Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD) worldwide, but its molecular pathogenesis is not well-defined and there are no specific treatments. In humans, there is ...a strong genetic component determining susceptibility to DN. However, specific genes controlling DN susceptibility in humans have not been identified. Here we describe a mouse model, combining type 1 diabetes with activation of the renin-angiotensin system (RAS), which develops robust kidney disease with features resembling human DN: heavy albuminuria, hypertension and glomerulosclerosis. Additionally, there is a powerful effect of genetic background regulating susceptibility to nephropathy; the 129 strain is susceptible to kidney disease, whereas the C57BL/6 strain is resistant. To examine the molecular basis of this differential susceptibility, we analyzed the glomerular transcriptome of young mice early in the course of their disease. We find dramatic differences in regulation of immune and inflammatory pathways, with up-regulation of pro-inflammatory pathways in the susceptible (129) strain and coordinate down-regulation in the resistant (C57BL/6) strain. Many of these pathways are also up-regulated in rat models and in humans with DN. Our studies suggest that genes controlling inflammatory responses, triggered by hyperglycemia and RAS activation, may be critical early determinants of susceptibility to DN.
How the university went global and became the heart of the information age The university is experiencing an unprecedented level of success today, as more universities in more countries educate more ...students in more fields. At the same time, the university has become central to a knowledge society based on the belief that everyone can, through higher education, access universal truths and apply them in the name of progress. This book traces the university's rise over the past hundred years to become the cultural linchpin of contemporary society, revealing how the so-called ivory tower has become profoundly interlinked with almost every area of human endeavor. David John Frank and John Meyer describe how, as the university expanded, student and faculty bodies became larger, more diverse, and more empowered to turn knowledge into action. Their contributions to society underscored the public importance of scholarship, and as the cultural authority of universities grew they increased the scope of their research and teaching interests. As a result, the university has become the bedrock of today's information-based society, an institution that is now implicated in the solution to every conceivable problem. But, as Frank and Meyer also show, the conditions that helped spur the university's recent ascendance are not immutable: eruptions of nationalism, authoritarianism, and illiberalism undercut the university's universalistic and rationalistic premises, and may threaten the centrality of the university itself.
To compare muscle imaging findings in different subtypes of myofibrillar myopathies (MFM) in order to identify characteristic patterns of muscle alterations that may be helpful to separate these ...genetic heterogeneous muscular disorders.
Muscle imaging and clinical findings of 46 patients with MFM were evaluated (19 desminopathy, 12 myotilinopathy, 11 filaminopathy, 1 alphaB-crystallinopathy, and 3 ZASPopathy). The data were collected retrospectively in 43 patients and prospectively in 3 patients.
In patients with desminopathy, the semitendinosus was at least equally affected as the biceps femoris, and the peroneal muscles were never less involved than the tibialis anterior (sensitivity of these imaging criteria to detect desminopathy in our cohort 100%, specificity 95%). In most of the patients with myotilinopathy, the adductor magnus showed more alterations than the gracilis muscle, and the sartorius was at least equally affected as the semitendinosus (sensitivity 90%, specificity 93%). In filaminopathy, the biceps femoris and semitendinosus were at least equally affected as the sartorius muscle, and the medial gastrocnemius was more affected than the lateral gastrocnemius. The semimembranosus mostly showed more alterations than the adductor magnus (sensitivity 88%, specificity 96%). Early adult onset and cardiac involvement was most often associated with desminopathy. In patients with filaminopathy, muscle weakness typically beginning in the 5th decade of life was mostly pronounced proximally, while late adult onset (>50 years) with distal weakness was more often present in myotilinopathy.
Muscle imaging in combination with clinical data may be helpful for separation of distinct myofibrillar myopathy subtypes and in scheduling of genetic analysis.
