Interstitial Aggregates Research Articles

A Randomized-Controlled Trial Targeting Cognition in Early Alzheimer's Disease by Improving Sleep with Trazodone (REST).

Alzheimer's disease (AD) is a leading cause of mortality and morbidity among aging populations worldwide. Despite arduous research efforts, treatment options for this devastating neurodegenerative disease are limited. Sleep disturbances, through their link to changes in neural excitability and impaired clearance of interstitial abnormal protein aggregates, are a key risk factor for the development of AD. Research also suggests that the neuroprotective effects of sleep are particularly active during slow wave sleep. Given the strong link between sleep disturbance and AD, targeting sleep in the prodromal stages of AD, such as in mild cognitive impairment (MCI), represents a promising avenue for slowing the onset of AD-related cognitive decline. In efforts to improve sleep in older individuals, several pharmacologic approaches have been employed, but many pose safety risks, concern for worsening cognitive function, and fail to effectively target slow wave sleep. Trazodone, a safe and widely used drug in the older adult population, has shown promise in inducing slow wave sleep in older adults, but requires more rigorous research to understand its effects on sleep and cognition in the prodromal stages of AD. In this review, we present the rationale and study design for our randomized, double-bind, placebo-controlled, crossover trial (NCT05282550) investigating the effects of trazodone on sleep and cognition in 100 older adults with amnestic MCI and sleep complaints.

Microvascular inflammation in the absence of human leukocyte antigen-donor-specific antibody and C4d: An orphan category in Banff classification with cytotoxic T and natural killer cell infiltration

Isolated microvascular inflammation (iMVI) without HLA donor-specific antibodies or C4d deposition in peritubular capillaries remains an enigmatic phenotype that cannot be categorized as antibody-mediated rejection (ABMR) in recent Banff classifications. We included 221 kidney transplant recipients with biopsies with ABMR (n = 73), iMVI (n = 32), and normal (n = 116) diagnoses. We compared peripheral blood leukocyte distribution by flow cytometry and inflammatory infiltrates in kidney transplant biopsies among groups. Flow cytometry showed fewer lymphocytes and total, CD4+, and CD8+ peripheral T cells in iMVI compared with ABMR and normal cases. ABMR and iMVI had fewer total natural Killer (NK) cells but more NKG2A+ NK cells. Immunohistochemistry indicated that ABMR and iMVI had greater CD3+ and CD68+ glomerular infiltration than normal biopsies, whereas CD8+ and TIA1+ cells showed only increased iMVI, suggesting they are cytotoxic T cells. Peritubular capillaries displayed more CD3+, CD56+, TIA1+, and CD68+ cells in both ABMR and iMVI. In contrast, iMVI had less plasma cell infiltration in peritubular capillaries and interstitial aggregates than ABMR. iMVI displayed decreased circulating T and NK cells mirrored by T cell and NK cell infiltration in the renal allograft, similar to ABMR. However, the lesser plasma cell infiltration in iMVI may suggest an antibody-independent underlying stimulus.

Combining Multiple Biomarkers to Evaluate the Environmental Stress in Cyprinid Populations

The Vilariça River was restored in order to improve the fish habitat due to the construction of dams. However, due to the pressure that agriculture exerts on water resources, it is crucial to evaluate its consequences on fish health from a histological perspective. The gonad histopathological changes of two cyprinid species were assessed microscopically and evaluated with semi-quantitative analysis. Histopathological changes in the gonad, gill, and liver were used as biomarkers in the determination of the Integrated Biomarker Response (IBR), as well as to evaluate the histopathological scores between seasons. The observation of the gonad histopathological changes showed that interstitial fibrosis and macrophage aggregates were present exclusively in the Summer and more prevalent in males of large size. In addition, the histopathological scores of the three organs were higher in the Summer. In terms of the severity degree, 98% and 68% of the fish showed pronounced and severe histopathological changes in the gill and liver, respectively, while 28% of the fish showed slight histopathological changes in the gonad. The IBR showed higher values in the Summer and in the middle stream and downstream, which is in agreement with the metal concentrations. Thus, this work showed a relationship between the anomalies present in the fish organs and the quality of the water (classified as polluted). Therefore, minimization measures are presented, such as improving the irrigation methods, preserving the vegetation cover; promoting reforestation in degraded and burned areas; and improving the riparian vegetation.

