A morphological and immunohistochemical study of ductal carcinoma in situ, invasive breast carcinoma of no special type, and mucinous carcinoma of the breast in comparison with solid papillary carcinoma regarding neuroendocrine marker expression.

The exact relationship between solid papillary carcinoma (SPC) and invasive breast carcinoma of no special type (IBC-NST) with neuroendocrine differentiation and SPC and mucinous carcinoma (MC) of the breast remains unclear. To clarify the relationship, we conducted a comparative study of morphological and neuroendocrine features between ductal carcinoma in situ (DCIS, 72 cases) and SPC in situ (35 cases), and IBC-NST (103 cases) and invasive SPC (92 cases). We also conducted the study between MC associated with and without SPC. Synaptophysin, chromogranin A, and INSM1 were employed for the immunohistochemical study. IBC-NST had occasionally a morphological similarity with invasive SPC. While 123 of 127 cases with SPC demonstrated diffuse staining with one or more of the neuroendocrine markers, the only one case of DCIS and none of IBC-NST showed it. Type B was observed in 16 of 18 cases of MC associated with SPC and in 13 of 33 cases of MC without it. All the cases of MC with SPC and 6 of 33 cases without it showed diffuse staining for at least one of the neuroendocrine markers. In conclusion, a careful distinction between invasive SPC and IBC-NST with neuroendocrine differentiation is required. We assume that SPC in situ is a potential candidate for precursor of IBC-NST with neuroendocrine differentiation. MC of the breast is suggested to have two pathogenetic pathways through SPC in situ or non-SPC in situ. SPC in situ is thought to be less common as a precursor of MC than non-SPC in situ.

Improving glycemic control by transitioning from the MiniMedTM 640G to 770G in Japanese adults with type 1 diabetes mellitus: a prospective, single-center, observational study.

The effectiveness of a hybrid closed-loop (HCL) system in improving glycemic control is unclear in Japanese individuals. Therefore, we assessed the effect impact of the MiniMed 770G HCL system on glycemic control in this population. This prospective, single-center, 24-week observational study (registration number: UMIN000047394) enrolled 23 individuals with type 1 diabetes mellitus using the Medtronic MiniMed 640G system. The primary endpoint was the improvement in time in the range of 70-180 mg/dL after transitioning to the MiniMed 770G HCL system. We observed an increase in time in range (from 64.1 [55.8-69.5] to 70.9 [67.1-74.4] %, interquartile range 25-75%, p < 0.001) and a decrease in glycated hemoglobin level (from 7.4 [7.0-7.9] to 7.1 [6.8-7.4] %, p = 0.003). There was a significant reduction in time above the range (181-250 mg/dL: 25.8 [20.9-28.6] to 19.5 [17.1-22.1] %, p < 0.001; >251 mg/dL: 8.7 [4.0-13.0] to 4.7 [3.6-9.1] %, p < 0.001). Time below the range remained unchanged (54-69 mg/dL: 1.8 [0.4-2.4] to 2.1 [0.4-3.9] %, p = 0.24; <54 mg/dL: 0.2 [0.0-1.0] to 0.5 [0.1-1.3] %, p = 0.14). In a subgroup of 12 patients with a high HCL implementation rate, the basal insulin infusion decreased immediately after mealtime insulin administration and increased after approximately 120 minutes. The ratings from questionnaires assessing treatment burden, satisfaction, and quality of life remained unchanged. The MiniMed 770G HCL system improved glycemic control and optimized insulin delivery, particularly in patients with high implementation rates.

Glial tone of aggression.

Anger transition is often abrupt. In this study, we investigated the mechanisms responsible for switching and modulating aggression levels. The cerebellum is considered a center for motor coordination and learning; however, its connection to social behavior has long been observed. Here, we used the resident-intruder paradigm in male mice and examined local field potential (LFP) changes, glial cytosolic ion fluctuations, and vascular dynamics in the cerebellar vermis throughout various phases of a combat sequence. Notably, we observed the emergence of theta band oscillations in the LFP and sustained elevations in glial Ca2+ levels during combat breakups. When astrocytes, including Bergmann glial cells, were photoactivated using channelrhodopsin-2, the theta band emerged and an early combat breakup occurred. Within a single combat sequence, rapid alteration of offensive (fight) and passive (flight) responses were observed, which roughly correlated with decreases and increases in glial Ca2+, respectively. Neuron-glial interactions in the cerebellar vermis may play a role in adjusting Purkinje cell excitability and setting the tone of aggression. Future anger management strategies and clinical control of excessive aggression and violent behavior may be realized by developing a therapeutic strategy that adjusts glial activity in the cerebellum.

Module-Assembled Elastomer Showing Large Strain Stiffening Capability and High Stretchability.