Future drought is projected to occur under warmer temperature conditions as climate change progresses, referred to here as global-change-type drought, yet quantitative assessments of the triggers and ...potential extent of drought-induced vegetation die-off remain pivotal uncertainties in assessing climate-change impacts. Of particular concern is regional-scale mortality of overstory trees, which rapidly alters ecosystem type, associated ecosystem properties, and land surface conditions for decades. Here, we quantify regional-scale vegetation die-off across southwestern North American woodlands in 2002-2003 in response to drought and associated bark beetle infestations. At an intensively studied site within the region, we quantified that after 15 months of depleted soil water content, >90% of the dominant, overstory tree species (Pinus edulis, a piǫn) died. The die-off was reflected in changes in a remotely sensed index of vegetation greenness (Normalized Difference Vegetation Index), not only at the intensively studied site but also across the region, extending over 12,000 km2 or more; aerial and field surveys confirmed the general extent of the die-off. Notably, the recent drought was warmer than the previous subcontinental drought of the 1950s. The limited, available observations suggest that die-off from the recent drought was more extensive than that from the previous drought, extending into wetter sites within the tree species' distribution. Our results quantify a trigger leading to rapid, drought-induced die-off of overstory woody plants at subcontinental scale and highlight the potential for such die-off to be more severe and extensive for future global-change-type drought under warmer conditions.
Obesity results from chronic energy surplus and excess lipid storage in white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) efficiently burns lipids through adaptive thermogenesis. ...Studying mouse models, we show that cyclooxygenase (COX)-2, a rate-limiting enzyme in prostaglandin (PG) synthesis, is a downstream effector of β-adrenergic signaling in WAT and is required for the induction of BAT in WAT depots. PG shifted the differentiation of defined mesenchymal progenitors toward a brown adipocyte phenotype. Overexpression of COX-2 in WAT induced de novo BAT recruitment in WAT, increased systemic energy expenditure, and protected mice against high-fat diet-induced obesity. Thus, COX-2 appears integral to de novo BAT recruitment, which suggests that the PG pathway regulates systemic energy homeostasis.
Here we studied plasma metabolomic profiles as determinants of progression to end-stage renal disease (ESRD) in patients with type 2 diabetes (T2D). This nested case–control study evaluated 40 cases ...who progressed to ESRD during 8–12 years of follow-up and 40 controls who remained alive without ESRD from the Joslin Kidney Study cohort. Controls were matched with cases for baseline clinical characteristics, although controls had slightly higher eGFR and lower levels of urinary albumin excretion than cases. Plasma metabolites at baseline were measured by mass spectrometry–based global metabolomic profiling. Of the named metabolites in the library, 262 were detected in at least 80% of the study patients. The metabolomic platform recognized 78 metabolites previously reported to be elevated in ESRD (uremic solutes). Sixteen were already elevated in the baseline plasma of our cases years before ESRD developed. Other uremic solutes were either not different or not commonly detectable. Essential amino acids and their derivatives were significantly depleted in the cases, whereas certain amino acid–derived acylcarnitines were increased. All findings remained statistically significant after adjustment for differences between study groups in albumin excretion rate, eGFR, or HbA1c. Uremic solute differences were confirmed by quantitative measurements. Thus, abnormal plasma concentrations of putative uremic solutes and essential amino acids either contribute to progression to ESRD or are a manifestation of an early stage(s) of the disease process that leads to ESRD in T2D.
The uremic solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) are generated by colon bacteria acting on food components that escape absorption in the small bowel. The production of these ...potentially toxic compounds may thus be influenced by diet. This study examined whether production of PCS and IS is different in vegetarians and omnivores.
The production of PCS and IS was assessed by measuring their urinary excretion rates in participants with normal kidney function. Studies were carried out in 15 vegetarians and 11 individuals consuming an unrestricted diet. Participants recorded food intake over 4 days and collected urine over the final 2 days of each of two study periods, which were 1 month apart.
Average PCS excretion was 62% lower (95% confidence interval 95% CI, 15-83) and average IS excretion was 58% lower (95% CI, 39-71) in vegetarians than in participants consuming an unrestricted diet. Food records revealed that lower excretion of PCS and IS in vegetarians was associated with a 69% higher (95% CI, 20-139) fiber intake and a 25% lower (95% CI, 3-42) protein intake. PCS and IS excretion rates varied widely among individual participants and were not closely correlated with each other but tended to remain stable in individual participants over 1 month.