FC 109: Microvascular Inflammation in Kidney Transplant Biopsies in the Absence of HLA-DSA Displays Intense Cytotoxic T-Cell and NK Cell but not Plasma Cell Infiltration

Abstract BACKGROUND AND AIMS Microvascular inflammation (MVI) without evidence of HLA-donor-specific antibodies (HLA-DSA) or C4d+ deposition remains an enigmatic phenotype, which cannot be classified as antibody-mediated rejection (ABMR) according to recent Banff classifications. We aimed to compare peripheral blood lymphocyte (PBL) distribution and infiltrating immune cells in kidney transplant (KT) biopsies presenting MVI (g + ptc ≥ 2) without C4d+ and HLA-DSA, ABMR and normal histology to explore the role of immune cells in these entities. METHODS A total of 221 allograft biopsies with ABMR (n = 73), MVI (n = 32) and normal (n = 116) diagnoses were analysed. RESULTS MVI patients showed a decrease in the absolute number of T-cells compared with ABMR and normal cases (P = 0.020 and P = 0.006) due to a significant decrease of CD4+ T-cells compared to normal cases (P = 0.013) and a reduction of CD8+ T-cells compared with ABMR (P = 0.029). ABMR and MVI presented a lower absolute number of circulating Natural Killer (NK) cells than normal cases. Immunohistochemistry assessment was performed in 22 ABMR, 13 MVI and 16 normal cases. Glomeruli in ABMR and MVI had more T-cells and CD68+ infiltration than normal biopsies, although TIA1+ was only increased in MVI (P < 0.001), suggesting increased T-cell cytotoxic capacity. Peritubular capillaries displayed more circulating T-cells, CD56+ TIA1+ and CD68+ in ABMR and MVI groups. Contrarily, MVI cases showed mild circulating plasma cell infiltration (CD138+) in peritubular capillaries (P = 0.059) and interstitial aggregates (P = 0.024) compared with ABMR (Figure 1). CONCLUSION In conclusion, MVI without HLA-DSA and C4d+ displays decreased circulating T-cell and NK cells, and intense T-cell and NK cell cytotoxic infiltration in the allograft, similar to ABMR. However, the deficiency of plasma cell infiltration in MVI suggests a different underlying stimulus from ABMR.

Myocardial involvement in COVID-19: data from 102 unselected autopsies during the first wave of pandemic

Abstract Background Myocardial involvement in COVID-19 has been described as either coronary artery related ischemic lesions, lymphocyte myocarditis or microangiopathy. Assessment of the link between COVID-19 and the cause of death has been hampered by the limited number of autopsies performed during the pandemics and risk factors associated with the type and extent of myocardial damage remain poorly described. In Russia, the mandatory autopsy approach has been advocated for the cases of suspected COVID-19 related deaths. Purpose To describe the prevalence, extent and risk factors associated with myocardial damage in an unselected cohort of patients deceased with COVID-19. Methods Consecutive patients with PCR-confirmed or suspected COVID-19 who died either in-hospital (clinical autopsy) or out-of-hospital (forensic autopsy) during COVID-19 pandemic underwent post-mortem PCR on pulmonary parenchymal tissue. Tissue PCR-positive cases were referred for histology study of pulmonary and extrapulmonary organ specimens through a central laboratory. Based on the extent of diffuse alveolar damage (DAD), COVID-19 was categorized as either being related to death or a concomitant condition not associated with death. Myocardial involvement was categorized as either (1) coronary artery related myocardial infarction, (2) microangiopathy with interstitial edema and erythrocyte aggregates occluding the capillaries with or without lymphomononuclear infiltration and (3) lymphocyte myocarditis. The presence of myocardial involvement was assessed with regard to age, gender and autopsy-verified significant coronary artery disease (CAD) and diabetes (information available only for the clinical autopsy cohort). Results 102 autopsies were included, of whom 42 were clinical and 60 forensic (age 73±15 years, 50% men; 58% had CAD). Ten patients from the clinical autopsy cohort had diabetes (24%). Deaths were COVID-19 related in 80 patients (78%). Myocardial infarction was noted in 3 (2.9%) patients. Microangiopathy was seen in 45 (44%) and lymphocyte myocarditis in 2 (1.9%) patients, of whom it was the primary cause of death in one. The prevalence of microangiopathy did not differ between patients with and without significant DAD (46% vs 45%, p=0.848). Patients with diabetes were more likely to have microangiopathy with lymphomononuclear infiltration in the myocardium than patients without diabetes (40% vs 3.1%, p=0.008; OR=22, 95% CI 1.63–305, p=0.020 after adjustment for age, gender and CAD) Conclusion Systematically performed autopsies revealed causative association between SARS-CoV2 and death in the vast majority. Myocardial involvement was observed in nearly half of the patients and was not related to the extent of DAD. Myocarditis appears to be a rare finding, though it can be the primary cause of death. Microangiopathy with capillary occlusion and lymphomononuclear infiltration in the myocardium was associated with the history of diabetes. Funding Acknowledgement Type of funding sources: None.

