Negative-mass exciton polaritons induced by dissipative light-matter coupling in an atomically thin semiconductor.

Dispersion engineering is a powerful and versatile tool that can vary the speed of light signals and induce negative-mass effects in the dynamics of particles and quasiparticles. Here, we show that dissipative coupling between bound electron-hole pairs (excitons) and photons in an optical microcavity can lead to the formation of exciton polaritons with an inverted dispersion of the lower polariton branch and hence, a negative mass. We perform direct measurements of the anomalous dispersion in atomically thin (monolayer) WS2 crystals embedded in planar microcavities and demonstrate that the propagation direction of the negative-mass polaritons is opposite to their momentum. Our study introduces the concept of non-Hermitian dispersion engineering for exciton polaritons and opens a pathway for realising new phases of quantum matter in a solid state.

Proof-of-concept for the detection of early osteoarthritis pathology by clinically applicable endomicroscopy and quantitative AI-supported optical biopsy.

OBJECTIVE: Clinical trials for osteoarthritis (OA), the leading cause of global disability, are unable to pinpoint the early, potentially reversible disease with clinical technology. Hence, disease-modifying drug candidates cannot be tested early in the disease. To overcome this obstacle, we asked whether early OA-pathology detection is possible with current clinical technology. METHODS: We determined the relationship between two sensitive early OA markers, atomic force microscopy (AFM)-measured human articular cartilage (AC) surface stiffness, and location-matched superficial zone chondrocyte spatial organizations (SCSOs), asking whether a significant loss of surface stiffness can be detected in early OA SCSO stages. We then tested whether current clinical technology can visualize and accurately diagnose the SCSOs using an approved probe-based confocal laser-endomicroscope and a random forest (RF) model. RESULTS: We demonstrated a correlation between AC surface stiffness and the SCSO (rrm = -0.91; 95%CI: -0.97, -0.73), and an extensive loss of surface stiffness specifically in those ACs with early OA-typical SCSO (95%CIs: string SCSO: 269-173 kPa, double string SCSO: 77-46 kPa). This established the SCSO as a visualizable, functionally relevant surrogate marker of early OA AC surface pathology. Moreover, SCSO-based stiffness discrimination worked well in each patient's AC. We then demonstrated feasibility of visualizing the SCSO by clinical laser-endomicroscopy and, importantly, accurate SCSO diagnosis using RF. CONCLUSION: We present the proof-of-concept of early OA-pathology detection with available clinical technology, introducing a future-oriented, AI-supported, non-destructive quantitative optical biopsy for early disease detection. Operationalizing SCSO recognition, this approach allows testing for correlations between local tissue architectures with other experimental and clinical read-outs, but needs clinical validation and a larger sample size for defining diagnostic thresholds.

Use of electron microscopy in core biopsy diagnosis of oncocytic renal tumors.

The distinction between oncocytoma and chromophobe renal cell carcinoma, important clinically, may be challenging, especially as the tissue sample size decreases. Ancillary studies can be helpful, although subject to interpretation and sample variability. The aim of this study was to examine the value of electron microscopy in differentiating between oncocytoma and chromophobe renal cell carcinoma on formalin fixed paraffin embedded needle core biopsies. Twenty renal needle core biopsies were evaluated. Despite formalin fixation and paraffin embedding, the classic ultrastructural features of these neoplasms were retained, revealing 80% sensitivity and 100% specificity by initial work-up.

Different glycolytic pathways for glucose and fructose in the halophilic archaeon Halococcus saccharolyticus.

