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Our study is the first to demonstrate a high-temporal-resolution record of mineral composition in a Greenland ice core over the past 100 years. To reconstruct past variations in the sources and transportation processes of mineral dust in northwestern Greenland, we analysed the morphology and mineralogical composition of dust in the SIGMA-D ice core from 1915 to 2013 using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS). The results revealed that the ice core dust consisted mainly of silicate minerals and that the composition varied substantially on multi-decadal and inter-decadal scales, suggesting that the ice core minerals originated from different geological sources in different periods during the past 100 years. The multi-decadal variation trend differed among mineral types. Kaolinite, which generally formed in warm and humid climatic zones, was abundant in colder periods (1950–2004), whereas mica, chlorite, feldspars, mafic minerals, and quartz, which formed in arid, high-latitude, and local areas, were abundant in warmer periods (1915–1949 and 2005–2013). Comparison to Greenland surface temperature records indicates that multi-decadal variation in the relative abundance of these minerals was likely affected by local temperature changes in Greenland. Trajectory analysis shows that the minerals were transported mainly from the western coast of Greenland in the two warming periods, which was likely due to an increase in dust sourced from local ice-free areas as a result of shorter snow/ice cover duration in the Greenland coastal region during the melt season caused by recent warming. Meanwhile, ancient deposits in northern Canada, which were formed in past warmer climates, seem to be the best candidate during the colder period (1950–2004). Our results suggest that SEM–EDS analysis can detect variations in ice core dust sources during recent periods of low dust concentration.

We present a new framework for global ocean–sea-ice model simulations based on phase 2 of the Ocean Model Intercomparison Project (OMIP-2), making use of the surface dataset based on the Japanese 55-year atmospheric reanalysis for driving ocean–sea-ice models (JRA55-do). We motivate the use of OMIP-2 over the framework for the first phase of OMIP (OMIP-1), previously referred to as the Coordinated Ocean–ice Reference Experiments (COREs), via the evaluation of OMIP-1 and OMIP-2 simulations from 11 state-of-the-science global ocean–sea-ice models. In the present evaluation, multi-model ensemble means and spreads are calculated separately for the OMIP-1 and OMIP-2 simulations and overall performance is assessed considering metrics commonly used by ocean modelers. Both OMIP-1 and OMIP-2 multi-model ensemble ranges capture observations in more than 80 % of the time and region for most metrics, with the multi-model ensemble spread greatly exceeding the difference between the means of the two datasets. Many features, including some climatologically relevant ocean circulation indices, are very similar between OMIP-1 and OMIP-2 simulations, and yet we could also identify key qualitative improvements in transitioning from OMIP-1 to OMIP-2. For example, the sea surface temperatures of the OMIP-2 simulations reproduce the observed global warming during the 1980s and 1990s, as well as the warming slowdown in the 2000s and the more recent accelerated warming, which were absent in OMIP-1, noting that the last feature is part of the design of OMIP-2 because OMIP-1 forcing stopped in 2009. A negative bias in the sea-ice concentration in summer of both hemispheres in OMIP-1 is significantly reduced in OMIP-2. The overall reproducibility of both seasonal and interannual variations in sea surface temperature and sea surface height (dynamic sea level) is improved in OMIP-2. These improvements represent a new capability of the OMIP-2 framework for evaluating process-level responses using simulation results. Regarding the sensitivity of individual models to the change in forcing, the models show well-ordered responses for the metrics that are directly forced, while they show less organized responses for those that require complex model adjustments. Many of the remaining common model biases may be attributed either to errors in representing important processes in ocean–sea-ice models, some of which are expected to be reduced by using finer horizontal and/or vertical resolutions, or to shared biases and limitations in the atmospheric forcing. In particular, further efforts are warranted to resolve remaining issues in OMIP-2 such as the warm bias in the upper layer, the mismatch between the observed and simulated variability of heat content and thermosteric sea level before 1990s, and the erroneous representation of deep and bottom water formations and circulations. We suggest that such problems can be resolved through collaboration between those developing models (including parameterizations) and forcing datasets. Overall, the present assessment justifies our recommendation that future model development and analysis studies use the OMIP-2 framework.

The sixth version of the Model for Interdisciplinary Research on Climate (MIROC), called MIROC6, was cooperatively developed by a Japanese modeling community. In the present paper, simulated mean climate, internal climate variability, and climate sensitivity in MIROC6 are evaluated and briefly summarized in comparison with the previous version of our climate model (MIROC5) and observations. The results show that the overall reproducibility of mean climate and internal climate variability in MIROC6 is better than that in MIROC5. The tropical climate systems (e.g., summertime precipitation in the western Pacific and the eastward-propagating Madden–Julian oscillation) and the midlatitude atmospheric circulation (e.g., the westerlies, the polar night jet, and troposphere–stratosphere interactions) are significantly improved in MIROC6. These improvements can be attributed to the newly implemented parameterization for shallow convective processes and to the inclusion of the stratosphere. While there are significant differences in climates and variabilities between the two models, the effective climate sensitivity of 2.6 K remains the same because the differences in radiative forcing and climate feedback tend to offset each other. With an aim towards contributing to the sixth phase of the Coupled Model Intercomparison Project, designated simulations tackling a wide range of climate science issues, as well as seasonal to decadal climate predictions and future climate projections, are currently ongoing using MIROC6.

