Subcutaneous endoscopically assisted ligation using miniport for the treatment of girls with inguinal hernia

Background This report describes the first miniport method using  subcutaneous endoscopically assisted ligation (SEAL) for the treatment of girls with inguinal hernia. To validate its safety and efficacy, the  authors evaluated their early experiences.Methods Between April 2014 and December 2014, 19 SEALs using miniport were performed on 14 patients at the Fukaya Red-Cross Hospital, Saitama, Japan. Their mean age was 6 years (range, 11–128 months). This technique was performed using two ports (a 5mm port placed using the open technique and an additional 2mm miniport). A 5mm laparoscope was inserted via the umbilicus. The miniport was introduced percutaneously in the inguinal region under laparoscopic guidance and manipulated around the medial or lateral   hemicircumference of the internal ring extraperitoneally to place a purse-string around the internal ring. The hernia sac and patent processus vaginalis were closed at the level of the internal inguinal ring   extraperitoneally with circuit suturing using the 2mm miniport. Only the umbilical fascia was closed with an absorbable suture. No skin sutures were applied. We collected data regarding operative time, complications,and recurrence. Results The mean operative time was 20 ±6 min (unilateral, n =9) or 42± 8 min (bilateral, n= 5). The mean follow-up period was 12.8 ± 2.5 (range, 9–19) months. No intraoperative complications associated with theprocedure occurred and no hernial recurrences have been identified so far.Conclusion SEAL using miniport proved to be a successful operative procedure compared with other  laparoscopic percutaneous extraperitoneal closure procedures and produced excellent cosmetic results. SEAL using miniport for the treatment of girls with inguinal hernias appears to be safe, effective, and reliable.Keywords: inguinal hernia, miniport, SEA

p27KIP1 Deletions in Childhood Acute Lymphoblastic Leukemia

AbstractThe p27KIP1 gene, which encodes a cyclin-dependent kinase (CDK) inhibitor, has been assigned to chromosome band 12p12, a region often affected by cytogenetically apparent deletions or translocations in childhood acute lymphoblastic leukemia (ALL). As described here, fluorescence in situ hybridization (FISH) analysis of 35 primary ALL samples with cytogenetic evidence of 12p abnormalities revealed hemizygous deletions of p27KIP1 in 29 cases. Further analysis of 19 of these cases with two additional gene-specific probes from the 12p region (hematopoietic cell phosphatase, HCP and cyclin D2, CCND2) showed that p27KIP1 is located more proximally on the short arm of chromosome 12 and is deleted more frequently than either HCP or CCND2. Of 16 of these cases with hemizygous deletion of p27KIP1, only eight showed loss of HCP or CCND2, whereas loss of either of the latter two loci was uniformly associated with loss of p27KIP1. Missense mutations or mutations leading to premature termination codons were not detected in the coding sequences of the retained p27KIP1 alleles in any of the 16 ALL cases examined, indicating a lack of homozygous inactivation. By Southern blot analysis, one case of primary T-cell ALL had hemizygous loss of a single p27KIP1 allele and a 34.5-kb deletion, including the second coding exon of the other allele. Despite homozygous inactivation of p27KIP1 in this case, our data suggest that haploinsufficiency for p27KIP1 is the primary consequence of 12p chromosomal deletions in childhood ALL. The oncogenic role of reduced, but not absent, levels of p27KIP1 is supported by recent studies in murine models and evidence that this protein not only inhibits the activity of complexes containing CDK2 and cyclin E, but also promotes the assembly and catalytic activity of CDK4 or CDK6 in complexes with cyclin D

Small Molecules with Similar Structures Exhibit Agonist, Neutral Antagonist or Inverse Agonist Activity toward Angiotensin II Type 1 Receptor

Small differences in the chemical structures of ligands can be responsible for agonism, neutral antagonism or inverse agonism toward a G-protein-coupled receptor (GPCR). Although each ligand may stabilize the receptor conformation in a different way, little is known about the precise conformational differences. We synthesized the angiotensin II type 1 receptor blocker (ARB) olmesartan, R239470 and R794847, which induced inverse agonism, antagonism and agonism, respectively, and then investigated the ligand-specific changes in the receptor conformation with respect to stabilization around transmembrane (TM)3. The results of substituted cysteine accessibility mapping studies support the novel concept that ligand-induced changes in the conformation of TM3 play a role in stabilizing GPCR. Although the agonist-, neutral antagonist and inverse agonist-binding sites in the AT1 receptor are similar, each ligand induced specific conformational changes in TM3. In addition, all of the experimental data were obtained with functional receptors in a native membrane environment (in situ)

Evaluation of global ocean–sea-ice model simulations based on the experimental protocols of the Ocean Model Intercomparison Project phase 2 (OMIP-2)

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 processlevel 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

Evaluation of global ocean–sea-ice model simulations based on the experimental protocols of the Ocean Model Intercomparison Project phase 2 (OMIP-2)