The glucose and fructose degradation pathways were analyzed in the halophilic archaeon Halococcus saccharolyticus by 13C-NMR labeling studies in growing cultures, comparative enzyme measurements and cell suspension experiments. H. saccharolyticus grown on complex media containing glucose or fructose specifically 13C-labeled at C1 and C3, formed acetate and small amounts of lactate. The 13C-labeling patterns, analyzed by 1H- and 13C-NMR, indicated that glucose was degraded via an Entner-Doudoroff (ED) type pathway (100%), whereas fructose was degraded almost completely via an Embden-Meyerhof (EM) type pathway (96%) and only to a small extent (4%) via an ED pathway. Glucose-grown and fructose-grown cells contained all the enzyme activities of the modified versions of the ED and EM pathways recently proposed for halophilic archaea. Glucose-grown cells showed increased activities of the ED enzymes gluconate dehydratase and 2-keto-3-deoxy-gluconate kinase, whereas fructose-grown cells contained higher activities of the key enzymes of a modified EM pathway, ketohexokinase and fructose-1-phosphate kinase. During growth of H. saccharolyticus on media containing both glucose and fructose, diauxic growth kinetics were observed. After complete consumption of glucose, fructose was degraded after a lag phase, in which fructose-1-phosphate kinase activity increased. Suspensions of glucose-grown cells consumed initially only glucose rather than fructose, those of fructose-grown cells degraded fructose rather than glucose. Upon longer incubation times, glucose- and fructose-grown cells also metabolized the alternate hexoses. The data indicate that, in the archaeon H. saccharolyticus, the isomeric hexoses glucose and fructose are degraded via inducible, functionally separated glycolytic pathways: glucose via a modified ED pathway, and fructose via a modified EM pathway.

Is anti-h-caldesmon useful for distinguishing smooth muscle and myofibroblastic tumors? An immunohistochemical study.

Misinterpretation of positive staining of antibodies to desmin, smooth muscle actin, and muscle actin as representing smooth muscle differentiation in the context of a spindle cell tumor is not uncommon. Anti-h-caldesmon is a promising novel immunohistochemical reagent for more specific smooth muscle differentiation. We studied 72 tumors (11 leiomyosarcomas, 26 malignant fibrous histiocytomas [MFHs], 11 fibromatoses, 11 cellular cutaneous fibrous histiocytomas [CCFHs], 5 malignant peripheral nerve sheath tumors, 4 synovial sarcomas, and 4 cases of nodular fasciitis), the reactive myofibroblastic response in 5 cases of acute cholecystitis, and the desmoplastic response surrounding 5 invasive breast carcinomas. Tissues were examined for expression of h-caldesmon, desmin, smooth muscle actin, and muscle actin. Diffuse staining for h-caldesmon was present only within the leiomyosarcomas. Focal staining for h-caldesmon involving less than 1% of lesional cells was present in 3 of 26 MFHs and 1 of 11 CCFHs. There was overlap in staining for the other "myoid" markers in all of the lesions that contained myofibroblasts. Anti-h-caldesmon seems to be a reliable marker of smooth muscle differentiation, and its inclusion in a panel of myoid immunohistochemical reagents should allow distinction of smooth muscle and myofibroblastic tumors.

Robotic system for biopsy and therapy of breast lesions in a high-field whole-body magnetic resonance tomography unit.

RATIONALE AND OBJECTIVES: With magnetic resonance mammography, significant progress has been achieved in the diagnosis of small breast cancers. However, biopsy and therapy of suspicious lesions must take place at a later time. Diagnosis and simultaneous biopsy and therapy in one single examination would considerably reduce costs, strain on the patient, and side effects. METHODS: ROBITOM (Robotic system for biopsy and interventional therapy of mammary lesions) is used to approach a lesion found in the breast in an image-controlled manner under a high magnetic field (eg, 1.5 T). The robotic system works in the direct vicinity of the isocenter of a magnet and consists of a trocar, coaxial sleeve, biopsy needle, laser applicator, and a control and driving unit. It contains a rack, a driving unit along the three coaxes of space, and a gripping unit for instruments or biopsy sample removal. The system has six degrees of freedom. RESULTS: In vitro experiments in pig liver including eight targets (vitamin E capsules, 4 mm in diameter) were performed. All eight capsules were hit precisely by the robotic biopsy system. The procedure was performed directly in the isocenter of a 1.5-T whole-body scanner. CONCLUSIONS: The system allows the coordinates of a lesion in the breast to be approached in a high magnetic field without shifting the patient. A combination of imaging with biopsy and subsequent therapy (eg, laser therapy or cryotherapy) seems to be feasible in the future.

A human pituitary tumor-derived folliculostellate cell line.

