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Abstract Background Streptococcus canis is a commensal bacterium in companion animals. This microorganism can infect humans who have been in deep contact with or bitten by pet dogs, suggesting that the skin/soft tissue is one of infection entry sites. To understand pathological process in human cells, we aimed to determine S. canis transcriptomic changes in invasive environments of human keratinocytes. Methods We selected one isolate from candidates with whole-genome sequences, based on re-obtained cell invasion ability (CIA) data into human keratinocytes along with bacterial cytotoxicity. RNA-sequencing was conducted for the samples at baselines and 2 h/5 hr post-inoculation using NovaSeq 6000. Global/differential gene expression analyses [principal component analysis (PCA)/k-means clustering analysis/differentially expressed gene (DEG) analyses] were performed. We classified DEGs into their functional categories. To validate transcriptomic results, we did quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assays. Results FU1 isolate was selected from seven candidates, based on re-obtained CIA data with less cytotoxicity. Total read bases of 6.17–9.02 Gbp were obtained by RNA-sequencing. PCA and k-means clustering analysis indicated clustering according to their inoculation times. Volcano plots and Venn diagrams revealed that S. canis invasion into keratinocytes produced altered distributions of many genes. Gene ontology enrichment analysis showed most of the gene expressions were downregulated. DEG functional analysis showed the downregulated DEGs belonging to energy production and conversion/carbohydrate transport and metabolism/amino acid transport and metabolism/nucleotide transport and metabolism, with the upregulated DEGs belonging to transcription. qRT-PCR assays for downregulated/upregulated expressions of four genes (pgk–slo/opuAA–kdpB) validated transcriptomic results. Conclusion Our observations suggest that S. canis can downregulate its metabolism-associated gene expressions in human keratinocyte environments. The observed gene expression changes can imply the latent infection in human cells. Further investigation is needed to elucidate the underlying mechanisms for the latent infection.

Abstract Fenestranes, in which four rings share one carbon atom, have garnered much attention because of their flattened quaternary carbon centers. In addition, the rigid and nonplanar structures of heteroatom-containing fenestranes are attractive scaffolds for pharmaceutical applications. We report one-step syntheses of diaza-dioxa-fenestranes via the sequential (3 + 2) cycloadditions. Our synthesis employs readily synthesizable, nonbranched acyclic allenyl precursors that facilitate sequential cycloaddition reactions. We report the synthesis of 22 heteroatom-containing and differently substituted fenestranes with rings of varying sizes. The prepared diaza-dioxa-fenestranes are subjected to X-ray crystallography and DFT calculations, which suggest that replacing the carbon atoms at the non-bridgehead positions in the fenestrane skeleton with nitrogen and oxygen atoms results in a slight flattening of the quaternary carbon center. Moreover, one of our synthesized c,c-[5.5.5.5]fenestranes containing two isoxazoline rings possesses the flattest quaternary carbon center among previously synthesized heteroatom-containing fenestrane versions.

Abstract Background Degeneration of both intervertebral discs (IVDs) and facet joints in the lumbar spine has been associated with low back pain, but whether and how IVD/joint degeneration contributes to pain remains an open question. Joint degeneration can be identified by pairing T1 and T2 magnetic resonance imaging (MRI) with analysis techniques such as Pfirrmann grades (IVD degeneration) and Fujiwara scores (facet degeneration). However, these grades are subjective, prompting the need to develop an automated technique to enhance inter‐rater reliability. This study introduces an automated convolutional neural network (CNN) technique trained on clinical MRI images of IVD and facet joints obtained from public‐access Lumbar Spine MRI Dataset. The primary goal of the automated system is to classify health of lumbar discs and facet joints according to Pfirrmann and Fujiwara grading systems and to enhance inter‐rater reliability associated with these grading systems. Methods Performance of the CNN on both the Pfirrmann and Fujiwara scales was measured by comparing the percent agreement, Pearson's correlation and Fleiss kappa value for results from the classifier to the grades assigned by an expert grader. Results The CNN demonstrates comparable performance to human graders for both Pfirrmann and Fujiwara grading systems, but with larger errors in Fujiwara grading. The CNN improves the reliability of the Pfirrmann system, aligning with previous findings for IVD assessment. Conclusion The study highlights the potential of using deep learning in classifying the IVD and facet joint health, and due to the high variability in the Fujiwara scoring system, highlights the need for improved imaging and scoring techniques to evaluate facet joint health. All codes required to use the automatic grading routines described herein are available in the Data Repository for University of Minnesota (DRUM).

Abstract Objective The purpose of this study was to identify the M protein trans-acting positive regulator (Mga) orthologue and its adjacent M-like protein (SCM) alleles in Streptococcus canis. Results Using the 39 SCM allele isolates and polymerase chain reaction-based amplification and sequencing, we obtained the deduced Mga amino acid (AA) sequences. The 22 Mga sequences in whole-genome sequences were obtained by searching the National Collection of Type Cultures 12,191(T) Mga sequence into the database. The percentage identity to the type-strain Mga sequence was examined along with its size. The presence of the Mga-specific motifs was confirmed. Of the 62 strains, we identified 59 Mga sequences with an AA size of 509 (except for four different sizes). Percentage identity ranged from 96.66 to 100% with the confirmed Mga-specific motifs and diverse SCM allele populations. Our findings support the presence of an Mga orthologue and diverse SCM allele populations.

