Aftereffect of perceived motion trajectories.

If our visual system has a distinct computational process for motion trajectories, such a process may minimize redundancy and emphasize variation in object trajectories by adapting to the current statistics. Our experiments show that after adaptation to multiple objects traveling along trajectories with a common tilt, the trajectory of an object was perceived as tilting on the repulsive side. This trajectory aftereffect occurred irrespective of whether the tilt of the adapting stimulus was physical or an illusion from motion-induced position shifts and did not differ in size across the physical and illusory conditions. Moreover, when the perceived and physical tilts competed during adaptation, the trajectory aftereffect depended on the perceived tilt. The trajectory aftereffect transferred between hemifields and was not explained by motion-insensitive orientation adaptation or attention. These findings provide evidence for a trajectory-specific adaptable process that depends on higher-order representations after the integration of position and motion signals.

Identification of a novel splice-site WWOX variant with paternal uniparental isodisomy in a patient with infantile epileptic encephalopathy.

WOREE syndrome is an early infantile epileptic encephalopathy characterized by drug-resistant seizures and severe psychomotor developmental delays. We report a case of a WWOX splice-site mutation with uniparental isodisomy. A 1-year and 7-month-old girl presented with nystagmus and epileptic seizures from early infancy, with no fixation or pursuit of vision. Physical examination revealed small deformities, such as swelling of both cheeks, folded fingers, rocking feet, and scoliosis. Brain imaging revealed slight hypoplasia of the cerebrum. Electroencephalogram showed focal paroxysmal discharges during the interictal phase of seizures. Vitamin B6 and zonisamide were administered for early infantile epileptic encephalopathy; however, the seizures were not relieved. Despite altering the type and dosage of antiepileptic drugs and ACTH therapy, the seizures were intractable. Whole-exome analysis revealed the homozygosity of WWOX(NM_016373.4):c.516+1G>A. The WWOX mRNA sequencing using peripheral blood RNA confirmed that exon 5 was homozygously deleted. Based on these results, the patient was diagnosed with WOREE syndrome at 5 months. The WWOX variant found in this study is novel and has never been reported before. WOREE syndrome being extremely rare, further case series and analyses of its pathophysiology are warranted.

Team-based Learning Impact: A Comparative Study of Student and Faculty Facilitators.

BACKGROUND: Team-based learning (TBL) refers to the application of an active-learning method that has gained popularity across all health-care disciplines. This study aimed to assess nutrition students' perceptions of the roles of student versus faculty facilitators. METHODS: Participants in the study included, 117 2nd-year nutrition students registered in the "Introduction to Medicine" course in the 2022 academic year at a Japanese university. The first TBL session was faculty-led, whereas three students served as facilitators in the second. Upon completion of the course, learners and student facilitators completed a questionnaire on the student-led TBL. Responses to close-ended questions were analyzed using descriptive statistics, and those to open-ended questions were categorized into common themes. RESULTS: A total of 114 learners and 3 student facilitators responded to the questions. Learners found student-led TBL to be just as or more effective than faculty-led TBL in three respects: comprehension (93.0%), active participation (96.5%), and expectation of academic performance improvement (93.9%). According to student facilitators, it improved their knowledge, confidence, communication skills, and leadership abilities. Learners and facilitators indicated that student-led TBL was significantly more effective than faculty-led TBL. Thus, student-led TBL can enhance the ability of all students at different academic levels. DISCUSSION: Student-led TBL appears to be an effective learning strategy in higher education and further shifts toward student-centered learning in the course curriculum.

Functional Interrogation of Ca2+ Signals in Human Cancer Cells In Vitro and Ex Vivo by Fluorescent Microscopy and Molecular Tools.

Genetically encoded calcium indicators (GECIs) and high-resolution confocal microscopy enable dynamic visualization of calcium signals in cells and tissues. Two-dimensional and 3D biocompatible materials mimic the mechanical microenvironments of tumor and healthy tissues in a programmable manner. Cancer xenograft models and ex vivo functional imaging of tumor slices reveal physiologically relevant functions of calcium dynamics in tumors at different progression stages. Integration of these powerful techniques allows us to quantify, diagnose, model, and understand cancer pathobiology. Here, we describe detailed materials and methods used to establish this integrated interrogation platform, from generating transduced cancer cell lines that stably express CaViar (GCaMP5G + QuasAr2) to in vitro and ex vivo calcium imaging of the cells in 2D/3D hydrogels and tumor tissues. These tools open the possibility for detailed explorations of mechano-electro-chemical network dynamics in living systems.