Bone marrow examination of HIV-infected children in HAART era reveals a spectrum of abnormalities: a study from single tertiary care center of North India

Pediatric HIV is a significant contributor to childhood morbidity and mortality. As HIV infects bone marrow CD34-positive progenitor cells, the hematological abnormalities are well-expected. The viral load is much higher in children predisposing them to opportunistic infections and hematopoietic malignancies. The present study aimed to determine the spectrum of hematological abnormalities that may yield clinically useful information in HIV-infected children. This was a retrospective study of 19 HIV-infected children who underwent bone marrow examination. Overall, 20 peripheral blood and bone marrow samples were analyzed for morphological changes in all hematopoietic lineages. Immunohistochemistry was performed on trephine biopsy sections for evaluation of B and T cells and cytomegalovirus inclusions. Anemia was the most common cytopenia (95%), followed by thrombocytopenia (45%) and leukopenia (40%). Myelodysplasia was noted in 70% of cases. Dysmegakaryopoiesis was predominant in 65% of cases, while dyserythropoiesis was noted in 25% of cases. Hemophagocytosis and reactive cellular changes were noted in 20% of cases each. Benign lymphoid aggregates and granulomatous inflammation were observed in 15% and 10% of cases, respectively. Significant myelofibrosis was found in 35% of cases. One case showed infiltration by Burkitt lymphoma. Parvoviral inclusions were identified in 1 case. An interstitial increase and aggregates of CD8 + T cells and reduced CD4 + T cells were noted. CD20 + B cells were normal to mildly increased in the bone marrow. Bone marrow examination provides clinically significant information in pediatric HIV revealing the underlying cause of hematopoietic abnormalities and allows the exclusion of major hematological neoplasms.

An unusual case of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia presenting with intractable seizures and interference with automated testing

Lymphoplasmacytic lymphoma (LPL) is a B cell neoplasm composed of small lymphocytes, plasmacytoid lymphocytes, and plasma cells, which typically involves the bone marrow. Most cases of LPL present with Waldenstrom macroglobulinemia (WM) defined as the presence of monoclonal immunoglobulins of IgM type and LPL in the bone marrow. Herein, we present a case of LPL/WM presenting with intractable refractory seizures. A 71-year-old man with a 5-month history of seizures was brought to the emergency room after being found unresponsive. Automated hematology analysis revealed imprecise counts, wide variation, and multiple error flags. Peripheral smear review showed extracellular pale blue clumps of amorphous material. A marked cryoprecipitate of 7% was detected on a cryoglobulin screen. Serum protein electrophoresis (SPEP) detected a M-protein (1.58 g/dL) in the gamma region. Serum immunofixation revealed an IgM lambda monoclonal protein. A bone marrow biopsy showed hypercellularity with increased lymphocytes forming interstitial aggregates, admixed with plasmacytoid lymphocytes and plasma cells. Immunohistochemically, the lymphoma cells were positive for CD20 and negative for CD3, CD5, CD10, CD23, Cyclin D1 (Bcl-1), and Bcl-6. CD138 highlighted increased plasma cells. Flow cytometric analysis revealed 2.7% B cells with a predominance of lambda light chains, suggestive of a monoclonal B cell population. MYD88 mutational analysis revealed c.794T>C(p.L265P) mutation. A diagnosis of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia was established. The patient underwent plasmapheresis leading to significant improvement in his symptoms. This case highlights a rare, unusual presentation of LPL/WM where the interference in automated testing led to identification of cryoglobulinemia and subsequent diagnosis of LPL/WM.

The Discovery of Few-Layered Graphene Flakes in Paragenetic Association with Other Carbon Nano-sized Mineral Phases

Interstitial fibrous-matted micron-scale aggregates of few-layered graphene nano-flakes, multi-layered carbon nanotubes, fullerenes, and fullerenoids have been found between quartz and potassium feldspar grains of slag-like high temperature and shock-metamorphosed rocks (polymictous sandstones) of the Dzharakuduk area (Kyzyl-Kum Desert, Uzbekistan). This is the first finding of few-layered graphene nano-flakes as well as multi-layered carbon nanotubes (with ~10 A inner diameters) and their assemblages as mineral component of natural rocks. Amount of layers in natural few-layered graphene nano-flakes varied from 19 to 45. Mechanisms of few-layered graphene nano-flakes generation in natural rocks are discussed.

Interstitial eosinophilic infiltration in diabetic nephropathy is indicative of poor prognosis, with no therapy benefit from steroid.

Studies suggested that eosinophils in diabetes might be associated with severity of diabetic nephropathy (DN). In a retrospective study of 102 Chinese patients with biopsy-proven DN, we aimed to evaluate relationships of both blood and renal eosinophils (Eos) to the severity of DN and check whether Eos can serve as an indicator of prognosis as well as the therapeutic effect of steroids. One hundred and two patients diagnosed with DN were enrolled. Demographical and clinical data and histopathological scores were associated. Interstitial eosinophilic aggregates (IEA) were defined as the presence of ≥10 Eos in at least one high-power field. End-stage renal disease was defined as the end point. We observed that log2 (blood eosinophil counts) correlated with neutrophil counts, proteinuria, and tubulointerstitial inflammatory cell infiltration. IEA was observed in 33.3% of the DN patients and was associated with decreased estimated glomerular filtration rate, higher proteinuria, hematuria, higher HbA1c, increased blood eosinophil counts, tubular injury, tubulointerstitial chronicity, and interstitial inflammation. IEA was associated with worse renal prognosis (hazard ratio [HR] 2.424, P = 0.008). Consistently, urine eosinophil cationic protein (ECP) (ng/mgCr) was associated with renal injury and poor renal prognosis (HR 1.173, P = 0.020). Patients with IEA were more likely to be treated with steroid/immunosuppressants (47.1% vs 14.7%, P = 0.001) but did not show renal benefit. It suggested that both blood and renal infiltrated eosinophils were prevalent in DN and associated with severity of DN. IEA in renal pathology showed better fit in correlation with renal prognosis. Treatment with steroid/immunosuppressants showed no significant improvement regarding renal prognosis.

