Association of non-steroidal anti-inflammatory drug use with encephalopathy development: An analysis using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases.

Encephalopathy is the most severe complication of various common infections, including influenza and herpes, and it often results in death or severe neurological disability. The risk factors for viral encephalopathy include non-steroidal anti-inflammatory drug (NSAID) use; however, studies on NSAID-related encephalopathy are limited. In this study, we aimed to investigate the characteristics of NSAID-related encephalopathy. We investigated the incidence of NSAID-related encephalopathy using data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases containing reports on spontaneous adverse effects (AEs) published by the Pharmaceuticals and Medical Devices Agency. We used these databases to detect AEs based on reported odds ratios. By separating suspicious drugs, concomitant drugs, and drug interactions involving NSAIDs, we investigated the relationship between encephalopathy pathology and AEs of NSAIDs. Significant encephalopathy signals were detected for loxoprofen and etodolac in the FAERS database and loxoprofen in the JADER database. In the JADER database, significant encephalopathy signals in loxoprofen-treated patients were detected in 70-79-year-old, ≥80-year-old, influenza viral infection, and herpes virus infection groups. Significant encephalopathy signals in patients with herpes virus infection were detected in the ≥80-year-old and loxoprofen-treated groups. Regarding the involvement of loxoprofen in the development of encephalopathy, the JADER database listed loxoprofen as a suspect drug, without indicating any concomitant drug interactions. In conclusion, our findings suggest that loxoprofen and etodolac may be associated with viral encephalopathy. Accordingly, prudence is recommended when using loxoprofen in older individuals with viral infections.

MENS-associated increase of muscular protein content via modulation of caveolin-3 and TRIM72.

Microcurrent electrical neuromuscular stimulation (MENS) is known as an extracellular stimulus for the regeneration of injured skeletal muscle in sports medicine. However, the effects of MENS-associated increase in muscle protein content are not fully clarified. The purpose of this study was to investigate the effects of MENS on the muscular protein content, intracellular signals, and the expression level of caveolin-3 (Cav-3), tripartite motif-containing 72 (TRIM72) and MM isoenzyme of creatine kinase (CK-MM) in skeletal muscle using cell culture system. C2C12 myotubes on the 7th day of differentiation phase were treated with MENS (intensity: 10-20 microA, frequency: 0.3 Hz, pulse width: 250 ms, stimulation time: 15-120 min). MENS-associated increase in the protein content of myotubes was observed, compared to the untreated control level. MENS upregulated the expression of Cav-3, TRIM72, and CK-MM in myotubes. A transient increase in phosphorylation level of Akt was also observed. However, MENS had no effect on the phosphorylation level of p42/44 extracellular signal-regulated kinase-1/2 and 5'AMP-activated protein kinase. MENS may increase muscle protein content accompanied with a transient activation of Akt and the upregulation of Cav-3 and TRIM72.

Publisher Correction: Immediate tool incorporation processes determine human motor planning with tools.

This corrects the article DOI: 10.1038/ncomms5524.

Lactate increases myotube diameter via activation of MEK/ERK pathway in C2C12 cells.

AIM: Lactate is produced in and released from skeletal muscle cells. Lactate receptor, G-protein-coupled receptor 81 (GPR81), is expressed in skeletal muscle cells. However, a physiological role of extracellular lactate on skeletal muscle is not fully clarified. The purpose of this study was to investigate extracellular lactate-associated morphological changes and intracellular signals in C2C12 skeletal muscle cells. METHODS: Mouse myoblast C2C12 cells were differentiated for 5 days to form myotubes. Sodium lactate (lactate) or GPR81 agonist, 3,5-dihydroxybenzoic acid (3,5-DHBA), was administered to the differentiation medium. RESULTS: Lactate administration increased the diameter of C2C12 myotubes in a dose-dependent manner. Administration of 3,5-DHBA also increased myotube diameter. Not only lactate but also 3,5-DHBA upregulated the phosphorylation level of mitogen-activated protein kinase kinase 1/2 (MEK1/2), p42/44 extracellular signal-regulated kinase-1/2 (ERK1/2) and p90 ribosomal S6 kinase (p90RSK). MEK inhibitor U0126 depressed the phosphorylation of ERK-p90RSK and increase in myotube diameter induced by lactate. On the other hand, both lactate and 3,5-DHBA failed to induce significant responses in the phosphorylation level of Akt, mammalian target of rapamycin, p70 S6 kinase and protein degradation-related signals. CONCLUSION: These observations suggest that lactate-associated increase in the diameter of C2C12 myotubes is induced via activation of GRP81-mediated MEK/ERK pathway. Extracellular lactate might have a positive effect on skeletal muscle size.

