secretion is reduced in TRAF6ΔT mice due to sialadenitis that occurs in the parotid and submandibular glands, but not the sublingual glands. Consistent with pathological findings, both CD4+ and CD8+ T cells predominantly infiltrated the submandibular glands; however, sublingual infiltration was rare in TRAF6ΔT mice. The TH1 cytokine IFN-γ, the TH1 cell attractant chemokine CCL2, and its cognate receptor CCR2 were upregulated concomitantly in both the submandibular and sublingual glands. Interestingly, the TH17 cell attractant chemokine CCL20 and its cognate receptor CCR6 were selectively increased in the submandibular glands, but not in the sublingual glands of TRAF6ΔT mice. Thus, the expression of TRAF6 in T cells might be implicated in tissue-specific sialadenitis by regulating the chemokine-chemokine receptor system.

Energy level diagram of HC(NH2)2PbI3 single crystal evaluated by electrical and optical analyses.

Recently, organic-inorganic halide perovskites have received attention for applications in solar cells. Measurements of high-quality single crystals reveal lower defect densities and longer carrier lifetimes than those of conventional thin films, which result in improved electrical and optical properties. However, single crystal surfaces are sensitive to exposure to ambient conditions, and degrade under long-term storage in air. The surface also shows differences from the bulk in terms of its optical and electronic characteristics. For a heterojunction device, the interface at the single crystal is important. Understanding the difference between the surface and bulk properties offers insights into device design. Here, we prepared non-sliced and sliced formamidinium lead iodide (FAPbI3; FA+ = HC(NH2)2+) single crystals with a bandgap of 1.4 eV, which matches well with the requirements for solar cell photoabsorption layers. We evaluate the energy level diagrams of the surface and bulk regions, respectively. Our data indicate that the valence band maximum of the surface region is at a higher energy level than that of the bulk region. We also discuss hypotheses for the well-known and unexplained phenomena (multiple bandgaps and bandgap narrowing) seen in the absorption and photoluminescence spectra of single crystals. We conclude that these effects are likely caused by a combination of the degraded surface, Rashba-splitting in bulk, and self-absorption by the single crystal itself.

Similarity in Neuronal Firing Regimes across Mammalian Species.

UNLABELLED: The architectonic subdivisions of the brain are believed to be functional modules, each processing parts of global functions. Previously, we showed that neurons in different regions operate in different firing regimes in monkeys. It is possible that firing regimes reflect differences in underlying information processing, and consequently the firing regimes in homologous regions across animal species might be similar. We analyzed neuronal spike trains recorded from behaving mice, rats, cats, and monkeys. The firing regularity differed systematically, with differences across regions in one species being greater than the differences in similar areas across species. Neuronal firing was consistently most regular in motor areas, nearly random in visual and prefrontal/medial prefrontal cortical areas, and bursting in the hippocampus in all animals examined. This suggests that firing regularity (or irregularity) plays a key role in neural computation in each functional subdivision, depending on the types of information being carried. SIGNIFICANCE STATEMENT: By analyzing neuronal spike trains recorded from mice, rats, cats, and monkeys, we found that different brain regions have intrinsically different firing regimes that are more similar in homologous areas across species than across areas in one species. Because different regions in the brain are specialized for different functions, the present finding suggests that the different activity regimes of neurons are important for supporting different functions, so that appropriate neuronal codes can be used for different modalities.

Characteristics of cancer patients who died by suicide in the Tokyo metropolitan area.

The purpose of this study was to investigate the sociodemographic characteristics of cancer patients who died by suicide in comparison with cancer-free cases. Suicide data from the Tokyo Medical Examiner's Office from 2009 to 2013 were extracted retrospectively. A total of 503 (5.1%) out of 9841 people who committed suicide had cancer; age ranged from 26 to 97 years. The cancer patients were significantly older than the cancer-free cases. There were significantly more cancer patients with cohabiters than cancer-free cases with cohabiters. Only half of young to middle-aged subjects had a job in both groups. There were significantly more cancer patients who lived on pensions and welfare assistance, and less cancer patients who drink or smoke than those without cancer. Given the high incidence of suicide in elderly cancer patients, healthcare professionals should pay attention for risk even in cancer patients who have cohabiters, benefit from a pension, and do not drink or smoke.

Neurons in cortical area MST remap the memory trace of visual motion across saccadic eye movements.