Apatite-glaucony association in the Ediacaran Doushantuo Formation, South China and implications for marine redox conditions

Major phosphogenic events took place in the late Paleoproterozoic and the Ediacaran, both of which followed an episode of atmospheric oxygenation. These apparent coincidences have led to suggestions that the Precambrian phosphorus cycle was partly regulated by oceanic redox conditions, although direct evidence is lacking. In this paper, we report the discovery of glaucony in drill cores from the phosphorite-rich Ediacaran Doushantuo Formation at Weng'an, South China, which provides new insights into redox conditions and geochemical cycles during the deposition and early diagenesis of the lower Doushantuo Formation. The presence of flaser and lenticular bedding in the sandstones suggests deposition in a tidally-influenced shallow water environment. Apatite is present as millimeter-scale flasers in sandstones, but more commonly as intraclastic grains. Glaucony typically occurs as interstitial aggregates cementing and replacing detrital minerals and phosphatic grains, with an upsection decrease in abundance. The Doushantuo glauconies have consistently high K2O (7.5–9.6 wt%). In particular, phosphorite-hosted glaucony has generally higher total iron (TFe2O3) than sandstone-hosted glaucony, consistent with Al3+–Fe3+ substitution in the octahedral site, as supported by Raman peaks slightly shifted towards lower wavenumbers for higher Fe content. A decrease in detrital input probably resulted in limited Al availability during early diagenesis, which in turn led to the waning of glaucony upsection. The phosphate grains do not show any negative Ce anomalies, consistent with precipitation of authigenic apatite in suboxic environments with insignificant preferential remobilisation of Ce during deposition and early diagenesis. REE + Y features show variable diagenetic REE enrichment in phosphorites, but identical concave-down patterns. The wide occurrence of glaucony cement further documents the presence of a generally suboxic early diagenetic environment on the seafloor, which was in active exchange with bottom seawater. Slight fluctuations of redox states in the porewater and bottom water would have promoted the cycling of Fe, enrichment of phosphate and REE, and extensive glaucony authigenesis. Therefore, the glaucony-bearing phosphorites in the Doushantuo Formation are a direct result of Fe-redox driven diagenesis. Apatite-glaucony association likely forms in suboxic environments and is considered as a useful mineralogical proxy for paleoredox conditions on the Precambrian ocean floors.

High pressure melting of eclogites and metasomatism of garnet peridotites from Monte Duria Area (Central Alps, N Italy): A proxy for melt-rock reaction during subduction

In the Monte Duria area (Adula-Cima Lunga unit, Central Alps, N Italy) garnet peridotites occur in direct contact with migmatised orthogneiss (Mt. Duria) and eclogites (Borgo). Both eclogites and ultramafic rocks share a common high pressure (HP) peak at 2.8 GPa and 750 °C and post-peak static equilibration at 0.8–1.0 GPa and 850 °C. Garnet peridotites show abundant amphibole, dolomite, phlogopite and orthopyroxene after olivine, suggesting that they experienced metasomatism by crust-derived agents enriched in SiO2, K2O, CO2 and H2O. Peridotites also display LREE fractionation (LaN/NdN = 2.4) related to LREE-rich amphibole and clinopyroxene grown in equilibrium with garnet, indicating that metasomatism occurred at HP conditions. At Borgo, retrogressed garnet peridotites show low strain domains characterised by garnet compositional layering, cut by a subsequent low-pressure (LP) chlorite foliation, in direct contact with migmatised eclogites. Kfs + Pl + Qz + Cpx interstitial pocket aggregates and Cpx + Kfs thin films around symplectites after omphacite parallel to the Zo + Omp + Grt foliation in the eclogites suggest that they underwent partial melting at HP.The contact between garnet peridotites and eclogites is marked by a tremolitite layer. The same rock also occurs as layers within the peridotite lens, showing a boudinage parallel to the garnet layering of peridotites, flowing in the boudin necks. This clearly indicates that the tremolitite boudins formed when peridotites were in the garnet stability field. Tremolitites also show Phl + Tc + Chl + Tr pseudomorphs after garnet, both crystallised in a static regime postdating the boudins formation, suggesting that they derive from a garnet-bearing precursor. Tremolitites have Mg# > 0.90 and Al2O3 = 2.75 wt% pointing to ultramafic compositions but also show enrichments in SiO2, CaO, and LREE suggesting that they formed after the reaction between the eclogite-derived melt and the garnet peridotite at HP. To test this hypothesis, we performed a thermodynamic modelling at fixed P = 3 GPa and T = 750 °C to model the chemical interaction between the garnet peridotite and the eclogite-derived melt. Our results show that this interaction produces an Opx + Cpx + Grt assemblage plus Amp + Phl, depending on the water activity in the melt, suggesting that tremolitites likely derive from a previous garnet websterite with amphibole and phlogopite.Both peridotites and tremolitites also show a selective enrichment in LILE recorded by amphiboles in the spinel stability field, indicating that a fluid-assisted metasomatic event occurred at LP conditions, leading to the formation of a chlorite foliation post-dating the garnet layering in peridotites, and the retrogression of Grt-websterites in tremolitites.The Monte Duria area is a unique terrane where we can observe syn-deformation eclogite-derived melt interacting with garnet peridotite at HP, proxy of subduction environments.