Abstract Applying lattice strain to thin films, a critical factor to tailor their properties such as stabilizing a structural phase unstable at ambient pressure, generally necessitates heteroepitaxial growth to control the lattice mismatch with substrate. Therefore, while homoepitaxy, the growth of thin film on a substrate made of the same material, is a useful method to fabricate high‐quality thin films, its application to studying strain‐induced structural phases is limited. Contrary to this general belief, here the quasi‐homoepitaxial growth of Cs and Rb thin films is reported with substantial in‐plane compressive strain. This is achieved by utilizing the alkali‐metal layer existing in bulk crystal of kagome metals AV3Sb5 (A = Cs and Rb) as a structural template. The angle‐resolved photoemission spectroscopy measurements reveal the formation of metallic quantum well states and notable thickness‐dependent quasiparticle lifetime. Comparison with density functional theory calculations suggests that the obtained thin films crystalize in the face‐centered cubic structure, which is typically stable only under high pressure in bulk crystals. These findings provide a useful approach for synthesizing highly strained thin films by quasi‐homoepitaxy, and pave the way for investigating many‐body interactions in Fermi liquids with tunable dimensionality.

Streptococcal toxic shock syndrome (STSS) has a dramatic clinical course and high mortality rate. Here, we report a case of STSS complicated by primary peritonitis and bilateral empyema. A previously healthy young woman was diagnosed with STSS complicated by primary peritonitis and bilateral empyema. Blood culture results on admission were negative. Sever shock, respiratory failure, systemic inflammation, thrombocytopenia, renal failure, ascites, and pleural effusion occurred, mimicking thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure and organomegaly (TAFRO) syndrome. Retesting blood cultures identified Streptococcus pyogenes. Gram staining of ascites and pleural fluid indicated gram-positive cocci in chains. Antibiotics, immunoglobulins, and surgical intervention led to recovery without complications. Ex-post genotypic analyses showed uncommon emm103.0 (cluster E3) of emm long sequence (784 base) and novel sequence type 1363. STSS diagnosis can be difficult as it mimics other systemic inflammatory diseases. Therefore, it is crucial for clinicians to perform microbiological examinations from infection foci, even if the initial culture is negative.

Abstract A current key challenge in 2D materials is the realization of emergent quantum phenomena in hetero structures via controlling the moiré potential created by the periodicity mismatch between adjacent layers, as highlighted by the discovery of superconductivity in twisted bilayer graphene. Generally, the lattice structure of the original host material remains unchanged even after the moiré superlattice is formed. However, much less attention is paid for the possibility that the moiré potential can also modify the original crystal structure itself. Here, it is demonstrated that octahedral MoTe2 which is unstable in bulk is stabilized in a commensurate MoTe2/graphene hetero‐bilayer due to the moiré potential created between the two layers. It is found that the reconstruction of electronic states via the moiré potential is responsible for this stabilization, as evidenced by the energy‐gap opening at the Fermi level observed by angle‐resolved photoemission and scanning tunneling spectroscopies. The present results provide a fresh approach to realize novel 2D quantum phases by utilizing the moiré potential.

Abstract Fermi-surface (FS) nesting originating from Peierls’ idea of electronic instabilities in one-dimensional materials is a key concept to stabilize charge-density wave (CDW), whereas its applicability to two-dimensional (2D) materials is under intensive debate. Here we report unusual CDW associated with the higher-order FS nesting in monolayer 2D VS2. Angle-resolved photoemission spectroscopy and scanning tunneling microscopy uncovered stripe CDW with $$\sqrt {21} R10.9^\circ \times \sqrt 3 R30^\circ$$ 21 R 10 . 9 ∘ × 3 R 3 0 ∘ periodicity together with an energy-gap opening on the entire FS. We suggest that this CDW involves the higher-order FS-nesting vector 2q twice larger than that of the normal one (q), as supported by the anomalies in the calculated phonon dispersion and electronic susceptibility. The present results suggest that the cooperation of q and 2q nesting leads to the fully gapped CDW state unlike the case of conventional single q nesting which produces a partial gap, pointing to an intriguing mechanism of CDW transition.

Kagome metals are interesting for the coexistence of chiral charge density wave and superconductivity. Here, the structural distortion responsible for the charge density wave in KV3Sb5 is investigated by angle-resolved photoemission spectroscopy and first-principles calculations, providing microscopic insight into the charge density wave and superconducting mechanisms.

Abstract Topological Dirac semimetals (TDSs) offer an excellent opportunity to realize outstanding physical properties distinct from those of topological insulators. Since TDSs verified so far have their own problems such as high reactivity in the atmosphere and difficulty in controlling topological phases via chemical substitution, it is highly desirable to find a new material platform of TDSs. By angle-resolved photoemission spectroscopy combined with first-principles band-structure calculations, we show that ternary compound BaMg2Bi2 is a TDS with a simple Dirac-band crossing around the Brillouin-zone center protected by the C3 symmetry of crystal. We also found that isostructural SrMg2Bi2 is an ordinary insulator characterized by the absence of band inversion due to the reduction of spin–orbit coupling. Thus, XMg2Bi2 (X = Sr, Ba, etc.) serves as a useful platform to study the interplay among crystal symmetry, spin–orbit coupling, and topological phase transition around the TDS phase.

Monolayer transition metal dechalcogenides are a promising platform to study the interplay of low-dimensionality and electron correlations. Here, the authors report a Mott insulator state in monolayer 1T-TaSe2, that survives far above room temperature and is robust against external perturbations.