Pituitary cells have been used for the study of hormone synthesis, secretion, and regulation. However, the lack of human cell lines of pituitary origin has made such studies in humans very difficult. Activin, a member of the transforming growth factor-beta cytokine family, is secreted by the pituitary and serves, in addition to regulating hormone biosynthesis, as a regulator of cell growth and differentiation. In the human pituitary, folliculo-stellate cells secrete an activin-binding and -neutralizing protein, follistatin. However, the role of these cells in the autocrine/paracrine regulatory mechanisms of activin is poorly understood. We describe a human pituitary-derived folliculostellate cell line, designated PDFS, that was developed spontaneously from a clinically nonfunctioning pituitary macroadenoma. PDFS cells showed an epithelial-like morphology with long cytoplasmic processes. Electron microscopy revealed frequent intercellular junctions, including desmosomes, and cytogenetic analysis showed clonal characteristics with chromosomal abnormalities. These cells express vimentin and the nervous tissue-specific S-100 protein, specific markers of folliculostellate cells in the anterior pituitary, but no secretory pituitary cell markers. PDFS cells formed large colonies in an anchorage-independent transformation assay. They express follistatin and activin A and have an intact activin intracellular signaling pathway as determined by reporter assays. Therefore, this human cell line provides a useful model for studying the regulation of cell growth and cytokine production by factors endogenously produced in pituitary folliculostellate cells.

The medical engineering program of Forschungszentrum Karlsruhe.

The research activities of the Forschungszentrum Karlsruhe on minimally-invasive surgery (MIS) have for several years improved techniques and instrumentation for different types of MIS. Many types of instruments and robotic devices have been developed and new techniques implemented. In this paper we present the most recent results from our different projects, such as endoscopic heart surgery, tracking systems, a camera guidance device, telemanipulator systems, minimally-invasive breast biopsy in closed-bore MRI, endoscopic training simulators and developments using smart materials (e.g. Nitinol).

Hyalinizing spindle cell tumor with giant rosettes: a report of three cases with ultrastructural analysis.

We report the light microscopic, ultrastructural appearance and immunohistochemical staining profile of three distinctive soft-tissue tumors recently designated hyalinizing spindle cell tumor with giant rosettes. The tumors occurred in two men, 41 and 54 years old, and one woman, 62 years old. Two tumors arose in the lower extremities and one in the upper arm. Two tumors were resected and measured 3 and 13.2 cm in greatest diameter; a biopsy only was done of the third tumor. Grossly, the tumors had a tan, pink, or white cut surface. The largest tumor exhibited central cystic change. Microscopically, they all displayed similar features and were composed of fibromyxoid regions, with areas of hyalinization in two tumors and focal ossification in one tumor. Scattered throughout each of the tumors were rosette-like structures in which neoplastic cells were arranged around a central collagenous core. Ultrastructurally, the neoplastic cells demonstrated the features of fibroblasts. In all tumors, there was abundant extracellular collagen fibers and in one there were large aggregates of amorphous extracellular external lamina-like material. The center of the rosette-like structures was composed of banded collagen fibers and the cells at the periphery of the rosettes had ultrastructural features similar to the neoplastic spindle cells located elsewhere in the tumor. Immunohistochemically, the tumor cells stained for vimentin. There was focal staining of the widely distributed spindle cells and cells that formed the rosettes for Leu-7, S-100 protein, and CD34. In one tumor, there was faint diffuse staining of the spindle cells for neuron-specific enolase. One tumor (with the amorphous extracellular material) stained for type IV collagen. There was no staining for desmin, muscle actin, smooth muscle actin, keratin, or epithelial membrane antigen. These results demonstrate that hyalinizing spindle cell tumor with giant rosettes is composed of fibroblasts. We did not demonstrate any ultrastructural or immunohistochemical differences between the spindle cells that comprised the majority of the mass and those that surrounded the rosette-like structures. There was no ultrastructural evidence of neural differentiation to explain the focal S-100 protein and Leu-7 staining of the tumor cells.

Acetyl coenzyme A synthetase (ADP forming) from the hyperthermophilic Archaeon pyrococcus furiosus: identification, cloning, separate expression of the encoding genes, acdAI and acdBI, in Escherichia coli, and in vitro reconstitution of the active heterotetrameric enzyme from its recombinant subunits.