To assess the skill of seasonal to inter-annual predictions of the detrended sea ice extent in the Arctic Ocean (SIEAO) and to clarify the underlying physical processes, we conducted ensemble hindcasts, started on 1 January, 1 April, 1 July and 1 October for each year from 1980 to 2011, for lead times up to three years, using the Model for Interdisciplinary Research on Climate (MIROC) version 5 initialised with the observed atmosphere and ocean anomalies and sea ice concentration. Significant skill is found for the winter months: the December SIEAO can be predicted up to 11 months ahead (anomaly correlation coefficient is 0.42). This skill might be attributed to the subsurface ocean heat content originating in the North Atlantic. A plausible mechanism is as follows: the subsurface water flows into the Barents Sea from spring to fall and emerges at the surface in winter by vertical mixing, and eventually affects the sea ice variability there. Meanwhile, the September SIEAO predictions are skillful for lead times of up to two months, due to the persistence of sea ice in the Beaufort, Chukchi, and East Siberian seas initialised in July, as suggested by previous studies.

The Ocean Model Intercomparison Project (OMIP) is an endorsed project in the Coupled Model Intercomparison Project Phase 6 (CMIP6). OMIP addresses CMIP6 science questions, investigating the origins and consequences of systematic model biases. It does so by providing a framework for evaluating (including assessment of systematic biases), understanding, and improving ocean, sea-ice, tracer, and biogeochemical components of climate and earth system models contributing to CMIP6. Among the WCRP Grand Challenges in climate science (GCs), OMIP primarily contributes to the regional sea level change and near-term (climate/decadal) prediction GCs.OMIP provides (a) an experimental protocol for global ocean/sea-ice models run with a prescribed atmospheric forcing; and (b) a protocol for ocean diagnostics to be saved as part of CMIP6. We focus here on the physical component of OMIP, with a companion paper (Orr et al., 2016) detailing methods for the inert chemistry and interactive biogeochemistry. The physical portion of the OMIP experimental protocol follows the interannual Coordinated Ocean-ice Reference Experiments (CORE-II). Since 2009, CORE-I (Normal Year Forcing) and CORE-II (Interannual Forcing) have become the standard methods to evaluate global ocean/sea-ice simulations and to examine mechanisms for forced ocean climate variability. The OMIP diagnostic protocol is relevant for any ocean model component of CMIP6, including the DECK (Diagnostic, Evaluation and Characterization of Klima experiments), historical simulations, FAFMIP (Flux Anomaly Forced MIP), C4MIP (Coupled Carbon Cycle Climate MIP), DAMIP (Detection and Attribution MIP), DCPP (Decadal Climate Prediction Project), ScenarioMIP, HighResMIP (High Resolution MIP), as well as the ocean/sea-ice OMIP simulations.

Elbow flexion is essential for the functional use of the hand. The reconstructive procedure may also change depending on the location of the sarcoma. The nonresected muscle may alter the function of the elbow. If the proximal part of the triceps muscle remains intact, it is considered functional. Functional muscle transfer is not required in such cases. A 50-year-old patient presented with a soft-tissue defect after a wide resection of a leiomyosarcoma affecting the left elbow. The wide resection resulted in the resection of the distal third of the triceps brachii, exposing the olecranon. We performed reconstruction using a pedicled latissimus dorsi musculocutaneous flap. The flap was transferred to the elbow through a subcutaneous tunnel. Ten months after surgery, the elbow function improved. In our patient, the thoracodorsal nerve was cut to prevent mixed nerve signals. We found that patients with distal muscle defects do not require functional muscle grafting. Pedicled latissimus dorsi musculocutaneous flap transfer is a straightforward and useful procedure for reconstructing the upper arm region., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest.