Liver Transplantation for Mitochondrial Respiratory Chain Disorder: A Single-Center Experience and Excellent Marker of Differential Diagnosis.

Mitochondrial respiratory chain disorder (MRCD) can cause liver failure requiring liver transplantation (LT), although it is often difficult to diagnose before LT. From 2005 to 2016, 9 MRCD patients with the median age at LT of 6 months underwent LT in our institute. Their clinical courses were retrospectively reviewed and the laboratory parameters were compared between the MRCD patients and 10 patients with acute liver failure unrelated to MRCD (non-MRCD). Five patients had extrahepatic manifestations, including developmental disorders in 3 and failure to thrive in 3, before LT. Only 3 patients (33.3%) were diagnosed before LT. Between MRCD and non-MRCD, lactate was significantly high and lactate-to-pyruvate ratio (L/P ratio) tended to be higher in MRCD. From the receiver operating characteristic curve, the optimal cutoff value of lactate was 50.0 mg/dL and that of L/P ratio was 23.2. Patient survival rate of MRCD was 77.8%, although 2 patients with mitochondrial depletion syndrome suffered from de novo pulmonary hypertension after LT. Our experiences showed the difficulty of preoperative diagnosis, and preoperative extrahepatic manifestations did not always mean poor outcome. Our study showed that lactate value and L/P ratio can be excellent predictors of MRCD.

Niobate nanosheet membranes with enhanced stability for nanofiltration.

Niobate nanosheets are assembled into thin membranes by a vacuum filtration. The nanosheet membranes have a dense and stable structure in water via chemical cross-linking and show higher permeance and salt rejection compared with graphene oxide membranes. A water pathway model based on the void structure is presented to explain the membrane performances.

Ultrasound-guided plasma rich in growth factors injections and scaffolds hasten motor nerve functional recovery in an ovine model of nerve crush injury.

In the present study we evaluated the motor recovery process of peripheral nerve injury (PNI), based on electrophysiological and histomorphometric criteria, after treatment with plasma rich in growth factors (PRGF) injections and scaffolds in an ovine model. Three groups of sheep underwent a nerve crush lesion: the first group (n = 3) was left to recover spontaneously (SR); the second group was administered saline injections (SI; n = 5) and a third group (n = 6) received PRGF injections and scaffolds immediately after the crush injury. At post-intervention week 8, 70% of sheep in the PRGF group were CMAP-positive, with no electrophysiological response in the rest of the groups. Histomorphometric analysis 12 weeks after the surgical intervention revealed that the average axonal density of the SR (1184 ± 864 axons/µm2 ) and SI (3109 ± 2450 axons/µm2 ) groups was significantly inferior to the control (8427 ± 2433 axons/µm2 ) and also inferior to the PRGF group (5276 ± 4148 axons/µm2 ), showing no significant differences between the control and PRGF groups. The axonal size of the SR and SI groups was significantly smaller compared with the control group (18 ± 4 µm2 ), whereas the axonal size of the PRGF group (6 ± 5 µm2 ) did not show statistical differences from the control. Morphometry of the target muscles indicated that the PRGF group had the lowest percentage volume reduction 12 weeks after the crush injury. The PRGF group had larger muscle fibre areas than the SI and SR groups, although the differences did not reach statistical significance. Overall, these data suggest that the PRGF injections and scaffolds hastened functional axon recovery and dampened atrophy of the target muscles in an ovine model. Copyright © 2015 John Wiley & Sons, Ltd.

Heat shock transcription factor 1-associated expression of slow myosin heavy chain in mouse soleus muscle in response to unloading with or without reloading.