Elastomers are indispensable materials due to their flexible, stretchable, and elastic nature. However, the polymer network structure constituting an elastomer is generally inhomogeneous, limiting the performance of the material. Here, a highly stretchable elastomer with unprecedented strain-stiffening capability is developed based on a highly homogeneous network structure enabled by a module assembly strategy. The elastomer is synthesized by efficient end-linking of a star-shaped aliphatic polyester precursor with a narrow molecular-weight distribution. The resulting product shows high strength (≈26 MPa) and remarkable stretchability (stretch ratio at break ≈1900%), as well as good fatigue resistance and notch insensitivity. Moreover, it shows extraordinary strain-stiffening capability (>2000-fold increase in the apparent stiffness) that exceeds the performance of any existing soft material. These unique properties are due to strain-induced ordering of the polymer chains in a uniformly stretched network, as revealed by in situ X-ray scattering analyses. The utility of this great strain-stiffening capability is demonstrated by realizing a simple variable stiffness actuator for soft robotics.

A patient with mild respiratory COVID-19 infection who developed bilateral non-hemorrhagic adrenal infarction.

A 76-year-old woman was admitted to the emergency room of Nagano Municipal Hospital with the complain of severe back pain. Chest and abdominal enhanced computed tomography scans showed bilateral adrenal infarction and minute pulmonary nodules, but she had no respiratory symptoms. After admission, a family member of the patient was found to have been in close contact with a coronavirus disease 2019 (COVID-19) patient. Thus, polymerase chain reaction and antigen tests of severe acute respiratory syndrome coronavirus 2 were conducted, and both tests returned positive. D-dimer levels were normal on admission but increased 2 days thereafter. Anticoagulation therapy and steroid replacement were started, and the patient improved over about two weeks. One month after the onset of adrenal infarction, a rapid adrenocorticotropic hormone loading test was conducted, which revealed that the primary adrenal insufficiency due to adrenal infarction might have been caused by the COVID-19 infection. This case was rare and suggestive of adrenal infarction with COVID-19, which usually presents at the severe stage. In patients with COVID-19, attention should be paid to the onset of thrombosis, even with mild respiratory infection. We also suggest that patients with thrombosis should be suspected of having COVID-19 even in the absence of respiratory infectious symptoms in a situation of COVID-19 epidemic.

Enhancement of membrane vesicle production by disrupting the degP gene in Meiothermus ruber H328.

The phenomenon of membrane vesicle (MV) production is known to be common to all bacterial cells. Although MVs are expected to be employed in a variety of applications, improving MV productivity is essential for applications. Since the deletion of the degP gene, a periplasmic dual-function protease and chaperone, in Escherichia coli has successfully improved MV production capacity, we tried to enhance MV productivity in the thermophilic M. ruber H328 by deleting the degP gene. One gene (mrH_0331) was selected for degP gene from the H328 genome and we constructed the mutant strain ∆degP by deleting the degP gene of the H328 strain that was replaced with the htk gene showing thermophilic kanamaycin resistance by homologous recombination. The mutant strain ∆degP exhibited smooth growth but a lower level of turbidity at 60 °C although there was no difference in growth at 55 °C between the wild strain and the mutant strain. Finally, we have confirmed that incubation at 60 °C increases MV in the mutant strain ∆degP strain about fivefold by using two fluorescent dyes, DiI and FM4-64, which is followed by TEM analysis. The deletion of the degP gene presumably causes an increase in denatured proteins at 60 °C, leading to enhanced MV production. Meanwhile, the S-layer protein included in the outer membrane of the H328 strain increased in the MV fraction prepared from the mutant cells incubated at 60 °C. This indicates that this method is effective for MV production and that degP deletion enhances it in strain H328.

Emergent inequality and business cycles in a simple behavioral macroeconomic model.

Standard macroeconomic models assume that households are rational in the sense that they are perfect utility maximizers and explain economic dynamics in terms of shocks that drive the economy away from the steady state. Here we build on a standard macroeconomic model in which a single rational representative household makes a savings decision of how much to consume or invest. In our model, households are myopic boundedly rational heterogeneous agents embedded in a social network. From time to time each household updates its savings rate by copying the savings rate of its neighbor with the highest consumption. If the updating time is short, the economy is stuck in a poverty trap, but for longer updating times economic output approaches its optimal value, and we observe a critical transition to an economy with irregular endogenous oscillations in economic output, resembling a business cycle. In this regime households divide into two groups: poor households with low savings rates and rich households with high savings rates. Thus, inequality and economic dynamics both occur spontaneously as a consequence of imperfect household decision-making. Adding a few "rational" agents with a fixed savings rate equal to the long-term optimum allows us to match business cycle timescales. Our work here supports an alternative program of research that substitutes utility maximization for behaviorally grounded decision-making.