Perception of a stable visual world despite eye motion requires integration of visual information across saccadic eye movements. To investigate how the visual system deals with localization of moving visual stimuli across saccades, we observed spatiotemporal changes of receptive fields (RFs) of motion-sensitive neurons across periods of saccades in the middle temporal (MT) and medial superior temporal (MST) areas. We found that the location of the RFs moved with shifts of eye position due to saccades, indicating that motion-sensitive neurons in both areas have retinotopic RFs across saccades. Different characteristic responses emerged when the moving visual stimulus was turned off before the saccades. For MT neurons, virtually no response was observed after the saccade, suggesting that the responses of these neurons simply reflect the reafferent visual information. In contrast, most MST neurons increased their firing rates when a saccade brought the location of the visual stimulus into their RFs, where the visual stimulus itself no longer existed. These findings suggest that the responses of such MST neurons after saccades were evoked by a memory of the stimulus that had preexisted in the postsaccadic RFs ("memory remapping"). A delayed-saccade paradigm further revealed that memory remapping in MST was linked to the saccade itself, rather than to a shift in attention. Thus, the visual motion information across saccades was integrated in spatiotopic coordinates and represented in the activity of MST neurons. This is likely to contribute to the perception of a stable visual world in the presence of eye movements.

Meaning Reconstruction Process After Suicide: Life-Story of a Japanese Woman Who Lost Her Son to Suicide.

Although Japan has a high suicide rate, there is insufficient research on the experiences of suicide-bereaved individuals. We investigated the qualitative aspects of the meaning reconstruction process after a loss to suicide. We conducted a life-story interview using open-ended questions with one middle-aged Japanese woman who lost her son to suicide. We used a narrative approach to transcribe and code the participant's narratives for analysis. The analysis revealed three meaning groups that structured the participant's reactions to the suicide: making sense of her son's death and life, relationships with other people, and reconstruction of a bond with the deceased. The belief that death is not an eternal split and that there is a connection between the living and the deceased reduced the pain felt by our participant. Furthermore, the narratives worked as scaffolds in the meaning reconstruction process. We discuss our results in the light of cross-cultural differences in the grieving process.

Comparing Facilitator Priorities of Suicide Survivor Support Groups: A Cross-Cultural Comparison Between Japanese and American Groups.

A total of 56 Japanese and 59 American survivor of suicide support group facilitators were asked to rank the mutual aid objectives of their groups following Shulman's scheme in terms of their frequency and importance. Both American and Japanese facilitators showed an emphasis on personal adaptation goals (such as helping bereaved feel less isolated in their grief or encouraging bereaved to share their coping with loss experiences) over collective goals (such as raising monies for more research on mental illness or trying to combat societal suicide stigma in their local communities). Differences were also noted with American facilitators evaluating helping with problem solving, sharing different ways of coping, viewing personal issues as societal problems, and advocating for promoting social change as significantly higher than the Japanese did. We believe some of these contrasts reflect differences in American and Japanese cultural values.

Contribution of color signals to ocular following responses.

Ocular following responses (OFRs) are elicited at ultra-short latencies (< 60 ms) by sudden movements of the visual scene. In this study, we investigated the roles of color signals in OFRs in monkeys. To make physiologically isoluminant sinusoidal color gratings, we estimated the physiologically isoluminant points using OFRs and found that the physiologically isoluminant points were nearly independent of the spatiotemporal frequency of the gratings. We recorded OFRs induced by the motion of physiologically isoluminant color gratings and found that OFRs elicited by the motion of color gratings had different spatiotemporal frequency tuning from those elicited by the motion of luminance gratings. Additionally, OFRs to isoluminant color gratings had smaller peak responses, suggesting that color signals weakly contribute to OFRs compared with luminance signals. OFRs to the motion of stimuli composed of luminance and color signals were also examined. We found that color signals largely contributed to OFRs under low luminance signals regardless of whether color signals moved in the same or opposite direction to luminance signals. These results provide evidence of the multichannel visual computations underlying motor responses. We conclude that, in everyday situations, color information contributes cooperatively with luminance information to the generation of ocular tracking behaviors.

Face inversion decreased information about facial identity and expression in face-responsive neurons in macaque area TE.

To investigate the effect of face inversion and thatcherization (eye inversion) on temporal processing stages of facial information, single neuron activities in the temporal cortex (area TE) of two rhesus monkeys were recorded. Test stimuli were colored pictures of monkey faces (four with four different expressions), human faces (three with four different expressions), and geometric shapes. Modifications were made in each face-picture, and its four variations were used as stimuli: upright original, inverted original, upright thatcherized, and inverted thatcherized faces. A total of 119 neurons responded to at least one of the upright original facial stimuli. A majority of the neurons (71%) showed activity modulations depending on upright and inverted presentations, and a lesser number of neurons (13%) showed activity modulations depending on original and thatcherized face conditions. In the case of face inversion, information about the fine category (facial identity and expression) decreased, whereas information about the global category (monkey vs human vs shape) was retained for both the original and thatcherized faces. Principal component analysis on the neuronal population responses revealed that the global categorization occurred regardless of the face inversion and that the inverted faces were represented near the upright faces in the principal component analysis space. By contrast, the face inversion decreased the ability to represent human facial identity and monkey facial expression. Thus, the neuronal population represented inverted faces as faces but failed to represent the identity and expression of the inverted faces, indicating that the neuronal representation in area TE cause the perceptual effect of face inversion.