Human cancer cells generate spontaneous calcium transients and intercellular waves that modulate tumor growth.

Electrically excitable cells such as neurons transmit long-distance calcium or electrical signals to regulate their physiological functions. While the molecular underpinnings and down-stream effects of these intercellular communications in excitable cells have been well appreciated, little is known about whether and how non-excitable cancer cells spontaneously initiate and transmit long-distance intercellular signals. Here we report that non-excitable human colon and prostate cancer cells spontaneously initiate and spread intercellular calcium waves, in vitro and ex vivo. Xenograft model studies suggest that these calcium signals promote the growth rate of tumors in mice. Pharmacological studies elucidated that the inositol-trisphosphate-receptor (IP3R)-regulated calcium release from endoplasmic reticulum (ER), which is activated by the Gq-PLC-IP3R pathway, is a major cause for the initiation of spontaneous calcium transients. Further, the spatial-temporal characteristics of calcium dynamics can be tuned by the culture substrates of different mechanical stiffnesses. Our results provide evidence that calcium dynamics enables long-distance functional communication in non-excitable cancer cells and offer the potential to modulate calcium signaling for new cancer therapies.

Group II truncated haemoglobin YjbI prevents reactive oxygen species-induced protein aggregation in Bacillus subtilis.

Oxidative stress-mediated formation of protein hydroperoxides can induce irreversible fragmentation of the peptide backbone and accumulation of cross-linked protein aggregates, leading to cellular toxicity, dysfunction, and death. However, how bacteria protect themselves from damages caused by protein hydroperoxidation is unknown. Here, we show that YjbI, a group II truncated haemoglobin from Bacillus subtilis, prevents oxidative aggregation of cell-surface proteins by its protein hydroperoxide peroxidase-like activity, which removes hydroperoxide groups from oxidised proteins. Disruption of the yjbI gene in B. subtilis lowered biofilm water repellence, which associated with the cross-linked aggregation of the biofilm matrix protein TasA. YjbI was localised to the cell surface or the biofilm matrix, and the sensitivity of planktonically grown cells to generators of reactive oxygen species was significantly increased upon yjbI disruption, suggesting that YjbI pleiotropically protects labile cell-surface proteins from oxidative damage. YjbI removed hydroperoxide residues from the model oxidised protein substrate bovine serum albumin and biofilm component TasA, preventing oxidative aggregation in vitro. Furthermore, the replacement of Tyr63 near the haem of YjbI with phenylalanine resulted in the loss of its protein peroxidase-like activity, and the mutant gene failed to rescue biofilm water repellency and resistance to oxidative stress induced by hypochlorous acid in the yjbI-deficient strain. These findings provide new insights into the role of truncated haemoglobin and the importance of hydroperoxide removal from proteins in the survival of aerobic bacteria.

Nerve regeneration using the Bio 3D nerve conduit fabricated with spheroids.

Autologous nerve grafting is the gold standard method for peripheral nerve injury with defects. Artificial nerve conduits have been developed to prevent morbidity at the harvest site. However, the artificial conduit regeneration capacity is not sufficient. A Bio 3D printer is technology that creates three-dimensional tissue using only cells. Using this technology, a three-dimensional nerve conduit (Bio 3D nerve conduit) was created from several cell spheroids. We reported the first application of the Bio 3D nerve conduit for peripheral nerve injury. A Bio 3D nerve conduit that was created from several cells promotes peripheral nerve regeneration. The Bio 3D nerve conduit may be useful clinically to treat peripheral nerve defects.

Automatic Multi-functional Integration Program (AMFIP) towards all-optical mechano-electrophysiology interrogation.