Infectious aortic aneurysm (IAA) can be a rare but potentially fatal sequela of infectious inflammatory disease of the aortic wall with a high incidence of rupture. The definitive diagnosis is based on vascular imaging of the aneurysm using contrast-enhanced computed tomography (CE-CT) and identification of the causative microorganism from positive blood cultures (BCs). However, IAA remains extremely difficult to diagnose and treat in patients with prior antimicrobial treatment or with renal dysfunction. Here we describe a case of an 85-year-old woman with IAA caused by Arthrobacter russicus presenting with abdominal pain and fever that was initially diagnosed as a presumptive urinary tract infection and treated with empiric antimicrobial therapy. However, persistent abdominal pain with increased serological inflammation necessitated further evaluation. Unenhanced multimodality imaging considering the renal dysfunction revealed infectious aortitis of the infrarenal abdominal aorta, together with the initial culture results, leading to the tentative diagnosis of Klebsiella pneumoniae aortitis. Thereafter, serial monitoring with unenhanced magnetic resonance angiography (MRA) using thin-slab maximum intensity projection (TS-MIP) revealed acute aortic expansion strongly suggestive of a pseudoaneurysm that was successfully treated with early surgical repair under adequate infection control. Despite negative Gram staining and tissue culture results for the excised aortic wall, a definitive diagnosis of IAA secondary to A. russicus rather than K. pneumoniae was finally made by confirming the histologic findings consistent with IAA and the identification of A. russicus 16S rRNA on the resected aortic wall. The patient also developed a vascular graft infection during the postoperative course that required long-term systemic antimicrobial therapy. This case highlights the value of unenhanced MRA in the early detection of IAA in patients with renal dysfunction and the importance of a molecular diagnosis for identifying the causative microorganism in cases of culture- or tissue-negative IAA.

We have performed micro-/nanofocused angle-resolved photoemission spectroscopy (ARPES) on cleaved single-crystal surfaces of bismuth to clarify the spatially resolved electronic states. While the dominant area of the cleaved surface was found to display the well-known Rashba-spin-split surface state with the (111)-surface origin, the steplike region with a typical width of ∼10–20 µm shows distinctly different band structure and fermiology originating from the hard-to-cleave (100) surface. This unexpected mixture of the (100)-derived electronic states in a tiny area of the cleaved (111) surface is attributed to the crystal planes separated by a twin boundary, as supported by laser microscopy and electron backscatter diffraction measurements. The present study paves a pathway toward investigating electronic states associated with inhomogeneities and coexisting phases of hard-to-cleave crystal planes and complex materials by spatially resolved ARPES, making this technique a powerful method to investigate the interplay between local electronic states and crystal structures when combined with structural characterization techniques.

Extracting quasiparticle dispersion from photoemission data is challenging and often results in confusion when investigating low-energy excitations. As a solution the authors demonstrate a technique, which applies Bayesian analysis to extract the quasiparticle dynamics of a topological insulator from angle resolved photoemission spectroscopy (ARPES) data, and could be applied to other quantum materials.

Abstract Purpose The purpose of this study was to review our institutional experience with the EOS machine in order to identify the incidence and clinical significance of incidental extraspinal findings (IESF) in an adult spinal deformity population. Methods Our institutional database was queried for all full-length standing radiographs generated by the EOS machine. Dictations were reviewed and the number of incidental extraspinal findings were classified using a previously described system. All findings related to the spine were excluded. A subset of electronic medical records were reviewed to determine further workup for individual findings of suspected clinical significance. Results Original database query based on radiology reports returned a total of 1857 EOS studies. Duplicate studies, studies without the entire body, and patients with more than 1 study during the search period were excluded. 503 patient studies (55.5% female, mean age 59-years-old, range 18 to 91-years-old) met inclusion criteria. The overall rate of incidental extraspinal findings in our study was 60.4% (304 findings in 503 patients). Most findings were classified as Minor. The rate of Major and Moderate findings was 4.8%. The final rate of clinically significant incidental extraspinal findings was 0.8% and included 3 presumed metastatic lesions in long bones and 1 pulmonary nodule. Conclusion To our knowledge this is the first study that reports the rate of incidental extraspinal findings on full body EOS studies. We report a low rate (0.8%) of clinically significant incidental extraspinal findings which is lower than that of CT or MRI. Further research is warranted in comparing EOS and standard radiography.

Infective endocarditis (IE) involving mitral annular calcification (MAC) is a rare disease, but is potentially lethal due to frequent serious periannular complications, and therefore requires early diagnosis and prompt treatment. However, either reaching the correct diagnosis or the detection of periannular complications, even with conventional transesophageal echocardiography (TEE), remains challenging because calcium deposition obscures clear visualization of the area around the MAC. We describe a unique case of methicillin-resistant Staphylococcus aureus (MRSA) IE involving a calcified mitral annular abscess, which was initially misdiagnosed as Klebsiella pneumoniae IE. Accurate diagnosis of MAC-related IE as well as detection of the annular abscess were made possible by 4D TEE, leading to successful cardiac surgery, which confirmed MRSA IE pathologically, and the associated annular abscess. This case highlights the usefulness of 4D TEE for the accurate diagnosis and proper surgical planning. In addition, this case raises the limitations of the modified Duke criteria in cases of definite IE with dual bacteremia.