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.This research has been supported by the Integrated Research Program for Advancing Climate Models (TOUGOU) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan (grant nos. JPMXD0717935457 and JPMXD0717935561), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (grant no. 274762653), the Helmholtz Climate Initiative REKLIM (Regional Climate Change) and European Union's Horizon 2020 Research & Innovation program (grant nos. 727862 and 800154), the Research Council of Norway (EVA (grant no. 229771) and INES (grant no. 270061)), the US National Science Foundation (NSF) (grant no. 1852977), the National Natural Science Foundation of China (grant nos. 41931183 and 41976026), NOAA's Science Collaboration Program and administered by UCAR's Cooperative Programs for the Advancement of Earth System Science (CPAESS) (grant nos. NA16NWS4620043 and NA18NWS4620043B), and NOAA (grant no. NA18OAR4320123).Peer ReviewedPostprint (published version

An Id-like molecule, HHM, is a synexpression group-restricted regulator of TGF-β signalling

Transforming growth factor (TGF)-β induces various cellular responses principally through Smad-dependent transcriptional regulation. Activated Smad complexes cooperate with transcription factors in regulating a group of target genes. The target genes controlled by the same Smad-cofactor complexes are denoted a synexpression group. We found that an Id-like helix-loop-helix protein, human homologue of Maid (HHM), is a synexpression group-restricted regulator of TGF-β signalling. HHM suppressed TGF-β-induced growth inhibition and cell migration but not epithelial–mesenchymal transition. In addition, HHM inhibited TGF-β-induced expression of plasminogen activator inhibitor-type 1 (PAI-1), PDGF-B, and p21WAF, but not Snail. We identified a basic-helix-loop-helix protein, Olig1, as one of the Smad-binding transcription factors affected by HHM. Olig1 interacted with Smad2/3 in response to TGF-β stimulation, and was involved in transcriptional activation of PAI-1 and PDGF-B. HHM, but not Id proteins, inhibited TGF-β signalling-dependent association of Olig1 with Smad2/3 through physical interaction with Olig1. HHM thus appears to regulate a subset of TGF-β target genes including the Olig1-Smad synexpression group. HHM is the first example of a cellular response-selective regulator of TGF-β signalling with clearly determined mechanisms

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Formation of Fractures in Komagatake Volcano, Hokkaido

Fractures developed in the atrio of Komagatake Volcano, Hokkaido, are classified into three main types. 1) 1929 fractures along the atrio margin, 2) 1929 concentric fractures, and 3) the 1942 major fissure. The former two fractures were formed by settling and compaction due to welding as well as settling of the 1929 pyroclastic deposits, respectively. These fractures were strongly controlled by the older topography. The 1942 major fissure extending across the atrio for 1.6 km in NW-SE, was initially produced by doming due to the excess magma pressure, and enlarged by explosions and subsequent collapse of the wall

Design and Evaluation of Engineered Extracellular Vesicle (EV)-Based Targeting for EGFR-Overexpressing Tumor Cells Using Monobody Display

Background: Extracellular vesicles (EVs) are attracting interest as a new class of drug delivery vehicles due to their intrinsic nature of biomolecular transport in the body. We previously demonstrated that EV surface modification with tissue-specific molecules accomplished targeted EV-mediated DNA delivery. Methods: Here, we describe reliable methods for (i) generating EGFR tumor-targeting EVs via the display of high-affinity monobodies and (ii) in vitro measurement of EV binding using fluorescence and bioluminescence labeling. Monobodies are a well-suited class of small (10 kDa) non-antibody scaffolds derived from the human fibronectin type III (FN3) domain. Results: The recombinant protein consists of the EGFR-targeting monobody fused to the EV-binding domain of lactadherin (C1C2), enabling the monobody displayed on the surface of the EVs. In addition, the use of bioluminescence or fluorescence molecules on the EV surface allows for the assessment of EV binding to the target cells. Conclusions: In this paper, we describe methods of EV engineering to generate targeted delivery vehicles using monobodies that will have diverse applications to furnish future EV therapeutic development, including qualitative and quantitative in vitro evaluation for their binding capacity

Development of Faults and Growth of Usu-Shinzan Cryptodome in 1977-1982 at Usu Volcano, North Japan

Usu-Shinzan, a cryptodome uplifted about 180 m, was built on the summit of Usu Volcano during the 1977-1978 dacite eruption and subsequent activity until spring 1982. Numerous faults have developed associated with the growth of Usu-Shinzan, but their development was restricted to the northern harlf area of the volcano, possibly being controlled by the structure of the southern wall of Toya caldera which is overlain by the volcano. In the summit area, typical synthetic and antithetic faults were formed, which resulted in development of an asymmetric graben. The main fault coupled with hinge faults grew up to form a U-shaped fault block. Due to NE upward movement of the U-shaped block, the northern somma was cut by many strike-slip faults and pushed outward, and on the northern foot a number of strike-slip faults showing radial arrangement have been formed. Re-activation of some of the 1910 faults were observed. The development of these faults can be interpreted by means of intrusion of the dacite magma along the steep southern wall of the caldera under the volcano. Changes of fault activity with time suggest that the magma column expanded not only at the upper part but also notably inflated at the lower part after November 1977