Automatic operations of multi-functional and time-lapse live-cell imaging are necessary for the biomedical science community to study active, multi-faceted, and long-term biological phenomena. To achieve automatic control, most existing solutions often require the purchase of extra software programs and hardware that rely on the manufacturers' own specifications. However, these software programs are usually non-user-programmable and unaffordable for many laboratories. To address this unmet need, we have developed a novel open-source software program, titled Automatic Multi-functional Integration Program (AMFIP), as a new Java-based and hardware-independent system that provides proven advantages over existing alternatives to the scientific community. Without extra hardware, AMFIP enables the functional synchronization of the µManager software platform, the Nikon NIS-Elements platform, and other 3rd party software to achieve automatic operations of most commercially available microscopy systems, including but not limited to those from Nikon. AMFIP provides a user-friendly and programmable graphical user interface (GUI), opening the door to expanding the customizability for myriad hardware and software systems according to user-specific experimental requirements and environments. To validate the intended purposes of developing AMFIP, we applied it to elucidate the question whether single cells, prior to their full spreading, can sense and respond to a soft solid substrate, and if so, how does the interaction depend on the cell spreading time and the stiffness of the substrate. Using a CRISPR/Cas9-engineered human epithelial Beas2B (B2B) cell line that expresses mNeonGreen2-tagged mechanosensitive Yes-associated protein (YAP), we show that single B2B cells develop distinct substrate-stiffness-dependent YAP expressions within 10 hours at most on the substrate, suggesting that cells are able to sense, distinguish, and respond to mechanical cues prior to the establishment of full cell spreading. In summary, AMFIP provides a reliable, open-source, and cost-free solution that has the validated long-term utility to satisfy the need of automatic imaging operations in the scientific community.

[Factors Associated with Breastfeeding at One Month Postpartum: Focus on Nursing Guidance and Mothers' Breastfeeding Behavior].

OBJECTIVES: In this study, we aimed to clarify the factors associated with breastfeeding at one month postpartum, with focusing on midwives' nursing guidance and mothers' breastfeeding behavior. METHODS: A total of 158 mothers who participated in a medical examination two weeks after delivery were followed up with a questionnaire at two weeks and one month postpartum. Furthermore, we conducted multiple logistic regression analyses with breastfeeding at the one-month health checkup as the dependent variable and breastfeeding guidance and mothers' breastfeeding behavior as independent variables adjusted for birth history and delivery method, which were the confounding factors. RESULTS: For nursing guidance, we examined 149 individuals without missing data. In total, 71 (47.7%) mothers were found to be breastfeeding at one month postpartum. Breastfeeding probabilities were significantly higher in mothers who received guidance regarding the meaning of their infants' crying, changes in breast tension, breast care, and mothers' milk production, which were measured, with odds ratios ranging from 2.47 to 3.68. Breastfeeding odds ratios were significantly higher in mothers who inserted the nipple deeply into the baby's mouth such that the baby's lips spread outward, as well as in those who breastfed until the breast felt light and those who breastfed eight times a day than in mothers who did not, with odds ratios ranging from 2.27 to 5.86. CONCLUSION: This study indicated that early postpartum support, including guidance regarding the meaning of infants' crying, changes in breast tension, breast care, lactation measurement, and proper breastfeeding methods, is crucial in establishing breastfeeding.

Series module of quinone-based organic supercapacitor (> 6 V) with practical cell structure.

Inexpensive, high-performing, and environmentally friendly energy storage devices are required for smart grids that efficiently utilize renewable energy. Energy storage devices consisting of organic active materials are promising because organic materials, especially quinones, are ubiquitous and usually do not require harsh conditions for synthesis, releasing less CO2 during mass production. Although fundamental research-scale aqueous quinone-based organic supercapacitors have shown excellent energy storage performance, no practical research has been conducted. In this study, we aimed to develop a practical-scale aqueous-quinone-based organic supercapacitor. By connecting 12 cells of size 10 cm × 10 cm × 0.5 cm each in series, we fabricated a high-voltage (> 6 V) aqueous organic supercapacitor that can charge a smartphone at a 1 C rate. This is the first step in commercializing aqueous organic supercapacitors that could solve environmental problems, such as high CO2 emissions, air pollution by toxic metals, and limited electricity generation by renewable resources.