Orbit/CLASP determines centriole length by antagonising Klp10A in Drosophila spermatocytes.

After centrosome duplication, centrioles elongate before M phase. To identify genes required for this process and to understand the regulatory mechanism, we investigated the centrioles in Drosophila premeiotic spermatocytes expressing fluorescently tagged centriolar proteins. We demonstrated that an essential microtubule polymerisation factor, Orbit (the Drosophila CLASP orthologue, encoded by chb), accumulated at the distal end of centrioles and was required for the elongation. Conversely, a microtubule-severing factor, Klp10A, shortened the centrioles. Genetic analyses revealed that these two proteins functioned antagonistically to determine centriole length. Furthermore, Cp110 in the distal tip complex was closely associated with the factors involved in centriolar dynamics at the distal end. We observed loss of centriole integrity, including fragmentation of centrioles and earlier separation of the centriole pairs, in Cp110-null mutant cells either overexpressing Orbit or depleted of Klp10A Excess centriole elongation in the absence of the distal tip complex resulted in the loss of centriole integrity, leading to the formation of multipolar spindle microtubules emanating from centriole fragments, even when they were unpaired. Our findings contribute to understanding the mechanism of centriole integrity, disruption of which leads to chromosome instability in cancer cells.

Musculoskeletal design, control, and application of human mimetic humanoid Kenshiro.

We have been developing a human mimetic musculoskeletal humanoid called Kenshiro, whose design concept is to thoroughly pursue an unprecedented anatomical fidelity to the human musculoskeletal structure. We believe that research on human mimetic musculoskeletal humanoids advances our understanding of humans and expands the applications of humanoids-such as a human body simulator that can quantitatively analyze internal human motion data. This paper describes Kenshiro's musculoskeletal body characteristics, software system, and preliminary experiments explaining the concept of potential application.

When (not) to Look for Contrastive Alternatives: The Role of Pitch Accent Type and Additive Particles.

This study investigates how pitch accent type and additive particles affect the activation of contrastive alternatives. In Experiment 1, German listeners heard declarative utterances (e.g., The swimmer wanted to put on flippers) and saw four printed words displayed on screen: one that was a contrastive alternative to the subject noun (e.g., diver), one that was non-contrastively related (e.g., pool), the object (e.g., flippers), and an unrelated distractor. Experiment 1 manipulated pitch accent type, comparing a broad focus control condition to two narrow focus conditions: with a contrastive or non-contrastive accent on the subject noun (nuclear L+H* vs. H+L*, respectively, followed by deaccentuation). In Experiment 2, the utterances in the narrow focus conditions were preceded by the unstressed additive particle auch ("also"), which may trigger alternatives itself. It associated with the accented subject. Results showed that, compared to the control condition, participants directed more fixations to the contrastive alternative when the subject was realized with a contrastive accent (nuclear L+H*) than when it was realized with non-contrastive H+L*, while additive particles had no effect. Hence, accent type is the primary trigger for signaling the presence of alternatives (i.e., contrast). Implications for theories of information structure and the processing of additive particles are discussed.

SOMFlow: Guided Exploratory Cluster Analysis with Self-Organizing Maps and Analytic Provenance.

Clustering is a core building block for data analysis, aiming to extract otherwise hidden structures and relations from raw datasets, such as particular groups that can be effectively related, compared, and interpreted. A plethora of visual-interactive cluster analysis techniques has been proposed to date, however, arriving at useful clusterings often requires several rounds of user interactions to fine-tune the data preprocessing and algorithms. We present a multi-stage Visual Analytics (VA) approach for iterative cluster refinement together with an implementation (SOMFlow) that uses Self-Organizing Maps (SOM) to analyze time series data. It supports exploration by offering the analyst a visual platform to analyze intermediate results, adapt the underlying computations, iteratively partition the data, and to reflect previous analytical activities. The history of previous decisions is explicitly visualized within a flow graph, allowing to compare earlier cluster refinements and to explore relations. We further leverage quality and interestingness measures to guide the analyst in the discovery of useful patterns, relations, and data partitions. We conducted two pair analytics experiments together with a subject matter expert in speech intonation research to demonstrate that the approach is effective for interactive data analysis, supporting enhanced understanding of clustering results as well as the interactive process itself.

Protein Folding in the Presence of Water-Soluble Cyclic Diselenides with Novel Oxidoreductase and Isomerase Activities.