Mitral valve aneurysm (MVA) is a rare but life-threatening valvular pathologic entity most commonly associated with infective endocarditis (IE) of the aortic valve (AV). We describe a diabetic patient with ruptured anterior MVA secondary to capsular genotype V Streptococcus agalactiae (GBS) harboring novel ST1656 IE without AV involvement. Our patient presented with manifestations of various serious systemic and intracardiac complications, requiring early surgery, but ultimately died from non-cardiogenic causes. This case emphasizes the importance of treating MVA as a dangerous sequela of IE, of performing transesophageal echocardiography to make its accurate diagnosis and institute early surgical intervention, and of considering GBS as a rare but important causative agent of IE in elderly patients with comorbidities.

ABSTRACT: Objective: Dystrophic scoliosis is a serious skeletal manifestation of neurofibromatosis 1 (NF1). The condition requires surgical intervention that is frequently associated with poor outcome due to the high rate of impaired bone healing, pseudoarthrosis, and loosening of the spinal instrumentation. New therapeutic approaches are needed to improve surgical outcomes. Methods: Clinical, laboratory, and radiographic data are presented. Results: A 54-year-old woman with severe NF1 related dystrophic scoliosis and 3 prior surgical interventions underwent revision of lumbar fusion with intraoperative recombinant human bone morphogenetic protein (rhBMP-2) for loosening and a fracture of the left vertical rod at the L4 pedicle screw connection. Two days after surgery, a computed tomography (CT) scan revealed a left posterior iliac periscrew fracture. Given a high risk of mechanical failure, zoledronic acid and asfotase alfa were also administered at 3 and 7 months after surgery. At 14 months after surgery, back pain improved, and a CT scan showed stable spinal fusion and a healed left posterior iliac screw fracture. Conclusion: Combination therapy including asfotase alfa with rhBMP-2 and bisphosphonate resulted in solid arthrodesis after spinal surgery in NF1-related dystrophic scoliosis. Abbreviations: ALP alkaline phosphatase BSALP bone specific ALP CTx C-telopeptide HPP hypophosphatasia NF1 neurofibromatosis 1 NTx N-telopeptide P1NP procollagen type 1 intact N terminal pro PLP pyridoxal 5′-phosphate PPi inorganic pyrophosphate rhBMPs recombinant human bone morphogenetic protein

Previously reported cases of recurrent cellulitis/erysipelas affecting chronically lymphedematous skin regions have been demonstrated to be due to Streptococcus agalactiae isolates with closely related genetic background which may be suggestive of relapse rather than reinfection. Herein, we report the occurrence of three episodes of repetitive cellulitis caused by S. agalactiae strains with different genotypic and phenotypic characteristics, including different antimicrobial susceptibility patterns (tetracycline, macrolide/lincosamide, and fluoroquinolone classes), in the left upper extremity of a patient with lymphedema, following left mastectomy and axillary lymph node dissection. The genotypic and phenotypic characteristics of the three isolates were confirmed based on the random amplified polymorphic DNA patterns, DNA profiles of virulence factors (bca–rib–bac–lmb–cylE), data on biofilm formation and cell invasion, antimicrobial susceptibility testing results, antimicrobial resistance (AMR) genotypes, and amino acid mutations associated with AMR. These results revealed that reinfection with S. agalactiae, rather than recurrence, occurred during the three episodes. In conclusion, microbiologic studies such as blood cultures or tissue cultures are certainly helpful in the management of recurrent infections or invasive infections such as bacteremia in order to better target antimicrobial therapy, regardless of the data previously presented.

Background: Group A Streptococcus pyogenes (GAS) causes necrotizing soft tissue infections (NSTIs) necessitating exploration, surgical debridement, and possibly limb amputation. Case presentation: A 45-year-old man presented with traumatic injury of the left carpal region, vomiting, and diarrhea. The swelling and pain in the left forearm worsened with sensorimotor deficits, and his skin color deteriorated. Emergent exploration was performed for limb preservation; GAS was detected in an exudate, and debridement was performed on postoperative day 2 for streptococcal toxic shock syndrome. He recovered uneventfully and was discharged; however, he returned after 2 months with GAS-induced STI at the same site and received antimicrobial treatment. Conclusion: Exploration and subsequent debridement are crucial for effective treatment of NSTI.

Kagome metals AV_{3}Sb_{5} (A=K, Rb, and Cs) exhibit a unique superconducting ground state coexisting with charge-density wave (CDW), whereas how these characteristics are affected by carrier doping remains unexplored because of the lack of an efficient carrier-doping method. Here we report successful electron doping to CsV_{3}Sb_{5} by Cs dosing, as visualized by angle-resolved photoemission spectroscopy. We found that the electron doping with Cs dosing proceeds in an orbital-selective way, as characterized by a marked increase in electron filling of the Sb 5p_{z} and V 3d_{xz/yz} bands as opposed to the relatively insensitive nature of the V 3d_{xy/x^{2}-y^{2}} bands. By monitoring the temperature evolution of the CDW gap around the M[over ¯] point, we found that the CDW can be completely killed by Cs dosing while keeping the saddle point with the V 3d_{xy/x^{2}-y^{2}} character almost pinned at the Fermi level. The present result suggests a crucial role of multiorbital effect to the occurrence of CDW and provides an important step toward manipulating the CDW and superconductivity in AV_{3}Sb_{5}.