Feasibility of an Ultrasound-Based Method for Measuring Talar Displacement during the Anterior Drawer Stress Test Using a Telos Device: A Preliminary Study.

This study was conducted to measured talar displacement using ultrasound during an anterior drawer test (ADT) with a Telos device. Five adults (3 men and 2 women; 8 ankles; mean age: 23.2 y) with a history of ankle sprain and eight adults (5 men and 3 women; 16 ankles; mean age: 22.1 y) without a history of ankle sprain were recruited into a history of ankle sprain (HAS) and a control group, respectively. Talar displacement was observed in response to load forces applied by a Telos device during the ultrasound stress imaging test. The ultrasound probe was placed 5 mm inside from the center of the Achilles tendon on the posterior ankle along the direction of the major axis. The inter-rater reliability for the present method was classified as good and excellent (ICC(2,2) = 0.858 and 0.957 at 120 N and 150 N, respectively) in the control group and excellent (ICC(2,2) = 0.940 and 0.905 at 120 N and 150 N, respectively) in the HAS group, according to specific intraclass correlation coefficient values. We found that talar displacement during the ADT was lower in the HAS group than in the control group. Analysis of the receiver operating characteristic curve revealed that the quantitative ultrasound-based ADT using a Telos device was superior to the X-ray-based test in detecting reduced ankle joint mobility during the ADT (area under the curve of 0.905 and 0.726 at a force of 150 N using ultrasound-based and X-ray-based tests, respectively). Further investigation is needed; nevertheless, this preliminary study suggests that the ultrasound-based quantitative ADT using a Telos device might detect talar displacement more sensitively than the conventional stress X-ray.

Boys with attention-deficit/hyperactivity disorder perform wider and fewer finger tapping than typically developing boys - Peer comparisons and the effects of methylphenidate from an exploratory perspective.

AIM: This study aimed to investigate the differences in fine motor and coordination skills between boys with attention-deficit/hyperactivity disorder (ADHD) and typically developing (TD) boys and the effect of methylphenidate (MPH) in boys with ADHD. METHODS: Fourteen boys aged 7-12 years who were diagnosed with ADHD and previously treated with MPH were instructed to tap their thumbs and index fingers together repetitively for 10 s after attaching magnetic sensors. The participants executed "in-phase" and "anti-phase" tapping. A two-way analysis of variance for comparing boys with ADHD and TD boys and the paired t-test to investigate the effect of MPH between sessions with and without MPH were performed. RESULTS: Boys with ADHD showed a significantly lower "number of taps" and a significantly higher "average of local maximum distance" than TD boys. "Energy balance" was significantly lower in ADHD boys than in TD boys. MPH caused a significant difference in the "standard deviation (SD) of phase difference" in "anti-phase tapping." CONCLUSION: Our studies indicated that finger-tapping movements in boys with ADHD tended to be significantly wider and fewer than those in TD boys, and MPH may improve the phase difference of bimanual fine motor coordination skills in boys with ADHD who are above 1.0 SD. The results should be interpreted with caution because we conducted statistical tests for many outcomes and groups without considering the multiplicity factor from an exploratory perspective.

Interstitial pneumonia in immunocompetent laboratory rats caused by natural infection with Pneumocystis carinii.

Pneumocystis (P.) carinii is known to cause fatal pneumonia in immunocompromised rats. Cases of P. carinii interstitial pneumonia in immunocompetent rats have been shown histologically to present with perivascular lymphoid cuffs, which have previously been attributed to rat respiratory virus. This study aims to determine the prevalence and pathological characteristics of P. carinii in immunocompetent laboratory rats in experimental facilities in Japan. An epidemiological survey for this agent was performed using PCR to assess 1,981 immunocompetent rats from 594 facilities in Japan. We observed that 6 of the 1,981 rats (0.30%) from 4 out of 594 facilities (0.67%) were positive for P. carinii without infection of other known pathogens. Gross pulmonary lesions were found in 4 of the 6 affected rats. The lungs of these rats contained scattered dark red/gray foci. Histopathologically, the lungs exhibited interstitial pneumonia with lymphoid perivascular cuffs: Pneumocystis cysts were observed using Grocott's methenamine silver stain. To our knowledge, this report is the first to reveal the prevalence of natural P. carinii infection in immunocompetent laboratory rats in Japan.