AIM: The effects of heat shock transcription factor 1 (HSF1) deficiency on the fibre type composition and the expression level of nuclear factor of activated T cells (NFAT) family members (NFATc1, NFATc2, NFATc3 and NFATc4), phosphorylated glycogen synthase kinase 3α (p-GSK3α) and p-GSK3ß, microRNA-208b (miR-208b), miR-499 and slow myosin heavy chain (MyHC) mRNAs (Myh7 and Myh7b) of antigravitational soleus muscle in response to unloading with or without reloading were investigated. METHODS: HSF1-null and wild-type mice were subjected to continuous 2-week hindlimb suspension followed by 2- or 4-week ambulation recovery. RESULTS: In wild-type mice, the relative population of slow type I fibres, the expression level of NFATc2, p-GSK3 (α and ß), miR-208b, miR-499 and slow MyHC mRNAs (Myh7 and Myh7b) were all decreased with hindlimb suspension, but recovered after it. Significant interactions between train and time (the relative population of slow type I fibres; P = 0.01, the expression level of NFATc2; P = 0.001, p-GSKß; P = 0.009, miR-208b; P = 0.002, miR-499; P = 0.04) suggested that these responses were suppressed in HSF1-null mice. CONCLUSION: HSF1 may be a molecule in the regulation of the expression of slow MyHC as well as miR-208b, miR-499, NFATc2 and p-GSK3 (α and ß) in mouse soleus muscle.

Deficiency of heat shock transcription factor 1 suppresses heat stress-associated increase in slow soleus muscle mass of mice.

AIM: Effects of heat shock transcription factor 1 (HSF1) deficiency on heat stress-associated increase in slow soleus muscle mass of mice were investigated. METHODS: Both HSF1-null and wild-type mice were randomly assigned to control and heat-stressed groups. Mice in heat-stressed group were exposed to heat stress (41 °C for 60 min) in an incubator without anaesthesia. RESULTS: Significant increase in wet and dry weights, and protein content of soleus muscle in wild-type mice was observed seven days after the application of the heat stress. However, heat stress had no impact on soleus muscle mass in HSF1-null mice. Neither type of mice exhibited much effect of heat stress on HSF mRNA expression (HSF1, HSF2 and HSF4). On the other hand, heat stress upregulated heat shock proteins (HSPs) at the mRNA (HSP72) and protein (HSP72 and HSP110) levels in wild-type mice, but not in HSF1-null mice. The population of Pax7-positive nuclei relative to total myonuclei of soleus muscle in wild-type mice was significantly increased by heat stress, but not in HSF1-null mice. Furthermore, the absence of HSF1 gene suppressed heat stress-associated phosphorylation of Akt and p70 S6 kinase (p-p70S6K) in soleus muscle. CONCLUSION: Heat stress-associated increase in skeletal muscle mass may be induced by HSF1 and/or HSF1-mediated stress response that activates muscle satellite cells and Akt/p70S6K signalling pathway.

Employment status among non-retired cancer survivors in Japan.

Employed cancer patients confront some challenges as they attempt to return to work after treatment. We aimed to identify correlates of return to work for cancer survivors in Japan, with an emphasis on employment status. Participants were 260 patients (aged <65 years) who had received a cancer diagnosis ≥ 1 year previously and who were employed at the time of diagnosis. Participants completed questionnaires at consultations at any Regional Cancer Center Hospitals in Yamagata, Japan between 28 November 2011 and 9 December 2011. Logistic regression analysis was used to identify correlates of return to work. Data cross-tabulation was used to evaluate relationships to workplace and income-changes by employment status. A high proportion of patients (75.8%) had returned to work. Non-regularly employed survivors were less likely to return to work (odds ratio = 5.03; 95% confidence interval, 1.18-21.35). Individuals with poor health, advanced-stage tumours, of advanced age and women were significantly less likely to return to work. Only 52.8% of non-regular employees continued to be employed, and their income decreased by as much as 61.1%. Social and financial support policies should be organised based on more intensive study of employment circumstances.

Study on the usefulness of APR scores from the viewpoint of proinflammatory cytokines.

BACKGROUND: Delayed diagnosis and treatment of newborn infection adversely impact outcomes. Clinical laboratory parameters have aimed to obtain the most correct and prompt diagnosis and treatment of this disease. This study simultaneously observed changes over time in APR as well as proinflammatory cytokines and anti-proinflammatory cytokines and aims to clarify usefulness of APR scores. METHODS: We evaluated the usefulness of acute phase reactants (APR) in 46 newborns whose serum up to age 7 days had been stored, with comparison of three types (Group I: infection 15, Group F: fetal inflammatory response syndrome 17, and Group C: control 14) of APR-based scores, those of C-reactive protein (CRP), alpha1-acid glycoprotein (AGP), and haptoglobin (Hp), with proinflammatory cytokine levels. APR scores for CRP, AGP, and Hp and the levels of the proinflammatory cytokines IL-1ß, IL-6, IL-8, IL-10, and TNFα were determined. RESULTS: The cytokine levels started to increase from age 0 days and then decreased rapidly. The three APR scores, CRP, AG, and Hp, were elevated at age 0 days and then gradually decreased in infection (Group I) and fetal inflammatory response syndrome (Group F). The duration of antibiotic administration according to APR scores was significantly shorter in Group F than in Group I. CONCLUSION: This study demonstrated APR scores to be more useful for deciding whether antibiotics should be discontinued than proinflammatory cytokine levels.