Abstract Beauveriolide III (BeauIII) inhibited sterol O-acyltransferases 1 and 2 (SOAT1 and SOAT2), which are endoplasmic reticulum (ER) membrane proteins, in an enzyme-based assay, and selectively inhibited SOAT1 in a cell-based assay using SOAT1-/SOAT2-CHO cells. This discrepancy in SOAT inhibition by BeauIII was investigated. In the enzyme-based assay, BeauIII inhibited SOAT1 and SOAT2 to a similar extent using microsomes prepared from cells disrupted under the strongest sonication condition. In semi-intact SOAT1-/SOAT2-CHO cells prepared by a treatment with digitonin (plasma membrane permeabilized), BeauIII selectively inhibited SOAT1 (IC50; 5.0 µM (SOAT1) vs >90 µM (SOAT2)), while in those treated with saponin (plasma membrane and ER membrane permeabilized), BeauIII inhibited SOAT1 (IC50, 1.8 µM) and SOAT2 (5.9 µM). SOAT1-selective inhibition by BeauIII was reproduced in intact ER fractions prepared from SOAT1/SOAT2-CHO cells. A Western blotting analysis revealed that biotin-labeled beauveriolide bound to the SOAT1 protein prepared from SOAT1-CHO cells. We concluded that BeauIII binds to a putative active site responsible for SOAT1 that is located on the cytosolic side of the ER, while BeauIII is not accessible to the corresponding active site for SOAT2 located on the luminal side.

Abstract Recurrence following chemotherapy is observed in the majority of patients with pancreatic ductal adenocarcinoma (PDAC). Recent studies suggest that cancer stem cells (CSCs) may be involved in PDAC recurrence and metastasis. However, an efficient approach to targeting pancreatic CSCs remains to be established. Here we show that in cancer cells overexpressing the 67-kDa laminin receptor (67LR)-dependent cyclic GMP (cGMP) inducer, epigallocatechin-3-O-gallate (EGCG) and a phosphodiesterase 3 (PDE3) inhibitor in combination significantly suppressed the Forkhead box O3 and CD44 axis, which is indispensable for the CSC properties of PDAC. We confirmed that the EGCG and PDE3 inhibitor in combination strongly suppressed tumour formation and liver metastasis in vivo. We also found that a synthesized EGCG analog capable of inducing strong cGMP production drastically suppressed the CSC properties of PDAC and extended the survival period in vivo. In conclusion, the combination treatment of EGCG and a PDE3 inhibitor as a strong cGMP inducer could be a potential treatment candidate for the eradication of CSCs of PDAC.

A solution-phase automated synthesis of the versatile synthetic intermediate, Garner’s aldehyde, was demonstrated. tert-Butoxycarbonyl (Boc) protection, acetal formation, and reduction of the ester to the corresponding aldehyde were performed utilizing our originally developed automated synthesizer, ChemKonzert. The developed procedure was also useful for the synthesis of Garner’s aldehyde analogues possessing fluorenylmethyloxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz) protection.

Group A Streptococcus (GAS, Streptococcus pyogenes) causes invasive infections including streptococcal toxic shock syndrome (STSS) and local infections. To our knowledge, this is the first report of a case of an invasive GAS infection with pneumonia and pleural empyema (PE) followed by STSS (disseminated intravascular coagulation [DIC] and acute renal insufficiency) in a healthy male adult. He received combined supportive therapies of PE drainage, anti-DIC agent, hemodialysis, and antimicrobials and eventually made a clinical recovery. GAS isolated from PE was found to have emm1/speA genes, suggestive of a pathogenic strain. Clinicians should be aware of the possibility of this disease entity (pneumonia, PE, and STSS) in healthy male adults as well as children and adult women.

Streptococcus canis (Sc) is a zoonotic pathogen that is transferred mainly from companion animals to humans. One of the major virulence factors in Sc is the M-like protein encoded by the scm gene, which is involved in anti-phagocytic activities, as well as the recruitment of plasminogen to the bacterial surface in cooperation with enolase, and the consequent enhancement of bacterial transmigration and survival. This is the first reported human case of uncomplicated bacteremia following a dog bite, caused by Streptococcus canis harboring the scm gene. The similarity of the 16S rRNA from the infecting species to that of the Sc type strain, as well as the amplification of the species-specific cfg gene, encoding a co-hemolysin, was used to confirm the species identity. Furthermore, the isolate was confirmed as sequence type 9. The partial scm gene sequence harbored by the isolate was closely related to those of other two Sc strains. While this isolate did not possess the erm(A), erm(B), or mef(A), macrolide/lincosamide resistance genes, it was not susceptible to azithromycin: its susceptibility was intermediate. Even though human Sc bacteremia is rare, clinicians should be aware of this microorganism, as well as Pasteurella sp., Prevotella sp., and Capnocytophaga sp., when examining and treating patients with fever who maintain close contact with companion animals.

The discovery of high-temperature (high-Tc) superconductivity in one-monolayer FeSe on SrTiO3 has attracted tremendous attention. Subsequent studies suggested the importance of cooperation between intra-FeSe-layer and interfacial interactions to enhance Tc. However, the nature of intra-FeSe-layer interactions, which would play a primary role in determining the pairing symmetry, remains unclear. Here we have performed high-resolution angle-resolved photoemission spectroscopy of one-monolayer and alkaline-metal-deposited multilayer FeSe films on SrTiO3, and determined the evolution of quasiparticle band dispersion across Tc. We found that the band dispersion in the superconducting state deviates from the Bogoliubov-quasiparticle dispersion expected from the normal-state band dispersion with a constant gap size. This suggests highly anisotropic pairing originating from small momentum transfer and/or mass renormalization due to electron–boson coupling. This band anomaly is interpreted in terms of the electronic interactions within the FeSe layers that may be related to the high-Tc superconductivity in electron-doped FeSe.