Cerebral small vessel disease and brain white matter injury are worsened by cardiovascular risk factors including obesity. Molecular pathways in cerebral endothelial cells activated by chronic cerebrovascular risk factors alter cell-cell signaling, blocking endogenous and post-ischemic white matter repair. Using cell-specific translating ribosome affinity purification (RiboTag) in white matter endothelia and oligodendrocyte progenitor cells (OPCs), we identify a coordinated interleukin-chemokine signaling cascade within the oligovascular niche of subcortical white matter that is triggered by diet-induced obesity (DIO). DIO induces interleukin-17B (IL-17B) signaling that acts on the cerebral endothelia through IL-17Rb to increase both circulating and local endothelial expression of CXCL5. In white matter endothelia, CXCL5 promotes the association of OPCs with the vasculature and triggers OPC gene expression programs regulating cell migration through chemokine signaling. Targeted blockade of IL-17B reduced vessel-associated OPCs by reducing endothelial CXCL5 expression. In multiple human cohorts, blood levels of CXCL5 function as a diagnostic and prognostic biomarker of vascular cognitive impairment., Competing Interests: Declaration of interests The Regents of the University of California have filed a patent entitled “Serologic Detection of Silent Brain Ischemia” based on this work. G.X. and J.D.H. are co-inventors on this patent. J.D.H. is the founder of Sage Cerebrovascular Diagnostics, Inc., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Bovine-derived collagen gel has been used in the medical field as an injection formulation, but there are concerns about cross-infection such as bovine spongiform encephalopathy. In this study, we attempted to use fish as a safe alternative to bovine collagen., Objective: Fish collagen has not been used in clinical settings, so we examined its potential by comparing its properties with those of bovine-derived collagen., Methods: Collagen was extracted from the ventral skin of flatfish. It was cross-linked with 1%, 3%, or 5% of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and treated with 1%, 5%, or 10% of lactose. Hydroxyproline contents and Young's modulus (elasticity) were measured. In addition, these were injected under the back of BALB/c nude mice and the amount of hydroxyproline was observed. Histological examination of the samples was also conducted., Results: The amount of hydroxyproline in fish collagen was 3.3 ± 0.3 μg/mg. The 3% collagen gel treated with 5% EDC and 5% lactose had the highest Young's modulus and was closest to the bovine-derived collagen injection formulation. When injected into mice, it was retained in vivo for about 90 days., Conclusions: Fish collagen has a low denaturation temperature and is unstable and easily biodegrades in mammalian organisms. However, it is possible to approach the properties of conventional mammalian collagen by cross-linking and lactose treatment, suggesting that fish collagen can be used as a scaffold for cells in regenerative medicine., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Objective: Fragile soft clots and stiff clots remain challenging in the treatment of acute ischemic stroke. This study aims to investigate the impact of clot stiffness on the efficacy of thrombectomy devices and a new aspiration catheter with a hydro-separator., Methods: The Neurostar aspiration catheter has a novel hydro-separator technology that macerates clots by a stream of saline inside the catheter. The Neurostar catheter and two commercially available devices, the SOFIA aspiration catheter and Solitaire stent retriever, were tested in this study. We evaluated the efficacy of each device on clots with various stiffness in a simple in vitro model. We also assessed single-pass recanalization performance in challenging situations with large erythrocyte-rich clots and fibrin-rich clots in a realistic vascular model., Results: We observed an inverse association between the clot stiffness and recanalization rates. The aspiration catheter, SOFIA ingested soft clots but not moderately stiff clots. When removing soft clots with the stent retriever, fragmentation was observed, although relatively stiff clots were well-integrated and removed. The Neurostar ingested soft clots similar to the aspiration catheter, and also aspirated stiff clots by continuous suction with hydro-separator. In the experiments with challenging clots, the Neurostar led to significantly higher recanalization rates than the stent retriever and aspiration catheter., Conclusions: The stiffness of the clots affected the efficacy of endovascular thrombectomy based on the type of device. The Neurostar catheter with hydro-separator resulted in better success rates than a commercially available aspiration catheter and stent retriever in this experimental model.

Galanin, one of the most inducible neuropeptides, is widely present in developing brains, and its expression is altered by pathologic events (e.g., epilepsy, ischemia, and axotomy). The roles of galanin in brain development under both normal and pathologic conditions have been hypothesized, but the question of how galanin is involved in fetal and early postnatal brain development remains largely unanswered. In this study, using granule cell migration in the cerebellum of early postnatal mice (both sexes) as a model system, we examined the role of galanin in neuronal cell migration during normal development and after brain injury. Here we show that, during normal development, endogenous galanin participates in accelerating granule cell migration via altering the Ca 2+ and cAMP signaling pathways. Upon brain injury induced by the application of cold insults, galanin levels decrease at the lesion sites, but increase in the surroundings of lesion sites. Granule cells exhibit the following corresponding changes in migration: (1) slowing down migration at the lesion sites; and (2) accelerating migration in the surroundings of lesion sites. Experimental manipulations of galanin signaling reduce the lesion site-specific changes in granule cell migration, indicating that galanin plays a role in such deficits in neuronal cell migration. The present study suggests that manipulating galanin signaling may be a potential therapeutic target for acutely injured brains during development. SIGNIFICANCE STATEMENT Deficits in neuronal cell migration caused by brain injury result in abnormal development of cortical layers, but the underlying mechanisms remain to be determined. Here, we report that on brain injury, endogenous levels of galanin, a neuropeptide, are altered in a lesion site-specific manner, decreasing at the lesion sites but increasing in the surroundings of lesion sites. The changes in galanin levels positively correlate with the migration rate of immature neurons. Manipulations of galanin signaling ameliorate the effects of injury on neuronal migration and cortical layer development. These results shed a light on galanin as a potential therapeutic target for acutely injured brains during development., (Copyright © 2021 the authors.)