Acetyl-coenzyme A (acetyl-CoA) synthetase (ADP forming) represents a novel enzyme in archaea of acetate formation and energy conservation (acetyl-CoA + ADP + P(i) --> acetate + ATP + CoA). Two isoforms of the enzyme have been purified from the hyperthermophile Pyrococcus furiosus. Isoform I is a heterotetramer (alpha(2)beta(2)) with an apparent molecular mass of 145 kDa, composed of two subunits, alpha and beta, with apparent molecular masses of 47 and 25 kDa, respectively. By using N-terminal amino acid sequences of both subunits, the encoding genes, designated acdAI and acdBI, were identified in the genome of P. furiosus. The genes were separately overexpressed in Escherichia coli, and the recombinant subunits were reconstituted in vitro to the active heterotetrameric enzyme. The purified recombinant enzyme showed molecular and catalytical properties very similar to those shown by acetyl-CoA synthetase (ADP forming) purified from P. furiosus.

Chondromyxoid fibroma: a tumor showing myofibroblastic, myochondroblastic, and chondrocytic differentiation.

Chondromyxoid fibroma (CMF) is a rare primary benign tumor of bone that demonstrates variable histologic features and is often confused with chondrosarcoma. Although the chondroid elements in CMF have been reported to be S-100 protein positive and to have chondrocytic features ultrastructurally, the immunohistochemical and ultrastructural profile of CMF, especially with respect to the peripheral nonchondroid elements, has not been extensively studied. Formalin-fixed, paraffin-embedded tissue from 10 CMFs were stained immunohistochemically with antibodies to vimentin, desmin, muscle actin, smooth muscle actin, S-100 protein, and CD34. Six tumors were also examined ultrastructurally. The chondroid areas showed variable staining for S-100 protein but did not stain for muscle actin or smooth muscle actin. The peripheral areas surrounding the chondroid areas stained diffusely for smooth muscle actin and muscle actin but did not stain for S-100 protein. CD34 highlighted the extensive vascularity that was especially prominent in the peripheral areas; no tumor cells stained for CD34. There was no staining for desmin. Ultrastructural examination showed three different cell types. Some cells showed the classic features of chondrocytes, other cells had the features of myofibroblasts, and the third cell type had the features of both chondrocytes and myofibroblasts ("myochondroblasts"). These findings support the conclusion that CMF is a tumor showing myofibroblastic, myochondroblastic, and chondrocytic differentiation.

Clioquinol-zinc chelate: a candidate causative agent of subacute myelo-optic neuropathy.

BACKGROUND: 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol) was used clinically three decades ago as an oral antiparasitic agent and to increase intestinal absorption of zinc in patients with acrodermatitis enteropathica, a genetic disorder of zinc absorption. Use of clioquinol was epidemiologically linked to subacute myelo-optic neuropathy (SMON), characterized by peripheral neuropathy and blindness, which affected 10,000 patients in Japan. Discontinuation of oral clioquinol use led to elimination of SMON, however, the mechanism of how clioquinol induces neurotoxicity is unclear. MATERIALS AND METHODS: We tested the effect of clioquinol-metal chelates on neural crest-derived melanoma cells. The effect of clioquinol chelates on cells was further studied by electron microscopy and by a mitochondrial potential-sensitive fluorescent dye. RESULTS: Of the ions tested, only clioquinol-zinc chelate demonstrated cytotoxicity. The cytotoxicity of clioquinol-zinc chelate was extremely rapid, suggesting that its primary effect was on the mitochondria. Electron microscopic analysis demonstrated that clioquinol-zinc chelate caused mitochondrial damage. This finding was further confirmed by the observation that clioquinol-zinc chelate caused a decrease in mitochondrial membrane potential. CONCLUSIONS: We demonstrate that clioquinol, in the presence of zinc, is converted to a potent mitochondrial toxin. The phenomenon of clioquinol mediated toxicity appears to be specific to zinc and is not seen with other metals tested. Since clioquinol has been shown to cause increased systemic absorption of zinc in humans, it is likely that clioquinol-zinc chelate was present in appreciable levels in patients with SMON and may be the ultimate causative toxin of SMON.

Tumor induction of VEGF promoter activity in stromal cells.