Resistance to receptor tyrosine kinase inhibitors is a major obstacle in treatment of lung adenocarcinoma. Yamaguchi et al.identify the orphan receptor ROR1 as a potential target to overcome this resistance, by virtue of its role in promoting cell survival through stabilisation of caveolae.

We have performed angle-resolved photoemission spectroscopy on EuIn_{2}As_{2} which is predicted to be an axion insulator in the antiferromagnetic state. By utilizing soft-x-ray and vacuum-ultraviolet photons, we revealed a three-dimensional hole pocket centered at the Γ point of the bulk Brillouin zone together with a heavily hole-doped surface state in the paramagnetic phase. Upon entering the antiferromagnetic phase, the band structure exhibits a marked reconstruction characterized by the emergence of an “M”-shaped bulk band near the Fermi level. The qualitative agreement with first-principles band-structure calculations suggests the occurrence of bulk-band inversion at the Γ point in the antiferromagnetic phase. We suggest that EuIn_{2}As_{2} provides a good opportunity to study the exotic quantum phases associated with a possible axion-insulator phase.

A rare presentation of extramedullary multiple myeloma in the soft tissues of the bilateral thighs prompted a literature review of published cases of extramedullary multiple myeloma (EM-MM) and solitary plasmacytomas to determine the relative anatomic distribution of these lesions. All available published cases in English were included in the analysis, dating back to 1966 and including 2,538 extramedullary myeloma or solitary plasmacytoma lesions. Analysis of the anatomic location of EM-MM lesions demonstrates the majority being in the upper airway (33.8%), soft tissues including retroperitoneum and abdomen (14.1%), gastrointestinal tract (10.3%), central nervous system, head and neck (16.0%), and GU (2.4%). We were able to find only 44 documented cases of extremity soft tissue lesions, comprising 1.7% of all lesions.

Mycoplasma pneumoniae (Mp) is one of the main pathogens causing community-acquired pneumonia, particularly in young individuals. Host immune response appears to play an important role in prolonged symptoms, as well as in the recent increasing prevalence of drug-resistant Mp isolated from patients. Case 1 had a prolonged clinical course caused by drug-resistant Mp and received steroid therapy despite Mp susceptibility to some antimicrobial agents. Serum cytokine profiles revealed elevation of interleukin-6/-10 and interferon-γ in acute phase. Case 2 had mycoplasmal myocarditis without any respiratory symptoms, which resolved spontaneously without the administration of any antimicrobial agent. These observations suggest that host immune response probably contributes to the etiology of Mp-associated complications.

Sterically crowded diimine ligands with five aryl rings were prepared in one step in good yields using a micro-flow technique. X-ray crystallographic analysis revealed the detailed structure of the bulky ligands. The nickel complexes prepared from the ligands exerted high polymerization activity in the ethylene homopolymerization and copolymerization of ethylene with polar monomers.

A female newborn was admitted to our department 15 days after birth for insufficient sucking and jaundice. The patient’s blood and urine cultures were both positive for group B streptococcal (GBS) infection. A maternal vaginal sample at 35 weeks’ gestation was negative for GBS in culture-based microbiologic screening. The patient recovered shortly after receiving systemic antibiotic therapy. On the basis of clinical evidence of white stool and progressive jaundice, we suspected that the newborn had complications related to congenital biliary atresia (CBA); surgery was performed. Isolates from the mother’s vaginal sample obtained when the patient was 25 days old, along with neonatal blood, revealed identical patterns (serotype VIII and sequence type 1) of GBS capsular and multilocus sequence typing, suggestive of maternal transmission. Molecular epidemiologic examination may be useful to clarify the transmission route and etiology; culture-based microbiologic screening appears to have limitations for detecting the route of transmission.

26-year-old female with prior anterior cruciate ligament reconstruction developed an enlarging lytic bone lesion around the tibial screw with sequential imaging over the course of one year demonstrating progression of this finding, which was confirmed histologically to be a giant cell tumor of bone. The lesion originated around the postoperative bed, making the diagnosis challenging during the early course of the presentation. The case demonstrates giant cell tumor which originated in the metaphysis and subsequently grew to involve the epiphysis; therefore, early course of the disease not involving the epiphysis should not exclude this diagnosis.

On March 11, 2011, Japan experienced an earthquake of magnitude 9.0 and subsequent enormous tsunamis. This disaster destroyed many coastal cities and caused nearly 20,000 casualties. In the aftermath of the disaster, many tsunami survivors who lost their homes were forced to live in small temporary apartments. Although all tsunami survivors were at risk of deteriorating health, the elderly people were particularly at a great risk with regard to not only their physical health but also their mental health. In the present study, we performed a longitudinal cohort study to investigate and analyze health conditions and cognitive functions at 28, 32, and 42 months after the disaster in the elderly people who were forced to reside in temporary apartments in Kesennuma, a city severely damaged by the tsunamis. The ratio of people considered to be cognitively impaired significantly increased during the research period. On the other hand, the mean scores of the Kessler Psychological Distress Scale-6 and Athens Insomnia Scale improved based on the comparison between the data at 24 and 42 months. The multiple logistic regression analysis revealed that frequency of "out-of-home activities" and "walking duration" were independently associated with an increase in the ratio of people with cognitive impairment. We concluded that the elderly people living in temporary apartments were at a high risk of cognitive impairment and "out-of-home activities" and "walking" could possibly maintain the stability of cognitive functions.

