Enhancing Wear Resistance in Functionally Graded Metallic Components: Insights from Nanoindentation and Mechanical Analysis.

To manufacture metallic components with high wear resistance, treatments such as nitriding and carburising followed by quenching and tempering (NQT and CQT, respectively) are applied to various types of steel to increase the hardness (H) of the friction surface. However, the wear mechanism of the resulting functionally graded materials has not been fully understood. In this study, specimens of industrial 99.82% pure iron treated with NQT at 913 and 1033 K, and CQT at 1203 K, as well as hot-rolled sheets without heat treatment were examined by performing nanoindentation tests to measure changes in their H, reduced Young's moduli (Er), elastic deformation energies (We), and plastic deformation energies (Wp) along the depth direction. The relationship between Wp/We and the elastic strain resistance (H/Er) can be expressed for all specimens via the equation Wp/We = -1.0 + 0.16 (H/Er)-1. Furthermore, the obtained H/Er av measured at 5 µm intervals based on the specimen profile and wear volume has a good correlation depending to the sliding distance, as confirmed by the results of the ring-on-plate sliding tests conducted for the carbon-treated, nitrogen-treated, and hot-rolled specimens. This study provides a new approach, using H/Er parameters to identify the dominant factors affecting wear resistance at the initial stage of wear that may contribute to the development of wear-resistant materials.

Histological analysis of neuronal changes in the olfactory cortex during pregnancy.

Fluctuations in olfactory sensitivity are widely known to occur during pregnancy and may be responsible for hyperemesis gravidarum. These changes are thought to be caused by structural and functional alterations in neurons in response to marked changes of the hormonal milieu. In this study, we examined changes in neurons in the olfactory cortex during pregnancy and after delivery in rats. Dendritic spine densities were measured in the piriform cortex (PIR) and posterolateral cortical amygdala (COApl), which are involved in olfaction. The results showed increased numbers of dendritic spines in the PIR in mid-pregnancy and in the COApl during early and late pregnancy, but not in the motor area of the cerebral cortex, indicating a correlation with changes in olfactory sensitivity during pregnancy. Immunohistochemical analysis of expression of ovarian hormone receptors in these brain regions revealed a decrease in the number of estrogen receptor α-positive cells during pregnancy in the PIR and during pregnancy and the postpartum period in the COApl. Regarding pregnancy-related peptide hormones, oxytocin receptors were expressed in the PIR and COApl, while prolactin receptors were not found in these regions. Accordingly, oxytocin-containing neurites were distributed in both regions. These results suggest that the balance of these hormonal signals has an effect on olfactory sensitivity in pregnant females.

Detection of biomagnetic signals from induced pluripotent stem cell-derived cardiomyocytes using deep learning with simulation data.

The detection of spontaneous magnetic signals can be used for the non-invasive electrophysiological evaluation of induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs). We report that deep learning with a dataset that combines magnetic signals estimated using numerical simulation and actual noise data is effective in the detection of weak biomagnetic signals. To verify the feasibility of this method, we measured artificially generated magnetic signals that mimic cellular magnetic fields using a superconducting quantum interference device and attempted peak detection using a long short-term memory network. We correctly detected 80.0% of the peaks and the method achieved superior detection performance compared with conventional methods. Next, we attempted peak detection for magnetic signals measured from mouse iPS-CMs. The number of detected peaks was consistent with the spontaneous beats counted using microscopic observation and the average peak waveform achieved good similarity with the prediction. We also observed the synchronization of peak positions between simultaneously measured field potentials and magnetic signals. Furthermore, the magnetic measurements of cell samples treated with isoproterenol showed potential for the detection of chronotropic effects. These results suggest that the proposed method is effective and has potential application in the safety assessment of regenerative medicine and drug screening.

Validation of Wistar-Kyoto rats kept in solitary housing as an animal model for depression using voxel-based morphometry.