Difference in visual motion representation between cortical areas MT and MST during ocular following responses.

The middle temporal (MT) and medial superior temporal (MST) areas are successive stations of the visual motion-processing stream and project in parallel to the pontine nucleus, which is closely associated with rapid stabilization of gaze. We recorded the neural activities of MT and MST neurons of monkeys during short-latency ocular following responses (OFRs) elicited by large-field sinusoidal gratings with different spatial frequencies drifting at different temporal frequencies, and examined the dependence on spatiotemporal frequency. The results indicate that most MT/MST neurons were tuned almost separately for spatial and temporal frequencies of motion stimuli. The difference between MT and MST neurons was particularly striking for the optimal spatial frequency (higher for MT and lower for MST). The spatiotemporal frequency dependence of the OFRs could be reproduced by a weighted sum of the population activities of the MT and MST neurons. We conclude that MT and MST neurons work as spatiotemporal frequency sensors that extract motions of finer and coarser visual features and that both areas contribute to generation of OFRs.

Difference in perceptual and oculomotor responses revealed by apparent motion stimuli presented with an interstimulus interval.

To understand the mechanisms underlying visual motion analyses for perceptual and oculomotor responses and their similarities/differences, we analyzed eye movement responses to two-frame animations of dual-grating 3f5f stimuli while subjects performed direction discrimination tasks. The 3f5f stimulus was composed of two sinusoids with a spatial frequency ratio of 3:5 (3f and 5f), creating a pattern with fundamental frequency f. When this stimulus was shifted by 1/4 of the wavelength, the two components shifted 1/4 of their wavelengths and had opposite directions: the 5f forward and the 3f backward. By presenting the 3f5f stimulus with various interstimulus intervals (ISIs), two visual-motion-analysis mechanisms, low-level energy-based and high-level feature-based, could be effectively distinguished. This is because response direction depends on the relative contrast between the components when the energy-based mechanism operates, but not when the feature-based mechanism works. We found that when the 3f5f stimuli were presented with shorter ISIs (<100 ms), and 3f component had higher contrast, both perceptual and ocular responses were in the direction of the pattern shift, whereas the responses were reversed when the 5f had higher contrast, suggesting operation of the energy-based mechanism. On the other hand, the ocular responses were almost negligible with longer ISIs (>100 ms), whereas perceived directions were biased toward the direction of pattern shift. These results suggest that the energy-based mechanism is dominant in oculomotor responses throughout ISIs; however, there is a transition from energy-based to feature-tracking mechanisms when we perceive visual motion.

Contributions of retinal direction-selective ganglion cells to optokinetic responses in mice.

In the mouse retina, there are two distinct groups of direction-selective ganglion cells, ON and ON-OFF, that detect movement of visual images. To understand the roles of these cells in controlling eye movements, we studied the optokinetic responses (OKRs) of mutant mice with dysfunctional ON-bipolar cells that have a functional obstruction of transmission to ON direction-selective ganglion cells. Experiments were carried out to examine the initial and late phases of OKRs. The initial phase was examined by measurement of eye velocity using stimuli of sinusoidal grating patterns of various spatiotemporal frequencies that moved for 0.5 s. The mutant mice showed significant initial OKRs, although the range of spatiotemporal frequencies that elicited these OKRs was limited and the response magnitude was weaker than that in wild-type mice. To examine the late phase of the OKRs, the same visual patterns were moved for 30 s to induce alternating slow and quick eye movements (optokinetic nystagmus) and the slow-phase eye velocity was measured. Wild-type mice showed significant late OKRs with a stimulus in an appropriate range of spatiotemporal frequencies (0.0625-0.25 cycles/°, 0.75-3.0 Hz, 3-48°/s), but mutant mice did not show late OKRs in response to the same visual stimuli. The results suggest that two groups of direction-selective ganglion cells play different roles in OKRs: ON direction-selective ganglion cells contribute to both initial and late OKRs, whereas ON-OFF direction-selective ganglion cells contribute to OKRs only transiently.

Capability of insulator study by photoemission electron microscopy at SPring-8.

The observation method of photoemission electron microscopy (PEEM) on insulating samples has been established in an extremely simple way. Surface conductivity is induced locally on an insulating surface by continuous radiation of soft X-rays, and Au films close to the area of interest allow the accumulated charges on the insulated area to be released to ground level. Magnetic domain observations of a NiZn ferrite, local X-ray absorption spectroscopy of sapphire, high-resolution imaging of a poorly conducting Li0.9CoO2 film surface, and Au pattern evaporation on a fine rock particle are demonstrated. Using this technique, all users' experiments on poorly conducting samples have been performed successfully at the PEEM experimental station of SPring-8.