During hospitalization, pediatric patients or their parents may feel stressed. If patients need to stay in the hospital with a cast, they are prone to feeling more stressed. Fixation using a cast is an important clinical option, particularly in the case of skin grafts wherein fixation of the foot and ankle is essential to ensure the survival of the graft skin. However, the removal of the cast is also stressful for patients because it needs to be removed with a cast saw. To avoid further stress in pediatric patients, we cut the cast intraoperatively and then fixed the cast again using nylon cable ties. One week after surgery, we separated the patient's cast. Instead of using a cast saw, we used only scissors or nippers. Our cast removal method was easy, safe, and less stressful., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background and Purpose: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with an increased rate of cerebrovascular events including ischemic stroke and intracerebral hemorrhage. The mechanisms underlying cerebral endothelial susceptibility and response to SARS-CoV-2 are unknown yet critical to understanding the association of SARS-CoV-2 infection with cerebrovascular events., Methods: Endothelial cells were isolated from human brain and analyzed by RNA sequencing. Human umbilical vein and human brain microvascular cells were used in both monolayer culture and endothelialized within a 3-dimensional printed vascular model of the middle cerebral artery. Gene expression levels were measured by quantitative polymerase chain reaction and direct RNA hybridization. Recombinant SARS-CoV-2 S protein and S protein-containing liposomes were used to measure endothelial binding by immunocytochemistry., Results: ACE2 (angiotensin-converting enzyme-2) mRNA levels were low in human brain and monolayer endothelial cell culture. Within the 3-dimensional printed vascular model, ACE2 gene expression and protein levels were progressively increased by vessel size and flow rates. SARS-CoV-2 S protein-containing liposomes were detected in human umbilical vein endothelial cells and human brain microvascular endothelial cells in 3-dimensional middle cerebral artery models but not in monolayer culture consistent with flow dependency of ACE2 expression. Binding of SARS-CoV-2 S protein triggered 83 unique genes in human brain endothelial cells including upregulation of complement component C3., Conclusions: Brain endothelial cells are susceptible to direct SARS-CoV-2 infection through flow-dependent expression of ACE2. Viral S protein binding triggers a unique gene expression profile in brain endothelia that may explain the association of SARS-CoV-2 infection with cerebrovascular events.

To investigate whether oral intake of highly branched α-glucan isomaltodextrin (IMD) could stimulate ileal glucagon-like peptide-1 (GLP-1) secretion, we examined (1) the digestibility of IMD, (2) the digestion and absorption rates of IMD, in rat small intestine and (3) portal GLP-1 concentration in rats given IMD. In Expt 1, ileorectostomised rats were given a 3 % IMD diet for 10 d. Separately, a 16-h in vitro digestion of IMD, using porcine pancreatic α-amylase and brush-border membrane vesicles from rat small intestine, was conducted. In Expt 2, upon 24-h fasting, rats were given any of glucose, IMD and high-amylose maize starch (HAMS) (1 g/kg of body weight). In Expt 3, caecectomised rats were given 0·2 % neomycin sulphate and a 5 % IMD diet for 10 d. The in vivo and in vitro digestibility of IMD was 70-80 %. The fraction of IMD digested in vitro for the first 120 min was 67 % of that in maize starch. The AUC for 0-120 min of plasma glucose concentration was significantly lower in HAMS group and tended to be lower in IMD group than in the glucose group. Finally, we also observed that, when compared with control rats, glucose of IMD significantly stimulated and improved the concentration of portal active GLP-1 in antibiotic-administered, caecectomised rats. We concluded that IMD was slowly digested and the resulting glucose stimulated GLP-1 secretion in rat small intestine. Oral delivery of slowly released IMD glucose to the small intestine probably exerts important, yet unknown, physiological effects on the recipient.

Fat injections aid in the healing of radiation-induced skin damage. We hypothesized that the direct application of fat grafts to the surfaces of radiation-induced ulcers is also effective. Here, we aimed to evaluate the effectiveness of a combination treatment comprising fat injections around ulcers and fat grafts on ulcer surfaces. The dorsal skin of inbred rats was irradiated at a single dose of 20 Gy before producing ulcers. After the inguinal fat was harvested using the Coleman technique, the rats were divided into four groups: Group 1, ulcer wounds were covered using dressing materials and staples only; Group 2, fat was injected around the ulcers using a cannula; Group 3, fat was grafted onto ulcer surfaces; and Group 4, a combination of fat injection around the ulcers and fat grafts onto ulcer surfaces was employed. The mean healing time (± standard deviation) of each group was as follows: Group 1, 16.0 ± 2.2 days; Group 2, 14.5 ± 2.0 days; Group 3, 15.2 ± 1.7 days; and Group 4, 13.4 ± 1.0 days. The healing time of Group 4 was significantly shorter than that of Group 1 ( p  = .0005) and Group 3 ( p  = .023). In both groups that received fat grafts, fat tissue was observed in the dermis on hematoxylin-eosin-stained slides at 4 and 8 weeks after the ulcers were created. In conclusion, the combination treatment of fat grafted onto ulcer surfaces and injected around ulcers was effective in accelerating the epithelization of radiation-induced ulcers.

Background: Microsurgical lower extremity reconstruction is challenging because of high incidence of vascular thrombosis compared to microsurgical head and neck reconstruction. The risk of vascular pedicle thrombosis increases, if patients have arterial sclerosis or intimal dissection at the recipient artery. We performed selective and continuous transarterial heparin infusion for postoperative anticoagulant therapy., Methods: Fifteen patients (10 men and 5 women; mean age of 55.1 years; range of 16-86 years) received lower leg reconstruction using free flap. Postoperatively, a catheter was inserted into the femoral artery during surgery. Heparin infusion was performed through the catheter as a postoperative therapy for patients who had a risk factor of vascular pedicle thrombosis. Until two days post-operation, heparin was started between 5,000 and 10,000 IU per day. In postoperative days 3 and 4, half of the initial dose of heparin was administered. In postoperative days 5 and 6, 25% of the initial dose of heparin was administered., Results: Recipient arteries were the posterior tibial (n=11), anterior tibial (n=2), lateral circumflex femoral (n=1), and medial sural (n=1) arteries. Thirteen of the 15 cases showed arterial sclerosis or intimal dissection at the recipient artery. There was no case of vascular thrombosis. Hematoma formation at flap recipient was observed in four cases. Their initial heparin dose was than 8.5±1.7 U/kg/h., Conclusion: Continuous transarterial heparin infusion was an effective anticoagulant therapy for the patients who had received free tissue transfer to a lower extremity. The initial dose of heparin should not exceed 6.5 U/kg/h., Competing Interests: The authors declare no conflict of interest.