We have established a line of transgenic mice expressing the A. victoria green fluorescent protein (GFP) under the control of the promoter for vascular endothelial growth factor (VEGF). Mice bearing the transgene show green cellular fluorescence around the healing margins and throughout the granulation tissue of superficial ulcerative wounds. Implantation of solid tumors in the transgenic mice leads to an accumulation of green fluorescence resulting from tumor induction of host VEGF promoter activity. With time, the fluorescent cells invade the tumor and can be seen throughout the tumor mass. Spontaneous mammary tumors induced by oncogene expression in the VEGF-GFP mouse show strong stromal, but not tumor, expression of GFP. In both wound and tumor models the predominant GFP-positive cells are fibroblasts. The finding that the VEGF promoter of nontransformed cells is strongly activated by the tumor microenvironment points to a need to analyze and understand stromal cell collaboration in tumor angiogenesis.

Guide catheter exchange techniques: bi-coaxial and other methods.

Maintaining the position of a guidewire across coronary artery lesions during angioplasty is important to allow rapid and reliable access. Stabilizing these small caliber angioplasty guidewires during guide catheter replacement is often difficult, if not impossible at times. This article reviews the techniques for exchanging guide catheters while maintaining coronary guidewire position. It also introduces the bi-coaxial guide catheter exchange technique.

Apoptotic cells in peripheral blood from patients with low serum cobalamin.

Apoptotic leukocytes were found by using ultrastructural and light microscopic techniques to examine peripheral blood in ten of twelve patients with low serum cobalamin (vitamin B12) and rarely in normal controls. A total of 88 apoptotic cells (.14% of total leukocytes) were identified in all the patients. One patient also had apoptotic cells found on a routine blood smear. There was no correlation between the finding of these cells and nuclear hypersegmentation, serum cobalamin levels, serum intrinsic factor antibody, serum methylmalonic acid and homocysteine or the Schilling test. Two patients, however, with the most severe vitamin deficiency did not have increased numbers of apoptotic cells suggesting that these patients had lost the ability to initiate the cell death program.

Comparative analysis of Embden-Meyerhof and Entner-Doudoroff glycolytic pathways in hyperthermophilic archaea and the bacterium Thermotoga.

The Embden-Meyerhof (EM) or Entner-Doudoroff (ED) pathways of sugar degradation were analyzed in representative species of the hyperthermophilic archaeal genera Thermococcus, Desulfurococcus, Thermoproteus, and Sulfolobus, and in the hyperthermophilic (eu)bacterial genus Thermotoga. The analyses included (1) determination of 13C-labeling patterns by 1H- and 13C-NMR spectroscopy of fermentation products derived from pyruvate after fermentation of specifically 13C-labeled glucose by cell suspensions, (2) identification of intermediates of sugar degradation after conversion of 14C-labeled glucose by cell extracts, and (3) measurements of enzyme activities in cell extracts. Thermococcus celer and Thermococcus litoralis fermented 13C-glucose to acetate and alanine via a modified EM pathway (100%). This modification involves ADP-dependent hexokinase, 6-phosphofructokinase, and glyceraldehyde-3-phosphate:ferredoxin oxidoreductase (GAP:FdOR). Desulfurococcus amylolyticus fermented 13C-glucose to acetate via a modified EM pathway in which GAP:FdOR replaces GAP-DH/phosphoglycerate kinase. Thermoproteus tenax fermented 13C-glucose to low amounts of acetate and alanine via simultaneous operation of the EM pathway (85%) and the ED pathway (15%). Aerobic Sulfolobus acidocaldarius fermented 13C-labeled glucose to low amounts of acetate and alanine exclusively via the ED pathway. The anaerobic (eu)bacterium Thermotoga maritima fermented 13C-glucose to acetate and lactate via the EM pathway (85%) and the ED pathway (15%). Cell extracts contained glucose-6-phosphate dehydrogenase and 2-keto-3-deoxy-6-phosphogluconate aldolase, key enzymes of the conventional phosphorylated ED pathway, and, as reported previously, all enzymes of the conventional EM pathway. In conclusion, glucose was degraded by hyperthermophilic archaea to pyruvate either via modified EM pathways with different types of hexose kinases and GAP-oxidizing enzymes, by the nonphosphorylated ED pathway, or by a combination of both pathways. In contrast, glucose catabolism in the hyperthermophilic (eu)bacterium Thermotoga involves the conventional forms of the EM and ED pathways. The data are in accordance with various previous reports.