Biclonal splenic marginal zone lymphoma with T cell-rich background and aggressive transformation to large cell lymphoma

Marginal zone B cell lymphomas (MZL) are biologically heterogeneous, rarely demonstrating biclonality, complex cytogenetic abnormalities, or T cell predominance. We report a case of biclonal splenic MZL, T cell-rich variant with an abnormal karyotype that progressed to large B cell lymphoma. A 74-year-old female presented with pancytopenia, weight loss, fever, and splenomegaly. Microscopically, the spleen revealed an extensive, vaguely nodular lymphoid proliferation, composed of small lymphocytes, majority of which were reactive T cells. B cells were mostly small and < 5% of total lymphocytes. Focal follicular dendritic cell networks were present, but germinal centers were absent. Flow cytometric analysis revealed two distinct CD5 and CD10 negative B cell clones, one kappa positive and one lambda positive. Conventional cytogenetic analysis revealed the following abnormal karyotype: 47,XX,add(7)(q36),del(7)(q22),add(21)(p11.2),+mar[10]/46,XX[10]. Immunoglobulin heavy chain gene rearrangement showed two monoclonal peaks of different magnitude, consistent with biclonality. Overall, these features favored a low-grade splenic MZL. The staging bone marrow biopsy was normocellular with few interstitial lymphoid aggregates, composed of small lymphocytes, consistent with minimal involvement by low-grade B cell lymphoma. The patient improved without adjuvant chemotherapy; however, 12 months later, she developed anemia and lymphocytosis. Subsequent bone marrow biopsy showed extensive involvement by a large B cell lymphoma and complex karyotype with the previously identified abnormalities, as well as additional numerical and structural aberrations, consistent with cytogenetic evolution and biclonal gene rearrangement. These findings were consistent with transformation. This case demonstrates a unique pathological presentation of splenic MZL with disease progression, highlighting the importance of an integrated approach for lymphoma classification and the difficulties in diagnosing such cases.

Visible-light excited red-emitting vacancies at carbon interstitials as indicators of irradiated and annealed Type Ia diamonds

During the last decades many studies have been carried out to investigate how point defects and aggregates respond and evolve in natural Type Ia diamonds as a result of treatments, and a number of underlying mechanisms have been identified and interpreted. However, the analysis of radiation-induced creation/ionization of defects, as well as their migration and aggregation in secondary defect structures, often requires experimental approaches which can hardly constitute a simple-to-use diagnostic tool for the identification of artificially treated diamonds. Here we disclose a novel simple indicator of artificial exposure of Type Ia diamonds to ionizing radiations and subsequent annealing. This indicator consists in narrow photoluminescence lines in the red region, between 681 and 725 nm, we recently found to result from vacancies trapped by interstitial carbon aggregates and platelets. Our results demonstrate that interstitial structures become sites of vacancy trapping – by thermal migration of radiation-induced vacancies – only when diamond undergoes treatments. We give the rigorous validation of the new spectroscopic probe of artificial treatments analysing photoluminescence and infrared absorption spectra of well-known H1b and H1c centres in a hundred samples. Importantly, the method is based on emission lines which do not require neither high photon-energy excitation nor cryogenic temperatures.