Ischemic injury to white matter tracts is increasingly recognized to play a key role in age-related cognitive decline, vascular dementia, and Alzheimer's disease. Knowledge of the effects of ischemic axonal injury on cortical neurons is limited yet critical to identifying molecular pathways that link neurodegeneration and ischemia. Using a mouse model of subcortical white matter ischemic injury coupled with retrograde neuronal tracing, we employed magnetic affinity cell sorting with fluorescence-activated cell sorting to capture layer-specific cortical neurons and performed RNA-sequencing. With this approach, we identified a role for microtubule reorganization within stroke-injured neurons acting through the regulation of tau. We find that subcortical stroke-injured Layer 5 cortical neurons up-regulate the microtubule affinity-regulating kinase, Mark4, in response to axonal injury. Stroke-induced up-regulation of Mark4 is associated with selective remodeling of the apical dendrite after stroke and the phosphorylation of tau in vivo. In a cell-based tau biosensor assay, Mark4 promotes the aggregation of human tau in vitro. Increased expression of Mark4 after ischemic axonal injury in deep layer cortical neurons provides new evidence for synergism between axonal and neurodegenerative pathologies by priming of tau phosphorylation and aggregation.

The Southern Ocean is of great importance for the global stratification and biological carbon storage because it is connected to the global ocean conveyor by which atmospheric information absorbed in the Southern Ocean is redistributed globally and buffered over centuries. Therefore, understanding what controls the Southern Ocean climate, the global ocean conveyor, and links between them is a key to quantifying uncertainties in future climate projections. Based on a set of climate model experiments, here we show that the tide-induced micro-scale mixing in the Pacific deep ocean has significant impacts on the wintertime Southern Ocean climate through basin-scale reorganization of ocean stratification and resultant response of the global ocean conveyor. Specifically, Pacific deep water, which is modified by the deep ocean mixing while travelling south, reinforces the subsurface stratification and suppresses deep convection in the Southern Ocean. Resultant increase of the Ross Sea sea-ice leads to decrease of incoming shortwave radiation and strengthening of the westerly and storms. Because the Southern Ocean could regulate the global warming progress through its role as heat and carbon sink, our study implies that better representation of deep ocean mixing in climate models contributes to reliability improvement in regional-to-global climate projections.

Experience-dependent plasticity (EDP) is essential for anatomical and functional maturation of sensory circuits during development. Although the principal synaptic and circuit mechanisms of EDP are increasingly well studied experimentally and computationally, its molecular mechanisms remain largely elusive. EDP can be readily studied in the rodent barrel cortex, where each "barrel column" preferentially represents deflections of its own principal whisker. Depriving select whiskers while sparing their neighbours introduces competition between barrel columns, ultimately leading to weakening of intracortical, translaminar (i.e., cortical layer (L)4-to-L2/3) feed-forward excitatory projections in the deprived columns. The same synapses are potentiated in the neighbouring spared columns. These experience-dependent alterations of synaptic strength are thought to underlie somatosensory map plasticity. We used RNA sequencing in this model system to uncover cortical-column and -layer specific changes on the transcriptome level that are induced by altered sensory experience. Column- and layer-specific barrel cortical tissues were collected from juvenile mice with all whiskers intact and mice that received 11-12 days of long whisker (C-row) deprivation before high-quality RNA was purified and sequenced. The current dataset entails an average of 50 million paired-end reads per sample, 75 base pairs in length. On average, 90.15% of reads could be uniquely mapped to the mm10 reference mouse genome. The current data reveal the transcriptional changes in gene expression in the barrel cortex upon altered sensory experience in juvenile mice and will help to molecularly map the mechanisms of cortical plasticity., (© The Authors 2017. Published by Oxford University Press.)

Due to its continuing development after birth, the cerebellum represents a unique model for studying the postnatal orchestration of interneuron migration. The combination of fluorescent labeling and ex/in vivo imaging revealed a cellular highway network within cerebellar cortical layers (the external granular layer, the molecular layer, the Purkinje cell layer, and the internal granular layer). During the first two postnatal weeks, saltatory movements, transient stop phases, cell-cell interaction/contact, and degradation of the extracellular matrix mark out the route of cerebellar interneurons, notably granule cells and basket/stellate cells, to their final location. In addition, cortical-layer specific regulatory factors such as neuropeptides (pituitary adenylate cyclase-activating polypeptide (PACAP), somatostatin) or proteins (tissue-type plasminogen activator (tPA), insulin growth factor-1 (IGF-1)) have been shown to inhibit or stimulate the migratory process of interneurons. These factors show further complexity because somatostatin, PACAP, or tPA have opposite or no effect on interneuron migration depending on which layer or cell type they act upon. External factors originating from environmental conditions (light stimuli, pollutants), nutrients or drug of abuse (alcohol) also alter normal cell migration, leading to cerebellar disorders.