To describe clinical aspects of pandemic (H1N1) 2009 virus–associated pneumonia in children, we studied 80 such children, including 17 (21%) with complications, who were admitted to 5 hospitals in Japan during August–November 2009 after a mean of 2.9 symptomatic days. All enrolled patients recovered (median hospitalization 6 days). Timely access to hospitals may have contributed to favorable outcomes.

In tauopathies, a neural microtubule-associated protein tau (MAPT) is abnormally aggregated and forms neurofibrillary tangle. Therefore, inhibition of the tau aggregation is one of the key approaches for the treatment of these diseases. Here, we have identified a novel tau aggregation inhibitor, PE859. An oral administration of PE859 resulted in the significant reduction of sarkosyl-insoluble aggregated tau along with the prevention of onset and progression of the motor dysfunction in JNPL3 P301L-mutated human tau transgenic mice. These results suggest that PE859 is useful for the treatment of tauopathies.

This is a case report with serial imaging showing progression of diffuse osteonecrosis in a patient after a diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH). While bone marrow involvement in HLH has been long noted at histological evaluation and is itself one of the diagnosis criteria, to the best of our knowledge, there has been no previous publication addressing osseous image findings in a patient with HLH.

Tumors formed by a highly metastatic human lung cancer cell line are characterized by activated signaling via vascular endothelial growth factor (VEGF)-C through its receptor (VEGFR-3) and aggressive lymph node metastasis. In this study, we examined how these highly metastatic cancers acquired aggressive lymph node metastasis. Compared with their lower metastatic counterparts, the highly metastatic tumors formed by this cell line expressed higher amounts of interleukin (IL)-1α, with similarly augmented expression of IL-1α and IL-1β by tumor stromal cells and of VEGF-A and VEGF-C by tumor-associated macrophages. These tumor-associated macrophages were mainly of the M2 type. Administration of a macrophage-targeting drug suppressed the production of these potent angiogenic and lymphangiogenic factors, resulting in decreased tumor growth, angiogenesis, lymphangiogenesis, and lymph node metastasis. In Matrigel plug assays, the highly metastatic cells formed tumors that were extensively infiltrated by M2-type macrophages and exhibited enhanced angiogenesis and lymphangiogenesis. All of these responses were suppressed by the IL-1 receptor (IL-1R) antagonist anakinra. Thus, the IL-1α-driven inflammatory activation of angiogenesis and lymphangiogenesis seems to provide a highly metastatic tumor microenvironment favorable for lymph node metastasis through cross-talk with macrophages. Accordingly, the IL-1R/M2-type macrophage axis may be a good therapeutic target for patients with this form of lung cancer.

Clear cell adenocarcinoma of the ovary (OCC) is a chemo-resistant tumor with a relatively poor prognosis and is frequently associated with endometriosis. Although it is assumed that oxidative stress plays some role in the malignant transformation of this tumor, the characteristic molecular events leading to carcinogenesis remain unknown. In this study, an array-based comparative genomic hybridization (CGH) analysis revealed Met gene amplification in 4/13 OCC primary tumors and 2/8 OCC cell lines. Amplification of the AKT2 gene, which is a downstream component of the Met/PI3K signaling pathway, was also observed in 5/21 samples by array-based CGH analysis. In one patient, both the Met and AKT2 genes were amplified. These findings were confirmed using fluorescence in situ hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemistry. In total, 73 OCC cases were evaluated using real-time quantitative PCR; 37.0% demonstrated Met gene amplification (>4 copies), and 8.2% had AKT2 amplification. Furthermore, stage 1 and 2 patients with Met gene amplification had significantly worse survival than patients without Met gene amplification (p

Elucidation of how pancreatic cancer cells give rise to distant metastasis is urgently needed in order to provide not only a better understanding of the underlying molecular mechanisms, but also to identify novel targets for greatly improved molecular diagnosis and therapeutic intervention. We employed combined proteomic technologies including mass spectrometry and isobaric tags for relative and absolute quantification peptide tagging to analyze protein profiles of surgically resected human pancreatic ductal adenocarcinoma tissues. We identified a protein, dihydropyrimidinase-like 3, as highly expressed in human pancreatic ductal adenocarcinoma tissues as well as pancreatic cancer cell lines. Characterization of the roles of dihydropyrimidinase-like 3 in relation to cancer cell adhesion and migration in vitro, and metastasis in vivo was performed using a series of functional analyses, including those employing multiple reaction monitoring proteomic analysis. Furthermore, dihydropyrimidinase-like 3 was found to interact with Ezrin, which has important roles in cell adhesion, motility, and invasion, while that interaction promoted stabilization of an adhesion complex consisting of Ezrin, c-Src, focal adhesion kinase, and Talin1. We also found that exogenous expression of dihydropyrimidinase-like 3 induced activating phosphorylation of Ezrin and c-Src, leading to up-regulation of the signaling pathway. Taken together, the present results indicate successful application of combined proteomic approaches to identify a novel key player, dihydropyrimidinase-like 3, in pancreatic ductal adenocarcinoma tumorigenesis, which may serve as an important biomarker and/or drug target to improve therapeutic strategies.