Major depressive disorder is a common psychiatric condition often resistant to medication. The Wistar-Kyoto (WKY) rat has been suggested as an animal model of depression; however, it is still challenging to translate results from animal models into humans. Solitary housing is a mild stress paradigm that can simulate the environment of depressive patients with limited social activity due to symptoms. We used voxel-based morphometry to associate the solitary-housed WKY (sWKY) rat model with data from previous human studies and validated our results with behavioural studies. As a result, atrophy in sWKY rats was detected in the ventral hippocampus, caudate putamen, lateral septum, cerebellar vermis, and cerebellar nuclei (p < 0.05, corrected for family-wise error rate). Locomotor behaviour was negatively correlated with habenula volume and positively correlated with atrophy of the cerebellar vermis. In addition, sWKY rats showed depletion of sucrose consumption not after reward habituation but without reward habituation. Although the application of sWKY rats in a study of anhedonia might be limited, we observed some similarities between the regions of brain atrophy in sWKY rats and humans with depression, supporting the translation of sWKY rat studies to humans.

Diurnal Variation of Brain Activity in the Human Suprachiasmatic Nucleus.

The suprachiasmatic nucleus (SCN) is the central clock for circadian rhythms. Animal studies have revealed daily rhythms in the neuronal activity in the SCN. However, the circadian activity of the human SCN has remained elusive. In this study, to reveal the diurnal variation of the SCN activity in humans, we localized the SCN by employing an areal boundary mapping technique to resting-state functional images and investigated the SCN activity using perfusion imaging. In the first experiment (n = 27, including both sexes), we scanned each participant four times a day, every 6 h. Higher activity was observed at noon, while lower activity was recorded in the early morning. In the second experiment (n = 20, including both sexes), the SCN activity was measured every 30 min for 6 h from midnight to dawn. The results showed that the SCN activity gradually decreased and was not associated with the electroencephalography. Furthermore, the SCN activity was compatible with the rodent SCN activity after switching off the lights. These results suggest that the diurnal variation of the human SCN follows the zeitgeber cycles of nocturnal and diurnal mammals and is modulated by physical lights rather than the local time.

Asymptomatic subarachnoid hemorrhage following carotid endarterectomy: illustrative case.

BACKGROUND: Carotid endarterectomy (CEA) and carotid artery stenting are common surgical interventions for internal carotid artery stenosis. Cerebral hyperperfusion syndrome (CHS) is a well-known complication of both procedures that can lead to intracranial hemorrhage and worsen clinical outcomes. Here, the authors report a rare case of non-aneurysmal subarachnoid hemorrhage (SAH) following CEA and review the relevant literature. OBSERVATIONS: A 70-year-old woman with hypertension and diabetes presented with progressive visual loss in the right eye and was diagnosed with ocular ischemic syndrome. Imaging revealed severe right cervical carotid artery stenosis. CEA was performed with no complications. Postoperatively, the patient's blood pressure was tightly controlled, with no evidence of CHS. However, an asymptomatic SAH was detected on postoperative day 7. Careful observation and blood pressure control were maintained. Since follow-up magnetic resonance imaging (MRI) showed no enlarging of the SAH and the patient was asymptomatic, she was discharged on postoperative day 15 with a modified Rankin scale score of 0. LESSONS: This case highlights the potential occurrence of non-aneurysmal SAH as a rare complication of CEA, even in asymptomatic patients. Repeated postoperative MRI is necessary to detect such complications. It is crucial to carefully control blood pressure after CEA regardless of symptoms.

Roles of Stress Response in Autophagy Processes and Aging-Related Diseases.

The heat shock factor 1 (HSF1)-mediated stress response pathway and autophagy processes play important roles in the maintenance of proteostasis. Autophagy processes are subdivided into three subtypes: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Recently, molecular chaperones and co-factors were shown to be involved in the selective degradation of substrates by these three autophagy processes. This evidence suggests that autophagy processes are regulated in a coordinated manner by the HSF1-mediated stress response pathway. Recently, various studies have demonstrated that proteostasis pathways including HSF1 and autophagy are implicated in longevity. Furthermore, they serve as therapeutic targets for aging-related diseases such as cancer and neurodegenerative diseases. In the future, these studies will underpin the development of therapies against various diseases.

