Restoration of linear disturbances from oil-and-gas exploration in boreal landscapes: How can network models help?

In western Canada, decades of oil-and-gas exploration have fragmented boreal landscapes with a dense network of linear forest disturbances (seismic lines). These seismic lines are implicated in the decline in wildlife populations that are adapted to function in unfragmented forest landscapes. In particular, anthropogenic disturbances have led to a decline of woodland caribou populations due to increasing predator access to core caribou habitat. Restoration of seismic lines aims to reduce the landscape fragmentation and stop the decline of caribou populations. However, planning restoration in complex landscapes can be challenging because it must account for a multitude of diverse aspects. To assist with restoration planning, we present a spatial network optimization approach that selects restoration locations in a fragmented landscape while addressing key environmental and logistical constraints. We applied the model to develop restoration scenarios in the Redrock-Prairie Creek caribou range in northwestern Alberta, Canada, which includes a combination of caribou habitat and active oil-and-gas and timber extraction areas. Our study applies network optimization at two distinct scales to address both the broad-scale restoration policy planning and project-level constraints at the level of individual forest sites. We first delineated a contiguous set of coarse-scale regions where restoration is most cost-effective and used this solution to solve a fine-scale network optimization model that addresses environmental and logistical planning constraints at the level of forest patches. Our two-tiered approach helps address the challenges of fine-scale spatial optimization of restoration activities. An additional coarse-scale optimization step finds a feasible starting solution for the fine-scale restoration problem, which serves to reduce the time to find an optimal solution. The added coarse-scale spatial constraints also make the fine-scale restoration solution align with the coarse-scale landscape features, which helps address the broad-scale restoration policies. The approach is generalizable and applicable to assist restoration planning in other regions fragmented by oil-and-gas activities.

Origin and functional heterogeneity of fibroblasts.

The inherent plasticity and resiliency of fibroblasts make this cell type a conventional tool for basic research. But where do they come from, are all fibroblasts the same, and how do they function in disease? The first fibroblast lineages in mammalian development emerge from the ooze of primary mesenchyme during gastrulation. They are cells that efficiently create and negotiate the extracellular matrix of the mesoderm in order to migrate and meet their developmental fate. Mature fibroblasts in epithelial tissues live in the interstitial spaces between basement membranes that spatially delimit complex organ structures. While the function of resident fibroblasts in healthy tissues is largely conjecture, the accumulation of fibroblasts in pathologic lesions offers insight into biologic mechanisms that control their function; fibroblasts are poised to coordinate fibrogenesis in tissue injury, neoplasia, and aging. Here, we examine the developmental origin and plasticity of fibroblasts, their molecular and functional definitions, the epigenetic control underlying their identity and activation, and the evolution of their immune regulatory functions. These topics are reviewed through the lens of fate mapping using genetically engineered mouse models and from the perspective of single-cell RNA sequencing. Recent observations suggest dynamic and heterogeneous functions for fibroblasts that underscore their complex molecular signatures and utility in injured tissues.

Quantifying fear effects on prey demography in nature.

In recent years, it has been argued that the effect of predator fear exacts a greater demographic toll on prey populations than the direct killing of prey. However, efforts to quantify the effects of fear have primarily relied on experiments that replace predators with predator cues. Interpretation of these experiments must consider two important caveats: (1) the magnitude of experimenter-induced predator cues may not be realistically comparable to those of the prey's natural sensory environment, and (2) given functional predators are removed from the treatments, the fear effect is measured in the absence of any consumptive effects, a situation which never occurs in nature. We contend that demographic consequences of fear in natural populations may have been overestimated because the intensity of predator cues applied by experimenters in the majority of studies has been unnaturally high, in some instances rarely occurring in nature without consumption. Furthermore, the removal of consumption from the treatments creates the potential situation that individual prey in poor condition (those most likely to contribute strongly to the observed fear effects via starvation or reduced reproductive output) may have been consumed by predators in nature prior to the expression of fear effects, thus confounding consumptive and fear effects. Here, we describe an alternative treatment design that does not utilize predator cues, and in so doing, better quantifies the demographic effect of fear on wild populations. This treatment substitutes the traditional cue experiment where consumptive effects are eliminated and fear is simulated with a design where fear is removed and consumptive effects are simulated through the experimental removal of prey. Comparison to a natural population would give a more robust estimate of the effect of fear in the presence of consumption on the demographic variable of interest. This approach represents a critical advance in quantifying the mechanistic pathways through which predation structures ecological communities. Discussing the merits of both treatments will motivate researchers to go beyond simply describing the existence of fear effects and focus on testing their true magnitude in wild populations and natural communities.