The protein disulfide isomerase (PDI) family, found in the endoplasmic reticulum (ER) of the eukaryotic cell, catalyzes the formation and cleavage of disulfide bonds and thereby helps in protein folding. A decrease in PDI activity under ER stress conditions leads to protein misfolding, which is responsible for the progression of various human diseases, such as Alzheimer's, Parkinson's, diabetes mellitus, and atherosclerosis. Here we report that water-soluble cyclic diselenides mimic the multifunctional activity of the PDI family by facilitating oxidative folding, disulfide formation/reduction, and repair of the scrambled disulfide bonds in misfolded proteins.

Discriminating Non-Native Segmental Length Contrasts Under Increased Task Demands.

The present study examines how vulnerable perception of second language prosody is to increased task demands. German learners of Japanese, German non-learners without exposure to Japanese, and Japanese native listeners were tested in their ability to discriminate consonant length contrasts (compared to vowel length contrasts that served as a control condition). Memory load was increased by a longer inter-stimulus interval (2500 ms compared to 300 ms) and the demand on attention control was enhanced through the addition of the acoustic complexity of the stimuli (i.e., through a task-irrelevant pitch fall that occurred simultaneously with a consonant length contrast). The results showed high discrimination abilities, in all groups, when task demands were lowest. With increased task demands, only non-native listeners' discrimination abilities decreased: non-learners were strongly affected by both increased memory load and higher demand on attention control, while learners were only affected by the latter. The task-irrelevant acoustic complexity of the stimuli had a stronger impact on performance than increased memory load did. The findings suggest that second language learners established novel phonological representations but that the ability to use them could only be applied in the absence of distracting acoustic information. The non-native listeners' reduced sensitivity under increased task demands explains why even advanced learners still face difficulties in daily listening situations with numerous distractions.

Selenoglutathione Diselenide: Unique Redox Reactions in the GPx-Like Catalytic Cycle and Repairing of Disulfide Bonds in Scrambled Protein.

Selenoglutathione (GSeH) is a selenium analogue of naturally abundant glutathione (GSH). In this study, this water-soluble small tripeptide was synthesized in a high yield (up to 98%) as an oxidized diselenide form, i.e., GSeSeG (1), by liquid-phase peptide synthesis (LPPS). Obtained 1 was applied to the investigation of the glutathione peroxidase (GPx)-like catalytic cycle. The important intermediates, i.e., GSe- and GSeSG, besides GSeO2H were characterized by 77Se NMR spectroscopy. Thiol exchange of GSeSG with various thiols, such as cysteine and dithiothreitol, was found to promote the conversion to GSe- significantly. In addition, disproportionation of GSeSR to 1 and RSSR, which would be initiated by heterolytic cleavage of the Se-S bond and catalyzed by the generated selenolate, was observed. On the basis of these redox behaviors, it was proposed that the heterolytic cleavage of the Se-S bond can be facilitated by the interaction between the Se atom and an amino or aromatic group, which is present at the GPx active site. On the other hand, when a catalytic amount of 1 was reacted with scrambled 4S species of RNase A in the presence of NADPH and glutathione reductase, native protein was efficiently regenerated, suggesting a potential use of 1 to repair misfolded proteins through reduction of the non-native SS bonds.

Design principles of a human mimetic humanoid: Humanoid platform to study human intelligence and internal body system.

Many systems and mechanisms in the human body are not fully understood, such as the principles of muscle control, the sensory nervous system that connects the brain and the body, learning in the brain, and the human walking motion. To address this knowledge deficit, we propose a human mimetic humanoid with an unprecedented degree of anatomical fidelity to the human musculoskeletal structure. The fundamental concept underlying our design is to consider the human mechanism, which contrasts with the conventional engineering approach used in the design of existing humanoids. We believe that the proposed human mimetic humanoid can be used to provide new opportunities in science, for instance, to quantitatively analyze the internal data of a human body in movement. We describe the principles and development of human mimetic humanoids, Kenshiro and Kengoro, and compare their anatomical fidelity with humans in terms of body proportions, skeletal structures, muscle arrangement, and joint performance. To demonstrate the potential of human mimetic humanoids, Kenshiro and Kengoro performed several typical human motions.

Isolated Oculomotor Nerve Palsy Due to Metastasis of Prostatic Cancer to the Cavernous Sinus.

A 69-year-old man with prostatic cancer under palliative care developed isolated right-sided oculomotor nerve palsy with pupillary impairment and persistent ocular pain. Cranial magnetic resonance imaging demonstrated metastasis of prostatic cancer to the right-sided cavernous sinus and orbital apex. In the English language literature, there are only six reported cases of isolated oculomotor nerve palsy secondary to prostatic cancer. In all cases, although there was metastatic lesion in the vicinity of the cavernous sinus, ocular pain did not develop. In the current patient, because metastatic tumour might involve the right-sided oculomotor nerve as well as lacrimal nerve, ocular pain developed.