Strategies to reprogram the tumor microenvironment are being explored to improve cancer immunotherapy. In one approach, we have targeted dendritic cells (DC) to improve their function with adjuvant vector cells (aAVC) that are engineered from NKT ligand-loaded CD1d(+) allogeneic cells transfected with tumor antigen mRNAs. Here, we report the finding that this approach also programs local immune responses by establishing tertiary lymphoid structures (TLS), which include expanded antigen-specific CD8(+) T-cell clones, mobilized DCs, and normalized tumor vasculature. aAVC therapy also expanded specific Vβ-expressing antitumor T-cell clones, leading to the formation of long-term memory T cells. When combined with PD-1 blockade, aAVC infusion triggered regression of poorly immunogenic tumor cells that did not respond to PD-1 blockade alone, as well as expansion of antigen-specific CD8(+) T-cell clones in the tumor. The findings of this study help to inform a next-generation platform for the generation of efficacious cancer vaccines. Cancer Res; 76(13); 3756-66. ©2016 AACR., (©2016 American Association for Cancer Research.)

Contacts with neighboring molecules in protein crystals inevitably restrict the internal motions of intrinsically flexible proteins. The resultant clear electron densities permit model building, as crystallographic snapshot structures. Although these still images are informative, they could provide biased pictures of the protein motions. If the mobile parts are located at a site lacking direct contacts in rationally designed crystals, then the amplitude of the movements can be experimentally analyzed. We propose a fusion protein method, to create crystal contact-free space (CCFS) in protein crystals and to place the mobile parts in the CCFS. Conventional model building fails when large amplitude motions exist. In this study, the mobile parts appear as smeared electron densities in the CCFS, by suitable processing of the X-ray diffraction data. We applied the CCFS method to a highly mobile presequence peptide bound to the mitochondrial import receptor, Tom20, and a catalytically relevant flexible segment in the oligosaccharyltransferase, AglB. These two examples demonstrated the general applicability of the CCFS method to the analysis of the spatial distribution of motions within protein molecules., (© 2016 The Protein Society.)

Twenty years have passed since distraction osteogenesis was introduced into the field of craniomaxillofacial surgery, with distraction osteogenesis gradually consolidating its position for midface advancement in syndromic craniosynostosis. On the other hand, no consensus has been reached regarding its adaptation to calvarial bone. We reported that distraction osteogenesis was useful in posterior cranial vault expansion, and subsequently, similar reports have been successively observed worldwide. In posterior cranial vault distraction, intracranial capacity could be greatly expanded due to its simultaneous expansion with the scalp, with little risk of relapse because new bone is regenerated in the distraction gap. The possibility was suggested that the standard of first carrying out fronto-orbital advancement (FOA) for brachycephaly observed in syndromic craniosynostosis will greatly change posterior cranial vault distraction.

Tom20 is located at the outer membrane of mitochondria and functions as a receptor for the N-terminal presequence of mitochondrial-precursor proteins. Recently, three atomic structures of the Tom20-presequence complex were determined using X-ray crystallography and classified into A-, M-, and Y-poses in terms of their presequence-binding modes. Combined with biochemical and NMR data, a dynamic-equilibrium model between the three poses has been proposed. To investigate this mechanism in further detail, we performed all-atom molecular dynamics (MD) simulations and replica-exchange MD (REMD) simulations of the Tom20-presequence complex in explicit water. In the REMD simulations, one major distribution and another minor one were observed in the converged free-energy landscape at 300 K. In the major distribution, structures similar to A- and M-poses exist, whereas those similar to Y-pose are located in the minor one, suggesting that A-pose in solution is more stable than Y-pose. A k-means clustering algorithm revealed a new pose not yet obtained by X-ray crystallography. This structure has double salt bridges between Arg14' in the presequence and Glu78 or Glu79 in Tom20 and can explain the binding affinity of the complex in previous pull-down assay experiments. Structural clustering and analyses of contacts between Tom20 and the presequence suggest smooth conformational changes from Y- to A-poses through low activation barriers. M-pose lies between Y- and A-poses as a metastable state. The REMD simulations thus provide insights into the energetics of the multiple-binding forms and help to detail the progressive conformational states in the dynamic-equilibrium model based on the experimental data.

In the brains of patients with fetal Minamata disease (FMD), which is caused by exposure to methylmercury (MeHg) during development, many neurons are hypoplastic, ectopic, and disoriented, indicating disrupted migration, maturation, and growth. MeHg affects a myriad of signaling molecules, but little is known about which signals are primary targets for MeHg-induced deficits in neuronal development. In this study, using a mouse model of FMD, we examined how MeHg affects the migration of cerebellar granule cells during early postnatal development. The cerebellum is one of the most susceptible brain regions to MeHg exposure, and profound loss of cerebellar granule cells is detected in the brains of patients with FMD. We show that MeHg inhibits granule cell migration by reducing the frequency of somal Ca(2+) spikes through alterations in Ca(2+), cAMP, and insulin-like growth factor 1 (IGF1) signaling. First, MeHg slows the speed of granule cell migration in a dose-dependent manner, independent of the mode of migration. Second, MeHg reduces the frequency of spontaneous Ca(2+) spikes in granule cell somata in a dose-dependent manner. Third, a unique in vivo live-imaging system for cell migration reveals that reducing the inhibitory effects of MeHg on somal Ca(2+) spike frequency by stimulating internal Ca(2+) release and Ca(2+) influxes, inhibiting cAMP activity, or activating IGF1 receptors ameliorates the inhibitory effects of MeHg on granule cell migration. These results suggest that alteration of Ca(2+) spike frequency and Ca(2+), cAMP, and IGF1 signaling could be potential therapeutic targets for infants with MeHg intoxication.