Therapeutic Targeting of the Gas6/Axl Signaling Pathway in Cancer.

Many signaling pathways are dysregulated in cancer cells and the host tumor microenvironment. Aberrant receptor tyrosine kinase (RTK) pathways promote cancer development, progression, and metastasis. Hence, numerous therapeutic interventions targeting RTKs have been actively pursued. Axl is an RTK that belongs to the Tyro3, Axl, MerTK (TAM) subfamily. Axl binds to a high affinity ligand growth arrest specific 6 (Gas6) that belongs to the vitamin K-dependent family of proteins. The Gas6/Axl signaling pathway has been implicated to promote progression, metastasis, immune evasion, and therapeutic resistance in many cancer types. Therapeutic agents targeting Gas6 and Axl have been developed, and promising results have been observed in both preclinical and clinical settings when such agents are used alone or in combination therapy. This review examines the current state of therapeutics targeting the Gas6/Axl pathway in cancer and discusses Gas6- and Axl-targeting agents that have been evaluated preclinically and clinically.

Normal tissue and tumor microenvironment adaptations to aerobic exercise enhance doxorubicin anti-tumor efficacy and ameliorate its cardiotoxicity in retired breeder mice.

Aerobic exercise is receiving increased recognition in oncology for its multiple purported benefits. Exercise is known to induce physiologic adaptations that improve patient quality-of-life parameters as well as all-cause mortality. There also is a growing body of evidence that exercise may directly alter the tumor microenvironment to influence tumor growth, metastasis, and response to anticancer therapies. Furthermore, the physiologic adaptations to exercise in normal tissues may protect against treatment-associated toxicity and allow for greater treatment tolerance. However, the exercise prescription required to induce these beneficial tumor-related outcomes remains unclear. This study characterized the aerobic adaptations to voluntary wheel running in normal tissues and the tumor microenvironment. Female, retired breeder BALB/c mice and syngeneic breast adenocarcinoma cells were utilized in primary tumor and metastasis models. Aerobic exercise was found to induce numerous adaptations across various tissues in these mice, although primary tumor growth and metastasis were largely unaffected. However, intratumoral hypoxia and global metabolism were altered in the tumors of exercising hosts relative to non-wheel running controls. Doxorubicin chemotherapy also was found to be more efficacious at delaying tumor growth with adjuvant aerobic exercise. Additionally, doxorubicin-induced cardiac toxicity was ameliorated in exercising hosts relative to non-wheel running controls. Taken together, these data suggest that the normal tissue and tumor microenvironment adaptations to aerobic exercise can improve doxorubicin efficacy while simultaneously limiting its toxicity.

Long-Term Outcome of Sciatic Nerve Regeneration Using Bio3D Conduit Fabricated from Human Fibroblasts in a Rat Sciatic Nerve Model.

Previously, we developed a Bio3D conduit fabricated from human fibroblasts and reported a significantly better outcome compared with artificial nerve conduit in the treatment of rat sciatic nerve defect. The purpose of this study is to investigate the long-term safety and nerve regeneration of Bio3D conduit compared with treatments using artificial nerve conduit and autologous nerve transplantation.We used 15 immunodeficient rats and randomly divided them into three groups treated with Bio3D (n = 5) conduit, silicon tube (n = 5), and autologous nerve transplantation (n = 5). We developed Bio3D conduits composed of human fibroblasts and bridged the 5 mm nerve gap created in the rat sciatic nerve. The same procedures were performed to bridge the 5 mm gap with a silicon tube. In the autologous nerve group, we removed the 5 mm sciatic nerve segment and transplanted it. We evaluated the nerve regeneration 24 weeks after surgery.Toe dragging was significantly better in the Bio3D group (0.20 ± 0.28) than in the silicon group (0.6 ± 0.24). The wet muscle weight ratios of the tibial anterior muscle of the Bio3D group (79.85% ± 5.47%) and the autologous nerve group (81.74% ± 2.83%) were significantly higher than that of the silicon group (66.99% ± 3.51%). The number of myelinated axons and mean myelinated axon diameter was significantly higher in the Bio3D group (14708 ± 302 and 5.52 ± 0.44 µm) and the autologous nerve group (14927 ± 5089 and 6.04 ± 0.85 µm) than the silicon group (7429 ± 1465 and 4.36 ± 0.21 µm). No tumors were observed in any of the rats in the Bio3D group at 24 weeks after surgery.The Bio3D group showed significantly better nerve regeneration and there was no significant difference between the Bio3D group and the nerve autograft group in all endpoints.