A Single Intradermal Injection of Autologous Adipose-Tissue-Derived Stem Cells Rejuvenates Aged Skin and Sharpens Double Eyelids.

Facial skin aging is the most visible manifestation of aging in the body. In this study, we aimed to rejuvenate aging skin via a one-time intradermal injection of autologous adipose-derived stem cells (ADSCs). Eight patients were enrolled for study. Photographs of patients taken immediately before and 1, 3, 6, and 12 months after ADSC injections were comparatively evaluated for visible skin manifestations. ADSCs were cultured from the abdominal-skin-derived subcutaneous fat tissue, and 1 × 108 cultured ADSCs were injected intradermally into the facial skin. Cultured myoblasts were incubated with the supernatant derived from ADSCs, and the effect was evaluated via glucose consumption and lactic acid production in the medium. Eight cases showed the shallowing and disappearance of wrinkles, including those of the glabella, lower eyelids, crow`s feet, and forehead and nasolabial grooves, a month to several months after treatment. Double eyelids became prominent, and facial pores significantly reduced in size. These effects lasted for over one year. Myoblasts cultured in the presence of an ADSC-derived exosome were activated compared to that of ADSCs cultured without supernatant. The result supports the role of muscle in ADSC skin rejuvenation. The present study first reports that a single intradermal administration of cultured ADSCs rejuvenates aged facial skin over the course of one year. Further, patients exhibited definite double eyelids and pore shrinkage, strongly indicating the active involvement of muscle, which was supported by an in vitro study. Our study also suggested the important role of biological factors delivered from injected stem cells, although the detailed mechanism of rejuvenation effects of ADSC skin injection remains to be clarified.

Origin of Unexpected Ir3+ in a Superconducting Candidate Sr2IrO4 System Analyzed by Photoelectron Holography.

The reason for the absence of superconductivity in Sr2IrO4 was estimated by photoelectron spectra and photoelectron holograms. The analysis of the La photoelectron hologram concluded that La atoms are substituted to Sr sites. Two O 1s peaks were observed and were identified as the oxygens in the IrO2 and SrO planes by photoelectron holography and density functional theory (DFT) calculations. In the Ir 4f spectrum of Sr2IrO4, an unexpected Ir3+ peak was observed as much as 50% of all of the Ir. The photoelectron hologram of Ir3+ showed a displacement of about 0.15 Å. This displacement is thought to be due to the oxygen vacancies in the IrO2 plane. These oxygen vacancies and the associated local displacement of the atoms might inhibit superconductivity in spite of sufficient electron doping.

Sensory and motor representations of internalized rhythms in the cerebellum and basal ganglia.

Both the cerebellum and basal ganglia are involved in rhythm processing, but their specific roles remain unclear. During rhythm perception, these areas may be processing purely sensory information, or they may be involved in motor preparation, as periodic stimuli often induce synchronized movements. Previous studies have shown that neurons in the cerebellar dentate nucleus and the caudate nucleus exhibit periodic activity when the animals prepare to respond to the random omission of regularly repeated visual stimuli. To detect stimulus omission, the animals need to learn the stimulus tempo and predict the timing of the next stimulus. The present study demonstrates that neuronal activity in the cerebellum is modulated by the location of the repeated stimulus and that in the striatum (STR) by the direction of planned movement. However, in both brain regions, neuronal activity during movement and the effect of electrical stimulation immediately before stimulus omission were largely dependent on the direction of movement. These results suggest that, during rhythm processing, the cerebellum is involved in multiple stages from sensory prediction to motor control, while the STR consistently plays a role in motor preparation. Thus, internalized rhythms without movement are maintained as periodic neuronal activity, with the cerebellum and STR preferring sensory and motor representations, respectively.