Fluorescence in situ hybridization for the diagnosis of NPHP1 deletion–related nephronophthisis on renal biopsy

Nephronophthisis is an autosomal recessive tubulointerstitial nephropathy that is a leading genetic etiology of end-stage renal disease in children and young adults. Approximately 60% of patients with a known genetic etiology of nephronophthisis are due to homozygous deletion of the NPHP1 gene. We identified a total of 45 renal biopsies from young patients with chronic kidney disease of undetermined etiology and analyzed them for the possibility of nephronophthisis due to NPHP1 deletion using interphase fluorescence in situ hybridization and/or polymerase chain reaction. Homozygous NPHP1 deletion was identified in 9 patients (20%). In cases with adequate tissue, both assays were performed and showed 100% agreement. Blinded histopathologic analysis was then performed and identified 6 lesions that were significantly more common in biopsies from patients with NPHP1 deletion-proven nephronophthisis than chronic kidney injury of other known etiologies. Many of the classically described nephronophthisis biopsy lesions such as tubular basement membrane duplication, presence of cysts, and mononuclear interstitial inflammation were not significantly associated with this disease when compared with biopsies from patients with chronic kidney injury due to other etiologies. There were, however, morphologic lesions that were strongly associated with NPHP1 deletion including tubular abnormalities such as diverticulum, florets, and macula densa-like change as well as interstitial Tamm-Horsfall aggregates, periglomerular fibrosis, and the absence of arteriosclerosis. Awareness of the histopathologic pattern of injury in nephronophthisis combined with testing for NPHP1 deletion enables renal pathologists to provide a definitive pathologic and genetic diagnosis in a subset of patients with this disease.

Red emission doublets in diamond from vacancies interacting with interstitial carbon aggregates in tunneling configurations

Carbon vacancies in diamond are emerging as light emitting systems with outstanding properties for photonics and quantum information. The feasibility of these applications is strictly related to specific spectral and kinetic features of vacancy light emissions which, in turn, depend on the environment of the light-emitting sites. Many vacancy variants are known, from the intrinsic one to those perturbed by N and Si atoms. However, no data is available on light emissions of vacancies interacting with interstitial carbon aggregates, despite the intrinsic nature of such systems. Here we report the analysis of two emission doublets at 1.87 and 1.82 eV, and at 1.76 and 1.71 eV. The latter is systematically accompanied by the infrared signature of interstitial carbon platelets at 1365 cm−1 and low-energy sidebands with 8 and 16 meV splitting, tentatively assigned to tunneling modes of the split-interstitial over four equivalent configurations. Energy splitting and photon energies are consistent with vacancies at interstitial carbon structures from previous first principle calculations which find here, for the first time, an experimental confirmation in photoluminescence spectra. The data has potential to open up a new technology by controlling vacancy generation and patterning in diamond via laser writing of oriented interstitial layers.

Scaffold-free high throughput generation of quiescent valvular microtissues

AimsThe major challenge of working with valvular interstitial cells in vitro is the preservation or recovery of their native quiescent state. In this study, a biomimetic approach is used which aims to engineer small volume, high quality valve microtissues, having a potential in regenerative medicine and as a relevant 3D in vitro model to provide insights into valve (patho)biology. Methods and resultsTo form micro-aggregates, porcine valvular interstitial cells were seeded in agarose micro-wells and cultured in medium supplemented with 250μM Ascorbic Acid 2-phosphate for 22days. Histology showed viable aggregates with normal nuclei and without any signs of calcification. Aggregates stained strongly for GAG and collagen I and reticular fibers were present. ECM formation was quantified and showed a significant increase of GAG, elastin and Col I during aggregate culture. Cultivation of VIC in aggregates also promoted mRNA expression of Col I/III/V, elastin, hyaluronan, biglycan, decorin, versican MMP-1/2/3/9 and TIMP-2 compared to monolayer cultured VIC. Phenotype analysis of aggregates showed a significant decrease in α-SMA expression, and an increase in FSP-1 expression at any time point. Furthermore, VIC aggregates did not show a significant difference in OCN, Egr-1, Sox-9 or Runx2 expression. ConclusionIn this study high quality valvular interstitial cell aggregates were generated that are able to produce their own ECM, resembling the native valve composition. The applied and completely cell driven 3D approach overcomes the problems of VIC activation in 2D, by downregulating α-SMA expression and stimulating a homeostatic quiescent VIC state.

Reproducible in vitro model for dystrophic calcification of cardiac valvular interstitial cells: insights into the mechanisms of calcific aortic valvular disease.

Calcific aortic valvular disease (CAVD) is the most prevalent valvular pathology in the United States. Development of a pharmacologic agent to slow, halt, or reverse calcification has proven to be unsuccessful as still much remains unknown about the mechanisms of disease initiation. Although in vitro models of some features of CAVD exist, their utility is limited by the inconsistency of the size and time course of the calcified cell aggregates. In this study, we introduce and verify a highly reproducible in vitro method for studying dystrophic calcification of cardiac valvular interstitial cells, considered to be a key mechanism of clinical CAVD. By utilizing micro-contact printing, we were able to consistently reproduce cell aggregation, myofibroblastic markers, programmed cell death, and calcium accumulation within aggregates of 50-400 μm in diameter on substrates with moduli from 9.6 to 76.8 kPa. This method is highly repeatable, with 70% of aggregates staining positive for Alizarin Red S after one week in culture. Dense mineralized calcium-positive nanoparticles were found within the valvular interstitial cell aggregates as shown by scanning electron microscopy (SEM) and energy dispersive spectrometry (EDS). The area of micro-contact printed aggregates staining positive for caspase 3/7 activity increased from 5.9 ± 0.9% to 12.6 ± 4.5% over one week in culture. Z-VAD-FMK reduced aggregates staining positive for Alizarin Red S by 60%. The state of cell stress is hypothesized to play a role in the disease progression; traction force microscopy indicates high substrate stresses along the aggregate periphery which can be modulated by altering the size of the aggregates and the modulus of the substrate. Micro-contact printing is advantageous over the currently used in vitro model as it allows the independent study of how cytokines, substrate modulus, and pharmacologic agents affect calcification. This controlled method for aggregate creation has the potential to be used as an in vitro assay for the screening of promising therapeutics to mitigate CAVD.