Root surface strain during canal shaping and its influence on apical microcrack development: a preliminary investigation.

AIM: To determine the root surface strain (RSS) generated during root canal shaping and its effects on apical microcrack development. METHODOLOGY: Twenty-five extracted human mandibular premolars were selected and decoronated. The teeth were instrumented with either the ProTaper (PT) or WaveOne (WO) (Dentsply Maillefer) NiTi rotary systems (n = 10 per group) or used as controls (n = 5). Instrumented root canals were enlarged to ProTaper F4 (size 40, 0.06 taper) or using WaveOne LARGE (size 40, 0.08 taper) instruments according to the manufacturer's instructions. An electrical strain gage (KFG02-120-C1-16, Kyowa Dengyo, Tokyo, Japan) was fixed on the proximal root surface and connected to a strain amplifier via a bridge box in order to measure RSS. During canal shaping, the strain output of the amplifier was recorded. The instantaneous RSS induced by each instrument and the maximum RSSs were determined. All teeth were then stained with contrast media and imaged with micro-computed tomography (micro-CT) at an isotropic resolution of 10 µm to detect microcracks. The mean maximum RSS values (microstrain) and mean number of microcracks recorded for both groups were tested for statistical significance using Mann-Whitney U-test. Presence/absence of microcracks in both groups was compared by chi-square tests. RESULTS: Increased baseline RSS from strain accumulation during canal shaping was observed, with similar maximum RSS (mean ± SD) for PT (416.6 ± 185.1 µstrain) and WO (398.2 ± 163.8 µstrain) (P = 0.94). The interevaluator reliability for microcrack detection using micro-CT had a kappa value of 0.998. Compared to the PT group, there was a trend for fewer samples with microcracks in the WO group (P = 0.051). On the micro-CT images, apical microcracks were detected in 20 PT and 11 WO samples (P = 0.10). The microcracks were observed in the buccolingual direction in all WO and 81% of PT samples. No vertical root fractures were found. The maximum RSS obtained during canal shaping was poorly correlated with the number of microcracks found (R(2)  = 0.093). CONCLUSIONS: Based on these preliminary data, canal shaping appears to cause apical microcracks regardless of the type of rotary instrument motion. Contrast-enhanced micro-CT was able to identify microcracks in roots.

Diagnostic usefulness of FDG-PET/CT in advanced malignant lymphoma of the uterus: report of two cases.

Summary Malignant lymphoma of the uterus is difficult to diagnose because of its rarity and nonspecific symptoms. However, recently, 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has become an important non-invasive diagnostic tool for the management of lymphoma patients. The authors report two cases of malignant lymphoma of the uterus, in which FDG-PET/CT was useful for diagnosis. Examination using ultrasonography or magnetic resonance imaging (MRI) demonstrated a normal-sized uterus and normal endometrium, but FDG-PET/CT showed FDG accumulation in the uterine body in both cases. Endometrial biopsy revealed diffuse large B-cell lymphoma, and chemotherapy with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) was initiated immediately. Primary malignant lymphoma of the female genitalia is reported to be rare. The present authors' experience with FDG-PET/CT suggests that malignant lymphoma of the female genitalia (including metastasis) may not be as rare as previously reported. Uterine malignant lymphoma may be overlooked by the examination of ultrasound, CT, or MRI.

Differential diagnosis of vertical root fractures using reconstructed three-dimensional models of bone defects.