The role of genetic inheritance in brain development has been well characterized, but little is known about the contributions of natural environmental stimuli, such as the effect of light-dark cycles, to brain development. In this study, we determined the role of light stimuli in neuronal cell migration to elucidate how environmental factors regulate brain development. We show that in early postnatal mouse cerebella, granule cell migration accelerates during light cycles and decelerates during dark cycles. Furthermore, cerebellar levels of insulin-like growth factor 1 (IGF-1) are high during light cycles and low during dark cycles. There are causal relationships between light-dark cycles, speed of granule cell migration, and cerebellar IGF-1 levels. First, changes in light-dark cycles result in corresponding changes in the fluctuations of both speed of granule cell migration and cerebellar IGF-1 levels. Second, in vitro studies indicate that exogenous IGF-1 accelerates the migration of isolated granule cells through the activation of IGF-1 receptors. Third, in vivo studies reveal that inhibiting the IGF-1 receptors decelerates granule cell migration during light cycles (high IGF-1 levels) but does not alter migration during dark cycles (low IGF-1 levels). In contrast, stimulating the IGF-1 receptors accelerates granule cell migration during dark cycles (low IGF-1 levels) but does not alter migration during light cycles (high IGF-1 levels). These results suggest that during early postnatal development light stimuli control granule cell migration by altering the activity of IGF-1 receptors through modification of cerebellar IGF-1 levels.

The use of porous concrete columns to decrease the amount of zinc in stormwater runoff is examined. The concentration of zinc in a simulated stormwater fluid (zinc acetate solution), fed through concrete columns (slashed circle10x10cm) decreased by 50-81%, suggesting physical adsorption of zinc by the porous concrete. We propose the use of porous concrete columns (slashed circle50x10cm) as the base of sewage traps. Longer-term, high-zinc concentration monitoring revealed that porous concrete blocks adsorb 38.6mgcm(-3) of zinc. A period of no significant zinc runoff (with an acceptable concentration of zinc in runoff of 0.03mgL(-1), a zinc concentration equal to the Japanese Environmental Standard) is estimated for 41years using a 1-ha catchment area with 20 porous concrete sewage traps. Scanning electron microscopy of the porous concrete used in this study indicates that the needle-like particles formed by hydration action significantly increase zinc adsorption. Evidence suggests that the hydrant is ettringite and has an important role in zinc adsorption, the resulting immobilization of zinc and the subsequent effects on groundwater quality., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Phosphoglycerate mutase (PGAM) is an enzyme of intermediary metabolism that converts 3-phosphoglycerate to 2-phosphoglycerate in glycolysis. Here, we discovered PGAM5 that is anchored in the mitochondrial membrane lacks PGAM activity and instead associates with the MAP kinase kinase kinase ASK1 and acts as a specific protein Ser/Thr phosphatase that activates ASK1 by dephosphorylation of inhibitory sites. Mutation of an active site His-105 in PGAM5 abolished phosphatase activity with ASK1 and phospho-Thr peptides as substrates. The Drosophila and Caenorhabditis elegans orthologs of PGAM5 also exhibit specific Ser/Thr phosphatase activity and activate the corresponding Drosophila and C. elegans ASK1 kinases. PGAM5 is unrelated to the other known Ser/Thr phosphatases of the PPP, MPP, and FCP families, and our results suggest that this member of the PGAM family has crossed over from small molecules to protein substrates and been adapted to serve as a specialized activator of ASK1.

Radial glia are highly polarized cells that serve as neuronal progenitors and as scaffolds for neuronal migration during construction of the cerebral cortex. How radial glial cells establish and maintain their morphological polarity is unknown. Using conditional gene targeting in mice, we demonstrate that adenomatous polyposis coli (APC) serves an essential function in the maintenance of polarized radial glial scaffold during brain development. In the absence of APC, radial glial cells lose their polarity and responsiveness to the extracellular polarity maintenance cues, such as neuregulin-1. Elimination of APC further leads to marked instability of the radial glial microtubule cytoskeleton. The resultant changes in radial glial function and loss of APC in radial glial progeny lead to defective generation and migration of cortical neurons, severely disrupted cortical layer formation, and aberrant axonal tract development. Thus, APC is an essential regulator of radial glial polarity and is critical for the construction of cerebral cortex in mammals.