A major challenge for oncologists and pharmacologists is to develop more potent and less toxic drugs that will decrease the tumor growth and improve the survival of lung cancer patients. Salinomycin is a polyether antibiotic used to kill gram-positive bacteria including mycobacteria, protozoans such as plasmodium falciparum, and the parasites responsible for the poultry disease coccidiosis. This old agent is now a serious anti-cancer drug candidate that selectively inhibits the growth of cancer stem cells. We investigated the impact of salinomycin on survival, colony growth, migration and invasion of the differentiated human non-small cell lung cancer lines LNM35 and A549. Salinomycin caused concentration- and time-dependent reduction in viability of LNM35 and A549 cells through a caspase 3/7-associated cell death pathway. Similarly, salinomycin (2.5-5 µM for 7 days) significantly decreased the growth of LNM35 and A549 colonies in soft agar. Metastasis is the main cause of death related to lung cancer. In this context, salinomycin induced a time- and concentration-dependent inhibition of cell migration and invasion. We also demonstrated for the first time that salinomycin induced a marked increase in the expression of the pro-apoptotic protein NAG-1 leading to the inhibition of lung cancer cell invasion but not cell survival. These findings identify salinomycin as a promising novel therapeutic agent for lung cancer.

A major challenge for oncologists and pharmacologists is to develop less toxic drugs that will improve the survival of lung cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa and was shown to be a highly safe compound. We investigated the impact of Frondoside A on survival, migration and invasion in vitro, and on tumor growth, metastasis and angiogenesis in vivo alone and in combination with cisplatin. Frondoside A caused concentration-dependent reduction in viability of LNM35, A549, NCI-H460-Luc2, MDA-MB-435, MCF-7, and HepG2 over 24 hours through a caspase 3/7-dependent cell death pathway. The IC50 concentrations (producing half-maximal inhibition) at 24 h were between 1.7 and 2.5 µM of Frondoside A. In addition, Frondoside A induced a time- and concentration-dependent inhibition of cell migration, invasion and angiogenesis in vitro. Frondoside A (0.01 and 1 mg/kg/day i.p. for 25 days) significantly decreased the growth, the angiogenesis and lymph node metastasis of LNM35 tumor xenografts in athymic mice, without obvious toxic side-effects. Frondoside A (0.1-0.5 µM) also significantly prevented basal and bFGF induced angiogenesis in the CAM angiogenesis assay. Moreover, Frondoside A enhanced the inhibition of lung tumor growth induced by the chemotherapeutic agent cisplatin. These findings identify Frondoside A as a promising novel therapeutic agent for lung cancer.

Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.

Patient-specific analysis of molecular networks is a promising strategy for making individual risk predictions and treatment decisions in cancer therapy. Although systems biology allows the gene network of a cell to be reconstructed from clinical gene expression data, traditional methods, such as bayesian networks, only provide an averaged network for all samples. Therefore, these methods cannot reveal patient-specific differences in molecular networks during cancer progression. In this study, we developed a novel statistical method called NetworkProfiler, which infers patient-specific gene regulatory networks for a specific clinical characteristic, such as cancer progression, from gene expression data of cancer patients. We applied NetworkProfiler to microarray gene expression data from 762 cancer cell lines and extracted the system changes that were related to the epithelial-mesenchymal transition (EMT). Out of 1732 possible regulators of E-cadherin, a cell adhesion molecule that modulates the EMT, NetworkProfiler, identified 25 candidate regulators, of which about half have been experimentally verified in the literature. In addition, we used NetworkProfiler to predict EMT-dependent master regulators that enhanced cell adhesion, migration, invasion, and metastasis. In order to further evaluate the performance of NetworkProfiler, we selected Krueppel-like factor 5 (KLF5) from a list of the remaining candidate regulators of E-cadherin and conducted in vitro validation experiments. As a result, we found that knockdown of KLF5 by siRNA significantly decreased E-cadherin expression and induced morphological changes characteristic of EMT. In addition, in vitro experiments of a novel candidate EMT-related microRNA, miR-100, confirmed the involvement of miR-100 in several EMT-related aspects, which was consistent with the predictions obtained by NetworkProfiler.

Lung adenocarcinoma (AD) represents a predominant type of lung cancer demonstrating significant morphologic and molecular heterogeneity. We sought to understand this heterogeneity by utilizing gene expression analyses of 432 AD samples and examining associations between 27 known cancer-related pathways and the AD subtype, clinical characteristics and patient survival. Unsupervised clustering of AD and gene expression enrichment analysis reveals that cell proliferation is the most important pathway separating tumors into subgroups. Further, AD with increased cell proliferation demonstrate significantly poorer outcome and an increased solid AD subtype component. Additionally, we find that tumors with any solid component have decreased survival as compared to tumors without a solid component. These results lead to the potential to use a relatively simple pathological examination of a tumor in order to determine its aggressiveness and the patient's prognosis. Additional results suggest the ability to use a similar approach to determine a patient's sensitivity to targeted treatment. We then demonstrated the consistency of these findings using two independent AD cohorts from Asia (N = 87) and Europe (N = 89) using the identical analytic procedures.