Clinical practice guidelines for rehabilitation nutrition in cerebrovascular disease, hip fracture, cancer, and acute illness: 2020 update.

BACKGROUND: Individuals undergoing rehabilitation often experience nutritional problems such as malnutrition, but there are no clinical practice guidelines (CPGs) specifically tailored to the combination of rehabilitation and nutritional care for these patients. The Japanese Association for Rehabilitation Nutrition aimed to develop CPGs for rehabilitation nutrition to support clinical decision making in daily practice. METHODS: A CPG committee and development process based on the Grading of Recommendations Assessment, Development and Evaluation system and the Minds Handbook for Clinical Practice Guideline Development 2014 was established. Four clinical questions were defined for patients undergoing rehabilitation for cerebrovascular disease, hip fracture, cancer, and acute illness. Literatures of randomised control trials (RCTs) up to April 2020 were searched for using the MEDLINE, EMBASE, CENTRAL, and Ichushi-web databases. After screening, full-text papers were assessed for eligibility for analysis. Subsequently, studies included in the systematic review were examined regarding their risk of bias, and underwent meta-analyses. A CPG development committee drafted the guidelines based on the systematic review report. Final recommendations were determined by the panel members. RESULTS: Four recommendations were made based on 4 to 9 RCTs for each disease/condition. The certainty of the evidence ranged from very low to low. Overall, the enhanced nutritional care was weakly recommended for rehabilitation patients with cerebrovascular disease, hip fracture, cancer, and acute illnesses. CONCLUSIONS: This CPG provides tentative recommendations for nutritional care of individuals undergoing rehabilitation. Due to low certainty of evidence and small sample sizes of the included studies, more high-quality and larger RCTs are needed to develop more practical CPGs.

Inhibition of the Axl pathway impairs breast and prostate cancer metastasis to the bones and bone remodeling.

Approximately 90% of cancer-related deaths result from cancer metastasis. In prostate and breast cancers, bone is the most common site of cancer cell dissemination. Key steps in the metastatic cascade are promoted through upregulation of critical cell signaling pathways in neoplastic cells. The present study assessed the role of the receptor tyrosine kinase Axl in prostate and breast cancer cell metastasis to bones using (i) Axl knockdown neoplastic cells and osteoclast progenitor cells in vitro, (ii) intracardiac injection of Axl knockdown tumor cells in vivo, and (iii) selective Axl inhibitor BGB324. Axl inhibition in neoplastic cells significantly decreased their metastatic potential, and suppression of Axl signaling in osteoclast precursor cells also reduced the formation of mature osteoclasts. In vivo, Axl knockdown in prostate and breast cancer cells significantly suppressed the formation and progression of bone metastases. Hence, therapeutic targeting of Axl may impair tumor metastasis to the bones through neoplastic and host cell signaling axes.

Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3.

Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation. Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction. Here, we report an 8-year-old boy with CDCBM3 showing a typical, but relatively mild, clinical presentation of CDCBM3 features. Whole-exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298C>A [p.(Ser433Tyr)]. To our knowledge, the mutation has never been reported previously. The variant was located distal to the nucleotide binding domain (NBD), in which previously-reported variants in CDCBM3 patients have been located. The computational structural analysis showed the p.433 forms the pocket with NBD. Variants in KIF2A have been reported in the NBD for CDCBM3, in the kinesin motor 3 domain, but not in the NBD in epilepsy, and outside of the kinesin motor domain in autism spectrum syndrome, respectively. Our patient has a variant, that is not in the NBD but at the pocket with the NBD, resulting in a clinical features of CDCBM3 with mild symptoms. The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies. We can call this spectrum "KIF2A syndrome" with variable severity.