Petrological, geochemical and isotopic characteristics of the Collo ultramafic rocks (NE Algeria)

The ultramafic rocks of the Collo region in northeastern Algeria crop out as “stratified” masses that cut across older metamorphic formations of the Petite Kabylie basement. Based on petrological compositions and mineralogical observations, these rocks are mainly peridotites and serpentinites. The peridotites are identified as lherzolites, but dunites may occur rarely. The lherzolites are composed of olivine, orthopyroxene, clinopyroxene and chromian spinel. Their chemical composition shows high MgO (34.4–37.5 wt%), Cr (0.14–0.27 wt%), Ni (0.14–0.26 wt%) and Co (34–133 ppm) contents and low CaO and Al2O3 concentrations (0.02–2.2 wt% and 0.5 to 2.8 wt%, respectively). The chromite, which represents approximately 1–3% of the rock, is ubiquitous and shows two different generations: primary millimetric euhedral crystals and secondary fine xenomorphic grains and interstitial aggregates. The primary chromites are alumino-ferro-magnesian crystals that show high Al2O3 (25.77%–27.36%) and MgO (10.70%–13.36%). Cr# (100 × Cr/(Al + Cr)) ranges from 45 to 48, and Mg# (100 × Mg/(Mg + Fe2+)) from 49 to 59. The secondary interstitial grains are iron-rich chromites. They show low Al2O3 (4.67%–9.54%) and MgO (4.60%–4.65%). Cr# is relatively high (77–88), whereas Mg# shows relatively low values, ranging from 22 to 25. Primary chromite and whole-rock chemistry show that the Collo ultramafic rocks belong to Alpine-type peridotites that were emplaced within an orogenic setting. The oxygen isotopic composition of both peridotites and chromites is consistent with their derivation from a mantle source (δ18O ranges from +3.0 to +5.9‰). Low δ18O values (<+4.4‰) are recorded in serpentinites and are attributed to the effect of serpentinization processes through high-temperature metasomatic fluids. Magnesite-bearing serpentinites show the lowest δ18O values. These are interpreted as the result of surface water input.

Gold and platinum group minerals in placers of the South Urals: Composition, microinclusions of ore minerals and primary sources

Gold and platinum group minerals from the gold placers of the South Urals are studied in order to identify the metal sources. In placers from the Main Uralian fault zone (MUF), the primary gold contains Ag (up to 29wt.%), Cu (up to 2wt.%) and Hg (up to 4wt.%) and its fineness ranges from 538 to 997‰. Tetra-auricupride and cupriferous gold (up to 20wt.% Cu) are common for the Nizhny Karabash placer of the MUF zone. In the eastern part of the South Urals, the placer gold is mainly characterized by high fineness of 900–1000‰ and low Cu contents (max 1.38wt.%). Most of the placer gold grains consist of the primary domains, which are rimmed by secondary high-fineness gold with diffuse and clear boundaries. The secondary gold also develops along the shear dislocations of primary gold. Gold contains microinclusions of geerite, balkanite, chalcopyrite, Se-bearing galena, sphalerite, pyrite, pyrrhotite, arsenopyrite and hematite.Twenty four (including five unnamed) platinum group minerals (PGMs) were found in 28 placers; those from the Kialim and Maly Iremel placers of the Miass placer zone were studied in details. In the Kialim placer, ruthenium is most abundant PGM, which hosts microinclusions of isoferroplatinum, ferroan platinum, laurite, cupriferous gold, a mineral similar in composition to tolovkite, heazlewoodite and unnamed RhSbS phase. The osmium contains microinclusions of erlichmanite and laurite. The iridium grains hosts various sulfides and arsenides of platinum group elements (PGEs). The inclusion-free PGMs form Ru compositional trend in contrast to Os–Ru trend of the Ir-depleted inclusion-hosted PGMs. The isoferroplatinum from the Maly Iremel placer hosts laurite, rhodarsenite, bowieite, a mineral similar in composition to miassite and unnamed sulfide of Pt (Pt1.11S2.00) and antimonide of Pd ((Pd2.41Rh0.43Fe0.17)3.01(Sb0.91Te0.09)1.00). Ruthenium is a host to isoferroplatinum, PGE sulfides and arsenides, and heazlewoodite. Osmium contains microinclusions of ferroan platinum; iridium is a host to a mineral similar in composition to hongshiite. Three types of PGM intergrowths were identified in the Maly Iremel samples: (1) the intergrowths of platy grains of ruthenium with isoferroplatinum and a mineral similar in composition to tulameenite; (2) the open-latticework intergrowths of platy crystals of ruthenium with interstitial aggregates made up of gold, isoferroplatinum and a mineral similar in composition to xingzhongite and (3) the intergrowths of osmium and irarsite and iridarsenite, which are developed along cleavage of the osmium grains. Nickel sulfides associated with some PGMs contain Ru (11.32wt.%) and Rh (2.21wt.%) in millerite and Ir (31.00wt.%), Ru (5.81wt.%) and Rh (2.87wt.%) in vaesite.The primary metal sources were determined on the basis of the mineral assemblages and composition of minerals, taking into account the nearby mineral deposits and directions of rivers. The rodingite-associated gold, gold-bearing massive sulfide and chromite deposits are major sources of gold and PGMs in placers of the Miass placer zone confined to the MUF structure of the South Urals. In the southern part of this structure, gold was mainly originated from orogenic gold–sulfide deposits associated with volcanic/volcaniclastic rocks and listvenite-associated gold deposits. The placer PGMs were derived from the adjacent ultramafic massifs of ophiolitic origin. The distance between the placers and primary deposits varies from 2 to 5km (up to 20km in the extended valley of the Miass River). Usage of ore microinclusions and associated PGMs in study of placer gold is far more advanced than an ordinary consideration of gold composition alone. This approach allowed us to identify the concrete sources for individual placers and to predict some mineralogical findings in already known primary occurrences.

