We measure the velocity dispersion, , and surface density, , of the molecular gas in nearby galaxies from CO spectral line cubes with spatial resolution 45-120 pc, matched to the size of individual ...giant molecular clouds. Combining 11 galaxies from the PHANGS-ALMA survey with four targets from the literature, we characterize ∼30,000 independent sightlines where CO is detected at good significance. and show a strong positive correlation, with the best-fit power-law slope close to the expected value for resolved, self-gravitating clouds. This indicates only a weak variation in the virial parameter vir ∝ 2/ , which is ∼1.5-3.0 for most galaxies. We do, however, observe enormous variation in the internal turbulent pressure Pturb ∝ 2, which spans ∼5 dex across our sample. We find , , and Pturb to be systematically larger in more massive galaxies. The same quantities appear enhanced in the central kiloparsec of strongly barred galaxies relative to their disks. Based on sensitive maps of M31 and M33, the slope of the - relation flattens at 10 M pc−2, leading to high for a given and high apparent vir. This echoes results found in the Milky Way and likely originates from a combination of lower beam-filling factors and a stronger influence of local environment on the dynamical state of molecular gas in the low-density regime.
Lesions associated with monoclonal light and heavy chains display a variety of glomerular, tubular interstitial, and vascular manifestations. While some of the entities are well recognized, including ...light and heavy chain deposition diseases, AL (light chain) and AH (heavy chain) amyloidosis, and light chain ("myeloma") cast nephropathy, other lesions centered on proximal tubules are much less accurately identified, properly diagnosed, and adequately understood in terms of pathogenesis and molecular mechanisms involved. These proximal tubule-centered lesions are typically associated with monoclonal light chains and have not been reported in patients with circulating monoclonal heavy chains.
To determine the incidence of proximal tubulopathies in a series of patients with monoclonal light chain-related renal lesions and characterize them with an emphasis on clinical correlations and elucidation of molecular mechanisms involved in their pathogenesis.
A study of 5410 renal biopsies with careful evaluation of light microscopic, immunofluorescence, and electron microscopic findings was conducted to identify these monoclonal light/heavy chain-related lesions. In selected cases, ultrastructural immunolabeling was performed to better illustrate and understand molecular mechanisms involved or to resolve specific diagnostic difficulties.
In all, 2.5% of the biopsies were diagnosed as demonstrating renal pathology associated with monoclonal light or heavy chains. Of these, approximately 46% were classified as proximal tubule-centered lesions, also referred to as monoclonal light chain-associated proximal tubulopathies. These proximal tubulopathies were divided into 4 groups defined by characteristic immunomorphologic manifestations associated with specific clinical settings.
These are important lesions whose recognition in the different clinical settings is extremely important for patients' clinical management, therapeutic purposes, and prognosis. These entities have been segregated into 4 distinct variants, conceptualized morphologically and clinically. Specific mechanisms involved in their pathogenesis are proposed.
Monoclonal gammopathy of renal significance (MGRS) regroups all renal disorders caused by a monoclonal immunoglobulin (MIg) secreted by a nonmalignant B-cell clone. By definition, patients with MGRS ...do not meet the criteria for overt multiple myeloma/B-cell proliferation, and the hematologic disorder is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). However, MGRS is associated with high morbidity due to the severity of renal and sometimes systemic lesions induced by the MIg. Early recognition is crucial, as suppression of MIg secretion by chemotherapy often improves outcomes. The spectrum of renal diseases in MGRS is wide, including old entities such as AL amyloidosis and newly described lesions, particularly proliferative glomerulonephritis with monoclonal Ig deposits and C3 glomerulopathy with monoclonal gammopathy. Kidney biopsy is indicated in most cases to determine the exact lesion associated with MGRS and evaluate its severity. Diagnosis requires integration of morphologic alterations by light microscopy, immunofluorescence (IF), electron microscopy, and in some cases by IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Complete hematologic workup with serum and urine protein electrophoresis, immunofixation, and serum-free light-chain assay is required. This review addresses the pathologic and clinical features of MGRS lesions, indications of renal biopsy, and a proposed algorithm for the hematologic workup.