OBJECTIVES: The purpose of this study was to evaluate the accuracy of diagnosing vertical root fractures (VRFs) by comparing the volume of bone defects in VRFs with those in non-VRFs on reconstructed three-dimensional (3D) models (TDMs) using CBCT. METHODS: 32 maxillary pre-molars and anterior teeth with radiolucent areas were evaluated on pre-operative CBCT images. Of the 32 teeth, 16 had a fractured root (VRF group) and 16 had a non-fractured root (non-VRF group). The radiolucent area of each tooth was traced in each dimension [mesiodistal, buccolingual and horizontal (the apicoincisal aspect)] by two observers, and 3D images were reconstructed with the Amira(®) software (Visage Imaging Inc., Richmond, Australia). The volume, V, of the TDM was divided into the coronal side and the periapical side at the horizontal slice through the apical foramen, and v was defined as the volume of the coronal side. The values of v/V were calculated for all cases. The Mann-Whitney U test was used to compare values between the VRF group and the non-VRF group (p < 0.05). A receiver operating characteristic (ROC) curve was constructed to select the optimal cut-point. RESULTS: There was a statistically significant difference in the value of v/V between the two groups (p < 0.05). With a cut-point derived from the ROC curve, and the sensitivity, specificity and accuracy of predicting the VRFs were 1.00, 0.75 and 0.88, respectively. CONCLUSIONS: Lesions resulting from VRFs can be distinguished from those of non-VRFs on 3D CBCT images with a high degree of accuracy, based on their different 3D shapes.

Immediate tool incorporation processes determine human motor planning with tools.

Human dexterity with tools is believed to stem from our ability to incorporate and use tools as parts of our body. However tool incorporation, evident as extensions in our body representation and peri-personal space, has been observed predominantly after extended tool exposures and does not explain our immediate motor behaviours when we change tools. Here we utilize two novel experiments to elucidate the presence of additional immediate tool incorporation effects that determine motor planning with tools. Interestingly, tools were observed to immediately induce a trial-by-trial, tool length dependent shortening of the perceived limb lengths, opposite to observations of elongations after extended tool use. Our results thus exhibit that tools induce a dual effect on our body representation; an immediate shortening that critically affects motor planning with a new tool, and the slow elongation, probably a consequence of skill related changes in sensory-motor mappings with the repeated use of the tool.

Clinical efficacy and treatment persistence of monthly minodronate for osteoporotic patients unsatisfied with, and shifted from, daily or weekly bisphosphonates: the BP-MUSASHI study.

UNLABELLED: This multi-center, prospective, open-label, observational study evaluated the effects of once-monthly minodronate (50 mg) on treatment persistence, bone turnover markers, bone mineral density, low back pain, and upper gastrointestinal symptoms in outpatients with osteoporosis previously treated with daily or weekly bisphosphonate products. INTRODUCTION: The purposes of this study were to investigate the effects of once-monthly oral minodronate (MIN 50 mg) on bone turnover markers and bone mineral density, low back pain, and upper gastrointestinal symptoms, as well as preference for and treatment persistence of MIN 50 mg among Japanese osteoporosis patients currently treated with daily or weekly bisphosphonates. METHODS: Study patients were allocated based on their preference to either the Switch group (patients willing to switch over to MIN 50 mg) or the Continue group (patients wanting to continue their current therapies). Patients' treatment persistence and satisfaction levels with the therapies were assessed using a self-administered questionnaire. The study endpoints were serum TRACP-5b, serum P1NP, bone mineral density, upper gastrointestinal symptoms, and low back pain. RESULTS: In total, 264 and 133 patients were allocated into the Switch and Continue groups, respectively. Approximately, 65 % of patients were willing to switch to MIN 50 mg, with the predominant reason being "less frequent dosing more convenient." Treatment persistence was significantly higher in the Switch group (MIN 50 mg) than the Continue group. Almost all patients with abnormal bone metabolism markers demonstrated normalization after switchover. MIN 50 mg alleviated low back pain and upper gastrointestinal symptoms induced by prior bisphosphonate use. CONCLUSIONS: MIN 50 mg alleviates low back pain, reduces bone turnover markers and increases bone density, and induces fewer upper gastrointestinal symptoms after switchover from prior bisphosphonate products, and therefore, it may provide patients with a more convenient treatment option and enhance long-term treatment persistence.

Do Tetranychus urticae males avoid mating with familiar females?