Apatite at Olympic Dam, South Australia: A petrogenetic tool

The >10,000milliontonne Olympic Dam Cu–Au–U–Ag deposit, (eastern Gawler Craton, South Australia) is one of the largest orebodies in the World. The deposit is hosted within the Olympic Dam Breccia Complex, placed at the centre of, and resulting from multiple brecciation and Fe-metasomatism of the Roxby Downs Granite (RDG). The latter is part of a larger batholith emplaced at ~1.6Ga. Apatite petrography and chemistry were studied in non-mineralised RDG and coeval granitoids and dolerites, as well as in mineralised RDG from deep (>2km) and distal (2.7km to NE) locations. In both latter cases, although the mineralisation corresponds to the same, early chalcopyrite–pyrite–magnetite±hematite stage identified in the outer and deeper zones of the deposit itself, the character of granite alteration differs: sericite–chlorite alteration with all feldspar replaced in the deep location; and red-stained K-feldspar on top of prevailing albitization in the distal location. Close-to end-member fluorapatite is a key accessory mineral in all igneous rocks and a common product of early hydrothermal alteration within mineralised granite. Variations in habit, morphology and textures correlate with chemical trends expressed as evolving Cl/F ratios, and concentrations of REE+Y (hereafter REY), Sr, Mn, S, Si and Na. Magmatic apatite is unzoned in the dolerite but features core to REY-enriched rim zonation in the granitoids. Increases in Cl- and Sr-contents correlate with rock basicity. Calculation of Cl in the vapour phase relative to melt at the apatite saturation temperature for zoned apatite in the RDG shows higher values for grains with inclusion-rich cores associated with mafic enclaves, concordant with assimilation of exotic material during magma crystallisation. Hydrothermal alteration of magmatic apatite is most varied in the dolerite where interaction with fluids is expressed as subtle changes in Cl- versus F- and REY-enrichment, and most importantly, S-enrichment in grains adjacent to crosscutting, carbonate–sulphide-bearing veins. Highly acidic fluids, which not only corroded apatite but also quartz, led to recycling of REY via subsequent crystallisation of discrete REY-bearing species, notably monazite. Hydrothermal apatite often occurs as interstitial aggregates and displays a wider range of textures indicating variability in local growth conditions and/or sustained interaction with evolving hydrothermal fluids. Apatite from the deep mineralisation is richer in Cl whereas increases in ΣREY and S correlate with higher Si in both deep and distal cases. The co-correlation between Na and S in apatite from distal mineralisation ties apatite crystallisation to replacement of albite by sericite+chlorite. The textural and chemical variation of apatite relative to magmatic to hydrothermal transition suggests that the mineral represents a petrogenetic tool to gain insights into mineralising processes at Olympic Dam. Apatite evolution clearly played a key contributing role in the elevated REY-concentrations seen at Olympic Dam. The marked differences in apatite chemistry between mineralised and non-mineralised lithologies show promise for potential application as a tool in mineral exploration, in which apatite chemistry represents a means for outlining spatial position within an alteration envelope, or identifying if a particular alteration system is barren or fertile with respect to Cu–Au mineralisation.