Candida Pneumonia in a Young Vegan Man with Diabetic Ketoacidosis.

A 39-year-old vegan man was admitted with diabetic ketoacidosis. He had also developed pneumonia that was unresponsive to antibiotics. Based on bronchoscopy findings, the diagnosis of Candida pneumonia was made, and the pulmonary shadow disappeared rapidly after antifungal therapy. Candida pneumonia has been mostly reported in severely immunocompromised patients. This is a rare case of Candida pneumonia that was found in a young vegan man with diabetes mellitus (DM). Although malnutrition caused by DM or an unbalanced diet is often underestimated as a cause of immunodeficiency, these conditions can be risk factors for serious opportunistic infections, including Candida pneumonia.

High-dose ubiquinol supplementation in multiple-system atrophy: a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial.

Background: Functionally impaired variants of COQ2, encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients. Methods: This study was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either ubiquinol (1500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who completed at least one efficacy assessment (full analysis set). Safety analyses included patients who completed at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771), where the drug name of MSA-01 was used to designate ubiquinol. Findings: Between June 26, 2018, and May 27, 2019, 139 patients were enrolled and randomly assigned to the ubiquinol group (n = 69) or the placebo group (n = 70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (-1.7 [95% CI, -3.2 to -0.2]; P = 0.023)). The ubiquinol group also showed better secondary efficacy outcomes (Barthel index, Scale for the Assessment and Rating of Ataxia, and time required to walk 10 m). Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n = 15 [23.8%]) and placebo (n = 21 [30.9%]). Interpretation: High-dose ubiquinol was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo. Funding: Japan Agency for Medical Research and Development.

A novel homozygous nonsense variant of LMF1 in pregnancy-induced hypertriglyceridemia with acute pancreatitis.

Hypertriglyceridemia (HTG)-induced pancreatitis during pregnancy could lead to maternal and fetal death. However, its genetic bases are not fully understood, and its treatment strategies are yet to be established. Here we report a case with a novel homozygous nonsense variant of LMF1 in pregnancy-associated HTG with acute pancreatitis. Our patient had childhood-onset severe HTG that had been well-controlled by dietary management in the non-pregnant period with plasma triglyceride (TG) levels at around 200 mg/dL. Milky plasma was noted at the first-trimester pregnancy checkup, followed by a severe increase in plasma TG (10,500 mg/dL) that resulted in pancreatitis in the last trimester. The implementation of strict dietary fat restriction (less than 4 grams per day) reduced plasma TG levels and led to successful delivery. Exome sequencing revealed a novel homozygous nonsense variant in LMF1 (c.697C>T, p.Arg233Ter). The activities of lipoprotein lipase (LPL) and hepatic lipase in post-heparin plasma were not abolished but reduced. The use of pemafibrate decreased plasma TG levels with a concomitant increase in LPL activity. HTG in childhood or early pregnancy is commonly assumed to be polygenic in origin but should be regarded as a feature suggestive of monogenic hyperchylomicronemia. Adequate TG monitoring and dietary fat restriction should be implemented to prevent potentially lethal events of pancreatitis.

Phenotypic screening using waveform analysis of synchronized calcium oscillations in primary cortical cultures.

At present, in vitro phenotypic screening methods are widely used for drug discovery. In the field of epilepsy research, measurements of neuronal activities have been utilized for predicting efficacy of anti-epileptic drugs. Fluorescence measurements of calcium oscillations in neurons are commonly used for measurement of neuronal activities, and some anti-epileptic drugs have been evaluated using this assay technique. However, changes in waveforms were not quantified in previous reports. Here, we have developed a high-throughput screening system containing a new analysis method for quantifying waveforms, and our method has successfully enabled simultaneous measurement of calcium oscillations in a 96-well plate. Features of waveforms were extracted automatically and allowed the characterization of some anti-epileptic drugs using principal component analysis. Moreover, we have shown that trajectories in accordance with the concentrations of compounds in principal component analysis plots were unique to the mechanism of anti-epileptic drugs. We believe that an approach that focuses on the features of calcium oscillations will lead to better understanding of the characteristics of existing anti-epileptic drugs and allow to predict the mechanism of action of novel drug candidates.