The two-spotted spider mite, Tetranychus urticae, usually lives in kin groups under common webs. Because only the first mating results in fertilisation in female T. urticae, adult males guard quiescent deutonymph females, those at the stage immediately before maturation, to ensure paternity. Therefore, the cost of precopulatory guarding time seems considerable for males. Moreover, the fitness indices of daughters from intra-population crosses were significantly lower than those of daughters from inter-population crosses, indicating that inbreeding depression exists in T. urticae. Therefore, we hypothesised that T. urticae males should be choosy in guarding familiar females to avoid inbreeding depression. Furthermore, webs should be a key element of the environment shared by familiar individuals. In this study, we demonstrated the inbreeding avoidance mechanism of T. urticae males in relation to webs produced by familiar females (known webs) or unfamiliar females (unknown webs). Regardless of surrounding webs (known or unknown), males preferred unfamiliar to familiar females. We further examined whether males detect unfamiliar females by their webs. When males had experienced a female's web without encountering that female, they subsequently preferred females that did not produce the surrounding webs in which the choice experiment was conducted. Results suggest that putative kin recognition for inbreeding avoidance in T. urticae males is based on the relationship between webs and females, and not on the discrimination of webs in shared environments.

Evaluation of primary prophylaxis with granulocyte colony-stimulating factor for epithelial ovarian cancer.

PURPOSE: Primary prophylaxis with G-CSF has been used to minimize myelosuppression caused by anticancer agents and to avoid severe neutropenia. The authors retrospectively examined the value of primary prophylaxis using granulocyte colony-stimulating factor (G-CSF) for epithelial ovarian cancer. MATERIALS AND METHODS: From 2001 to 2010, 105 patients with ovarian cancer receiving chemotherapy in the present hospital were divided into two groups: one received primary prophylaxis with G-CSF and the other did not receive it in compliance with the guidelines for G-CSF usage. The incidence of febrile neutropenia (FN), degree of neutropenia, frequency of G-CSF administration, number of days of hospitalization, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: Neutrophils decreased almost equally and the length of hospitalization was not significantly lower between the groups. Five-year PFS or OS showed no significant difference either. CONCLUSIONS: Primary prophylaxis with G-CSF in chemotherapy for epithelial ovarian cancer could be of low significance.

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction.

Isthmin (ISM) is a secreted 60-kDa protein that potently induces endothelial cell (EC) apoptosis. It suppresses tumor growth and angiogenesis in mice when stably overexpressed in cancer cells. Although αvß5 integrin serves as a low-affinity receptor for ISM, the mechanism by which ISM mediates antiangiogenesis and apoptosis in ECs remain to be fully resolved. In this work, we report the identification of cell-surface glucose-regulated protein 78 kDa (GRP78) as a high-affinity receptor for ISM (Kd=8.6 nM). We demonstrated that ISM-GRP78 interaction triggers apoptosis not only in activated ECs but also in cancer cells expressing high level of cell-surface GRP78. Normal cells and benign tumor cells tend to express low level of cell-surface GRP78 and are resistant to ISM-induced apoptosis. Upon binding to GRP78, ISM is internalized into ECs through clathrin-dependent endocytosis that is essential for its proapoptotic activity. Once inside the cell, ISM co-targets with GRP78 to mitochondria where it interacts with ADP/ATP carriers on the inner membrane and blocks ATP transport from mitochondria to cytosol, thereby causing apoptosis. Hence, ISM is a novel proapoptotic ligand that targets cell-surface GRP78 to trigger apoptosis by inducing mitochondrial dysfunction. The restricted and high-level expression of cell-surface GRP78 on cancer cells and cancer ECs make them uniquely susceptible to ISM-targeted apoptosis. Indeed, systemic delivery of recombinant ISM potently suppressed subcutaneous 4T1 breast carcinoma and B16 melanoma growth in mice by eliciting apoptosis selectively in the cancer cells and cancer ECs. Together, this work reveals a novel ISM-GRP78 apoptosis pathway and demonstrates the potential of ISM as a cancer-specific and dual-targeting anticancer agent.

Two is better than one: physical interactions improve motor performance in humans.

How do physical interactions with others change our own motor behavior? Utilizing a novel motor learning paradigm in which the hands of two - individuals are physically connected without their conscious awareness, we investigated how the interaction forces from a partner adapt the motor behavior in physically interacting humans. We observed the motor adaptations during physical interactions to be mutually beneficial such that both the worse and better of the interacting partners improve motor performance during and after interactive practice. We show that these benefits cannot be explained by multi-sensory integration by an individual, but require physical interaction with a reactive partner. Furthermore, the benefits are determined by both the interacting partner's performance and similarity of the partner's behavior to one's own. Our results demonstrate the fundamental neural processes underlying human physical interactions and suggest advantages of interactive paradigms for sport-training and physical rehabilitation.