ABSTRACT
Feedback from massive stars plays a key role in molecular cloud evolution. After the onset of star formation, the young stellar population is exposed by photoionization, winds, supernovae, ...and radiation pressure from massive stars. Recent observations of nearby galaxies have provided the evolutionary timeline between molecular clouds and exposed young stars, but the duration of the embedded phase of massive star formation is still ill-constrained. We measure how long massive stellar populations remain embedded within their natal cloud, by applying a statistical method to six nearby galaxies at $20{-}100~\mbox{${\rm ~pc}$}$ resolution, using CO, Spitzer 24$\rm \, \mu m$, and H α emission as tracers of molecular clouds, embedded star formation, and exposed star formation, respectively. We find that the embedded phase (with CO and 24$\rm \, \mu m$ emission) lasts for 2−7 Myr and constitutes $17{-}47{{\ \rm per\ cent}}$ of the cloud lifetime. During approximately the first half of this phase, the region is invisible in H α, making it heavily obscured. For the second half of this phase, the region also emits in H α and is partially exposed. Once the cloud has been dispersed by feedback, 24$\rm \, \mu m$ emission no longer traces ongoing star formation, but remains detectable for another 2−9 Myr through the emission from ambient CO-dark gas, tracing star formation that recently ended. The short duration of massive star formation suggests that pre-supernova feedback (photoionization and winds) is important in disrupting molecular clouds. The measured time-scales do not show significant correlations with environmental properties (e.g. metallicity). Future JWST observations will enable these measurements routinely across the nearby galaxy population.
For many years amyloidosis was considered an extremely rare, somewhat mysterious disease. However, in the last 2-3 decades its pathogenesis, particularly that of renal amyloidosis has been carefully ...dissected in the research laboratory using in-vitro and, to a lesser extent, in-vivo models. These have provided a molecular understanding of sequential events that take place in the renal mesangium leading to the formation of amyloid fibrils and eventual extrusion into the mesangial matrix, which itself becomes seriously damaged and, in due time, replaced by the fibrillary material. Amyloid, once considered to be an "inert" substance, has been proven to be involved in crucial biological processes that result in the destruction and eventual replacement of normal renal constituents. This review centers on mechanisms involved in the renal glomerular amyloidosis to understand its pathogenesis.
We estimate the star formation efficiency per gravitational free-fall time, , from observations of nearby galaxies with resolution matched to the typical size of a giant molecular cloud. This ...quantity, , is theoretically important but so far has only been measured for Milky Way clouds or inferred indirectly in a few other galaxies. Using new, high-resolution CO imaging from the Physics at High Angular Resolution in nearby Galaxies-Atacama Large Millimeter Array (PHANGS-ALMA) survey, we estimate the gravitational free-fall time at 60-120 pc resolution, and contrast this with the local molecular gas depletion time in order to estimate . Assuming a constant thickness of the molecular gas layer (H = 100 pc) across the whole sample, the median value of in our sample is 0.7%. We find a mild scale dependence, with higher measured at coarser resolution. Individual galaxies show different values of , with the median ranging from 0.3% to 2.6%. We find the highest in our lowest-mass targets, reflecting both long free-fall times and short depletion times, though we caution that both measurements are subject to biases in low-mass galaxies. We estimate the key systematic uncertainties, and show the dominant uncertainty to be the estimated line-of-sight (LOS) depth through the molecular gas layer and the choice of star formation tracers.
We compare the observed turbulent pressure in molecular gas, Pturb, to the required pressure for the interstellar gas to stay in equilibrium in the gravitational potential of a galaxy, PDE. To do ...this, we combine arcsecond resolution CO data from PHANGS-ALMA with multiwavelength data that trace the atomic gas, stellar structure, and star formation rate (SFR) for 28 nearby star-forming galaxies. We find that Pturb correlates with-but almost always exceeds-the estimated PDE on kiloparsec scales. This indicates that the molecular gas is overpressurized relative to the large-scale environment. We show that this overpressurization can be explained by the clumpy nature of molecular gas; a revised estimate of PDE on cloud scales, which accounts for molecular gas self-gravity, external gravity, and ambient pressure, agrees well with the observed Pturb in galaxy disks. We also find that molecular gas with cloud-scale in our sample is more likely to be self-gravitating, whereas gas at lower pressure it appears more influenced by ambient pressure and/or external gravity. Furthermore, we show that the ratio between Pturb and the observed SFR surface density, , is compatible with stellar feedback-driven momentum injection in most cases, while a subset of the regions may show evidence of turbulence driven by additional sources. The correlation between and kpc-scale PDE in galaxy disks is consistent with the expectation from self-regulated star formation models. Finally, we confirm the empirical correlation between molecular-to-atomic gas ratio and kpc-scale PDE reported in previous works.