FoxP2 protein decreases at a specific region in the chick midbrain after hatching.

Forkhead-box subclass P member 2 (FOXP2/FoxP2) protein, a transcription factor, regulates the development of certain brain functions, including human speech and animal vocalization. Although rapid progress has been made in demonstrating a relationship between FoxP2 expression in the brain and vocalization of the zebra finch, a typical vocal learner, the relationship in avian vocal non-learners, including chickens remains elusive. Because the midbrain plays a key role in innate vocalization development, we analyzed the FoxP2 protein in the midbrain of chicks, which do not cheep before hatching but cheep and call after hatching. Western blot analyses showed a significant reduction in FoxP2 protein in the chick midbrain after hatching compared with the findings before hatching. Quantitative immunohistochemistry revealed that FoxP2-immunoreactive (ir) cells significantly decreased at the stratum gris fibrosum (SGFS) of the optic tectum in the chick midbrain after hatching compared with the findings before hatching. These findings support the notion that FoxP2-ir cell numbers decrease at a specific region in the midbrain after hatching may be involved in innate vocalization of avian vocal non-learners.

Atomic Imaging of Interface Defects in an Insulating Film on Diamond.

The insulator/semiconductor interface structure is the key to electric device performance, and much interest has been focused on understanding the origin of interfacial defects. However, with conventional techniques, it is difficult to analyze the interfacial atomic structure buried in the insulating film. Here, we reveal the atomic structure at the interface between an amorphous aluminum oxide and diamond using a developed electron energy analyzer for photoelectron holography. We find that the three-dimensional atomic structure of a C-O-Al-O-C bridge between two dimer rows of the hydrogen-terminated diamond surface. Our results demonstrate that photoelectron holography can be used to reveal the three-dimensional atomic structure of the interface between a crystal and an amorphous film. We also find that the photoelectron intensity originating from the C-O bonds is strongly related to the interfacial defect density. We anticipate significant progress in the study of amorphous/crystalline interfaces based on their three-dimensional atomic structures analysis.

SOCS7-Derived BC-Box Motif Peptide Mediated Cholinergic Differentiation of Human Adipose-Derived Mesenchymal Stem Cells.

Adipose-derived mesenchymal stem cells (ADMSCs) are a type of pluripotent somatic stem cells that differentiate into various cell types such as osteoblast, chondrocyte, and neuronal cells. ADMSCs as donor cells are used to produce regenerative medicines at hospitals and clinics. However, it has not been reported that ADMSCs were differentiated to a specific type of neuron with a peptide. Here, we report that ADMSCs differentiate to the cholinergic phenotype of neurons by the SOCS7-derived BC-box motif peptide. At operations for patients with neurological disorders, a small amount of subcutaneous fat was obtained. Two weeks later, adipose-derived mesenchymal stem cells (ADMSCs) were isolated and cultured for a further 1 to 2 weeks. Flow cytometry analysis for characterization of ADMSCs was performed with CD73, CD90, and CD105 as positive markers, and CD14, CD31, and CD56 as negative markers. The results showed that cultured cells were compatible with ADMSCs. Immunocytochemical studies showed naïve ADMSCs immunopositive for p75NTR, RET, nestin, keratin, neurofilament-M, and smooth muscle actin. ADMSCs were suggested to be pluripotent stem cells. A peptide corresponding to the amino-acid sequence of BC-box motif derived from SOCS7 protein was added to the medium at a concentration of 2 µM. Three days later, immunocytochemistry analysis, Western blot analysis, ubiquitination assay, and electrophysiological analysis with patch cramp were performed. Immunostaining revealed the expression of neurofilament H (NFH), choline acetyltransferase (ChAT), and tyrosine hydroxylase (TH). In addition, Western blot analysis showed an increase in the expression of NFH, ChAT, and TH, and the expression of ChAT was more distinct than TH. Immunoprecipitation with JAK2 showed an increase in the expression of ubiquitin. Electrophysiological analysis showed a large holding potential at the recorded cells through path electrodes. The BC-box motif peptide derived from SOCS7 promoted the cholinergic differentiation of ADMSCs. This novel method will contribute to research as well as regenerative medicine for cholinergic neuron diseases.