PCS and IS production rates are markedly lower in vegetarians than in individuals consuming an unrestricted diet.
Despite molecular selection, patients (pts) with RAS wildtype mCRC represent a heterogeneous population including diversity in metastatic spread. We investigated metastatic patterns for their ...prognostic and predictive impact on maintenance therapy with 5‐fluorouracil/folinic acid ± panitumumab. The study population was stratified according to (1) number of involved metastatic sites (single vs multiple organ metastasis), liver‐limited disease vs (2) liver metastasis plus one additional site, and (3) vs liver metastasis plus ≥two additional sites. Kaplan‐Meier method and Cox regressions were used to correlate efficacy endpoints. Single organ metastasis was observed in 133 pts (53.6%) with 102 pts (41.1%) presenting with liver‐limited disease, while multiple organ metastases were reported in 114 pts (46.0). Multiple compared to single organ metastases were associated with less favorable PFS (HR 1.48, 95% CI 1.13‐1.93; P = .004) and OS (HR 1.37, 95% CI 0.98‐1.93; P = .068) of maintenance therapy. While metastatic spread involving one additional extrahepatic site was not associated with clearly impaired survival compared to liver‐limited disease, pts with liver metastasis plus ≥two additional sites demonstrated less favorable PFS (HR 1.92, 95% CI 1.30‐2.83; P < .001), and OS (HR 2.38, 95% CI 1.51‐3.76; P < .001) of maintenance therapy. Pmab‐containing maintenance therapy appeared active in both pts with multiple (HR 0.58; 95% CI, 0.39‐0.86; P = .006) as well as to a lesser numerical extent in pts with single organ metastasis (HR 0.83; 95% CI, 0.57‐1.21; P = .332; Interaction P = .183). These data may support clinical decisions when EGFR‐based maintenance therapy is considered.
What's new?
A variety of patterns in metastasis can occur in RAS wildtype metastatic colorectal cancer (mCRC). Heterogeneity in metastatic spread, however, challenges prognostic evaluation for patients with these tumors. Here, the prognostic and therapeutic significance of different metastatic patterns in RAS wildtype mCRC was investigated in patients on maintenance therapy with 5‐fluorouracil/folinic acid, with or without panitumumab. In patients who presented with liver‐limited disease, spread to one additional organ had limited impact on survival. Survival was less favorable for metastasis to multiple organs. Maintenance therapy involving panitumumab had greater effect in RAS wildtype mCRC patients with multiple organ metastasis.
Coral reef organisms are increasingly and simultaneously affected by global and local stressors such as ocean acidification (OA) and reduced light availability. However, knowledge of the interplay ...between OA and light availability is scarce. We exposed 2 calcifying coral reef species (the scleractinian coral Acropora millepora and the green alga Halimeda opuntia) to combinations of ambient and increased pCO₂ (427 and 1073 μatm, respectively), and 2 light intensities (35 and 150 μmol photons m−2 s−1) for 16 d. We evaluated the individual and combined effects of these 2 stressors on weight increase, calcification rates, O₂ fluxes and chlorophyll a content for the species investigated. Weight increase of A. millepora was significantly reduced by OA (48%) and low light intensity (96%) compared to controls. While OA did not affect coral calcification in the light, it decreased calcification in the dark by 155%, leading to dissolution of the skeleton. H. opuntia weight increase was not affected by OA, but decreased (40%) at low light. OA did not affect algae calcification in the light, but decreased calcification in the dark by 164%, leading to dissolution. Low light significantly reduced gross photosynthesis (56 and 57%), net photosynthesis (62 and 60%) and respiration (43 and 48%) of A. millepora and H. opuntia, respectively. In contrast to A. millepora, H. opuntia significantly increased chlorophyll content by 15% over the course of the experiment. No interactive effects of OA and low light intensity were found on any response variable for either organism. However, A. millepora exhibited additive effects of OA and low light, while H. opuntia was only affected by low light. Thus, this study suggests that negative effects of low light and OA are additive on corals, which may have implications for management of river discharge into coastal coral reefs.
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