Preoperative radiotherapy has been widely used to improve local control of disease and to improve survival in the treatment of rectal cancer. However, the response to radiotherapy differs among individual tumors. Our objective here was to identify a set of discriminating genes that can be used for characterization and prediction of response to radiotherapy in rectal cancer. Fifty-two rectal cancer patients who underwent preoperative radiotherapy were studied. Biopsy specimens were obtained from rectal cancer before preoperative radiotherapy. Response to radiotherapy was determined by histopathologic examination of surgically resected specimens and classified as responders or nonresponders. By determining gene expression profiles using human U95Av2 Gene Chip, we identified 33 novel discriminating genes of which the expression differed significantly between responders and nonresponders. Using this gene set, we were able to establish a new model to predict response to radiotherapy in rectal cancer with an accuracy of 82.4%. The list of discriminating genes included growth factor, apoptosis, cell proliferation, signal transduction, or cell adhesion-related genes. Among 33 discriminating genes, apoptosis inducers (lumican, thrombospondin 2, and galectin-1) showed higher expression in responders whereas apoptosis inhibitors (cyclophilin 40 and glutathione peroxidase) showed higher expression in nonresponders. The present study suggested the possibility that gene expression profiling may be useful in predicting response to radiotherapy to establish an individualized tailored therapy for rectal cancer. Global expression profiles of responders and nonresponders may provide insights into the development of novel therapeutic targets.

We treated four patients with scaphocephaly using a combination of distraction and contraction techniques and achieved satisfactory results. Radial osteotomies in the frontal and occipital bones flattened these abnormal bossing bones and accelerated the disappearance of bony bumps created by distraction. This technique facilitates the achievement of the desired shape of the skull through fine adjustments of the distraction and contraction devices.

Lymphangioma of the tongue is relatively rare and may cause facial structural deformity. Using a combination of a V-shaped and central resection, we successfully treated a 6-year-old girl who had massive lymphangioma of the tongue. Postoperatively, her tongue was located completely within her mouth with good cosmetic results. Sensory and motor nerves to the tongue appeared to be intact. Her speech was also improved.

Cisplatin (DDP) is one of the key drugs used to treat patients with ovarian cancer, although resistance to DDP can occur. Paclitaxel and SN-38 (an active metabolite of irinotecan (CPT-11)) are two drugs that are effective in patients with DDP-resistant ovarian cancer. To study how these drugs may overcome the intrinsic and / or acquired resistance of cancer cells to DDP, we investigated the effect of a combination of DDP with paclitaxel and a combination of DDP with SN-38 on three ovarian cancer cell lines, RTSG (intrinsically resistant cell line), KF (DDP-sensitive cell line), and KFra (acquired resistant cell line obtained from KF). We found that these combinations showed additive to synergistic antitumor activity. A time-dependent platinum (Pt) accumulation was observed in the DDP-sensitive KF cell line, while a decrease occurred in the KFra cell line. Little accumulation was observed in RTSG. Intracellular Pt accumulation was increased in all three cell lines by exposure to paclitaxel or SN-38. Ouabain, a Na(+),K(+)-ATPase inhibitor, decreased Pt accumulation in KF and KFra cell lines and inhibited the paclitaxel- and SN-38-induced increases in Pt accumulation in these cell lines. When we assessed the mRNA levels of the multidrug resistance-associated protein (MRP), which may be an efflux pump for DDP, the combination of paclitaxel or SN-38 with DDP down-regulated these levels, which are up-regulated by DDP alone. These results suggest that paclitaxel and SN-38 overcome DDP resistance of ovarian cell lines by controlling intracellular accumulation of DDP via both the influx and efflux systems.

We report a case of small-bowel perforation due to metastatic carcinoma of the breast during chemotherapy. Partial resection of the small intestine and primary anastomosis were performed. Although the patient made a good recovery from panperitonitis, she died of the disease on the 55th postoperative day. Since perforation during chemotherapy results in an extremely poor prognosis, special caution during chemotherapy is needed for patients with possible gastrointestinal involvement with tumor.

Object: The authors describe the use of distraction devices and surgical techniques of distraction osteogenesis for the treatment of patients with craniosynostosis., Methods: Since 1994, the authors have performed distraction procedures in 23 patients with craniosynostosis in whom osteogenesis was achieved. Thirteen of the 23 patients underwent a complete Le Fort III midface osteotomy and distraction. In 10 patients the distraction osteogenesis involved the cranial bone; six underwent combined forehead and midface distraction (Le Fort IV distraction) in which multiple internal devices were used after performing a Le Fort IV osteotomy. An external distraction procedure was used to treat the first two cases. Since 1996, the authors have used internal devices developed in their unit. Distraction was initiated 1 week after the osteotomy at the rate of 0.5 mm per day for the cranium and 1.0 mm per day for the midface. The consolidation phase after distraction was initiated was 2 to 3 months. No major complications such as intracranial infection or neurological deficits were observed during the course of distraction osteogenesis. The osteogenesis generated at the distraction site was considerably satisfactory; and recurrence of the deformity in the follow-up period was minimal., Conclusions: Distraction osteogenesis for craniofacial deformity has numerous advantages: 1) bone grafting is unnecessary; 2) the procedure is less invasive, has short operating time, and less blood loss occurs than in conventional craniofacial procedures; 3) no intracranial dead space is created; 4) there is a good amount of blood flow to the bone segment; and 5) soft-tissue expansion occurs. The authors believe that distraction osteogenesis is a versatile and stable option for the treatment of patients with craniosynostosis.