In vitro and ex vivo studies have elucidated the step-by-step process whereby some physicochemically abnormal light chains are processed by mesangial cells to form amyloid fibrils. Although crucial ...steps in the cascade of events have been determined, these findings have not been reproduced in vivo. This has led to some doubts as to the significance and clinical application of the information that has been deciphered. Here, we developed an animal model which uses mice injected with amyloidogenic light chains purified from the urine of patients with biopsy-proven, light-chain-associated glomerular amyloidosis which validated in vitro/ex vivo findings. This animal model showed internalization of the light chains utilizing caveolae followed by trafficking to the mature lysosomal compartment where fibrils were formed. This model permits evaluation of mesangial amyloidogenesis for prolonged periods of time, is potentially useful to test maneuvers to modulate events that take place, and can be used to design novel therapeutic interventions.
The present study evaluates the influence of continuous light on phenotypic sex ratios in Chirostoma estor, a temperature sex determination animal model. Relative gene expression levels of 5 day old ...larvae were performed on two early gonad differentiation genes (sox9 and foxl2), two stress axis activation genes (gcr1 and crf) and four reactive oxygen species (ROS) antagonist effector genes (sod2, ucp2, gsr and cat). Two light treatments were applied from fertilization; control (12L:12D) simulated natural photoperiod and a continuous illumination photoperiod. By the end of the trial (12 weeks after hatching), differentiated and normal gonads were clearly identifiable in both treatments by histological observations. Regarding sex ratio, 73% of phenotypic males were found in continuous illumination compared with 40% in controls. Consistently, the sox9 gene (involved in early testis differentiation) showed an over expression in 64% of the individual larvae analysed compared with foxl2 (ovarian differentiation) suggesting a masculinization tendency in continuous illumination. On the other hand, only 36% of individuals showed the same tendency in the control treatment consistent with phenotypic sex ratios found under normal culture conditions. Relative gene expression results did not show significant difference in sod2, ucp2 and gcr1 levels, but cat, gsr and crf showed significantly higher expression levels in the continuous illumination treatment suggesting that both, the stress axis and ROS response mechanisms were activated at this time. This study suggests, a link between continuous light, oxidative stress and environmental sex determination in vertebrates. However, further research is necessary to describe this possible upstream mechanism that may drive some aspects of sexual plasticity in vertebrates.
Our understanding of renal diseases with structured deposits has improved in the last two decades with the development of new diagnostic techniques that also changed the role of ultrastructural ...pathology in diagnostic decision-making. This review article addresses the current role of electron microscopy in the evaluation of structured deposits and discusses the impact of new developments. The diagnosis in a subset of structured deposits, amyloidosis, relies on morphologic and tinctorial characteristics at the light microscopic level. Congo red staining of tissue with demonstrable birefringence upon polarization has been regarded as the mainstay during tissue evaluation; however, there are pitfalls that must be considered, and electron microscopy remains a crucial adjunct investigative tool. Ultrastructurally the amyloid fibrils are unique with their characteristic appearance. They are randomly arranged, rigid, criss-crossing, non-branching, 7-15 nm (0.07-0.15 um) in diameter and of variable length. The morphology of fibrils is very similar in the different types of amyloidosis. By scanning electron microscopy amyloid fibrils appear artfully displayed. Immunofluorescence and immunohistochemical stains can be used to characterize the type of amyloidosis while mass spectroscopy is extremely useful in cases where typing of the amyloid using the above-mentioned techniques is difficult or equivocal.
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