Role of right temporoparietal junction for counterfactual evaluation of partner's decision in ultimatum game.

Humans assess the distributions of resources based on their aversion to unfairness. If a partner distributes in an unfair manner even though the partner had a less unfair distribution option, a recipient will believe that the partner should have chosen the counterfactual option. In this study, we investigated the neural basis for fairness evaluation of actual and counterfactual options in the ultimatum game. In this task, a partner chose one distribution option out of two options, and a participant accepted or rejected the option. The behavioral results showed that the acceptance rate was influenced by counterfactual evaluation (CE), among others, as defined by the difference of monetary amount between the actual and counterfactual options. The functional magnetic resonance imaging results showed that CE was associated with the right ventral angular gyrus (vAG) that provided one of convergent inputs to the supramarginal gyrus related to decision utility, which reflects gross preferences for the distribution options. Furthermore, inhibitory repetitive transcranial magnetic stimulation administered to the right vAG reduced the behavioral component associated with CE. These results suggest that our acceptance/rejection of distribution options relies on multiple processes (monetary amount, disadvantageous inequity, and CE) and that the right vAG causally contributes to CE.

Metastatic Lung Tumors from Colorectal Cancer with EGFR Mutations That Responded to Osimertinib.

A 50-year-old woman who had previously undergone right hemicolectomy and chemotherapy for colorectal cancer was hospitalized with respiratory failure. Chest computed tomography showed reticulonodular opacities and enlarged lymph nodes. A transbronchial biopsy revealed adenocarcinoma with epidermal growth factor receptor (EGFR) mutations T790M and L861Q. Treatment with the EGFR-tyrosine kinase inhibitor (TKI) osimertinib was started, and she achieved a partial response. We diagnosed her with metastatic lung tumors from colorectal cancer based on additional immunohistochemical staining and the EGFR mutation status (L861Q) of the specimens. Although cases with EGFR mutations have been rarely reported, an EGFR-TKI can be an effective treatment option for colorectal cancer.

Hypothalamic interaction with reward-related regions during subjective evaluation of foods.

The reward system implemented in the midbrain, ventral striatum, orbitofrontal cortex, and ventromedial prefrontal cortex evaluates and compares various types of rewards given to the organisms. It has been suggested that autonomic factors influence reward-related processing via the hypothalamus, but how the hypothalamus modulates the reward system remains elusive. In this functional magnetic resonance imaging study, the hypothalamus was parcellated into individual hypothalamic nuclei performing different autonomic functions using boundary mapping parcellation analyses. The effective interaction during subjective evaluation of foods in a reward task was then investigated between the human hypothalamic nuclei and the reward-related regions. We found significant brain activity decrease in the paraventricular nucleus (PVH) and lateral nucleus in the hypothalamus in food evaluation compared with monetary evaluation. A psychophysiological interaction analysis revealed dual interactions between the PVH and (1) midbrain region and (2) ventromedial prefrontal cortex, with the former correlated with the stronger tendency of participants toward food-seeking. A dynamic causal modeling analysis further revealed unidirectional interactions from the PVH to the midbrain and ventromedial prefrontal cortex. These results suggest that the PVH in the human hypothalamus interacts with the reward-related regions in the cerebral cortex via multiple pathways (i.e., the midbrain pathway and ventromedial prefrontal pathway) to evaluate rewards for subsequent decision-making.