Heart repair by reprogramming non-myocytes with cardiac transcription factors.

The adult mammalian heart possesses little regenerative potential following injury. Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodelling and susceptibility to arrhythmias. Cardiac fibroblasts account for a majority of cells in the heart and represent a potential cellular source for restoration of cardiac function following injury through phenotypic reprogramming to a myocardial cell fate. Here we show that four transcription factors, GATA4, HAND2, MEF2C and TBX5, can cooperatively reprogram adult mouse tail-tip and cardiac fibroblasts into beating cardiac-like myocytes in vitro. Forced expression of these factors in dividing non-cardiomyocytes in mice reprograms these cells into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodelling following myocardial infarction. Our results suggest a strategy for cardiac repair through reprogramming fibroblasts resident in the heart with cardiogenic transcription factors or other molecules.

Prevalence of chronic kidney disease in diabetic adult out-patients in Tanzania.

Despite the increasing number of patients with Diabetes Mellitus in sub-Saharan Africa, the magnitude of chronic kidney disease among diabetics has not been well established. A study done by Janmohamed et al. found chronic kidney disease in 83.7 % of diabetics which is relatively higher than the prevalence reported elsewhere. However this study was conducted in schistosoma endemic area along the shores of Lake Victoria. Schistosomiasis has been reported to cause a range of renal diseases. Interpretation of these findings should therefore take into account the possibility of schistosomiasis as a possible confounder.

Endothelial-to-mesenchymal transition contributes to cardiac fibrosis.

Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-beta1 (TGF-beta1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.

VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization.

Increased numbers of S100A4(+) cells are associated with poor prognosis in patients who have cancer. Although the metastatic capabilities of S100A4(+) cancer cells have been examined, the functional role of S100A4(+) stromal cells in metastasis is largely unknown. To study the contribution of S100A4(+) stromal cells in metastasis, we used transgenic mice that express viral thymidine kinase under control of the S100A4 promoter to specifically ablate S100A4(+) stromal cells. Depletion of S100A4(+) stromal cells significantly reduced metastatic colonization without affecting primary tumor growth. Multiple bone marrow transplantation studies demonstrated that these effects of S100A4(+) stromal cells are attributable to local non-bone marrow-derived S100A4(+) cells, which are likely fibroblasts in this setting. Reduction in metastasis due to the loss of S100A4(+) fibroblasts correlated with a concomitant decrease in the expression of several ECM molecules and growth factors, particularly Tenascin-C and VEGF-A. The functional importance of stromal Tenascin-C and S100A4(+) fibroblast-derived VEGF-A in metastasis was established by examining Tenascin-C null mice and transgenic mice expressing Cre recombinase under control of the S100A4 promoter crossed with mice carrying VEGF-A alleles flanked by loxP sites, which exhibited a significant decrease in metastatic colonization without effects on primary tumor growth. In particular, S100A4(+) fibroblast-derived VEGF-A plays an important role in the establishment of an angiogenic microenvironment at the metastatic site to facilitate colonization, whereas stromal Tenascin-C may provide protection from apoptosis. Our study demonstrates a crucial role for local S100A4(+) fibroblasts in providing the permissive "soil" for metastatic colonization, a challenging step in the metastatic cascade.

Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis.

BACKGROUND: In Goodpasture's disease, circulating autoantibodies bind to the noncollagenous-1 (NC1) domain of type IV collagen in the glomerular basement membrane (GBM). The specificity and molecular architecture of epitopes of tissue-bound autoantibodies are unknown. Alport's post-transplantation nephritis, which is mediated by alloantibodies against the GBM, occurs after kidney transplantation in some patients with Alport's syndrome. We compared the conformations of the antibody epitopes in Goodpasture's disease and Alport's post-transplantation nephritis with the intention of finding clues to the pathogenesis of anti-GBM glomerulonephritis. METHODS: We used an enzyme-linked immunosorbent assay to determine the specificity of circulating autoantibodies and kidney-bound antibodies to NC1 domains. Circulating antibodies were analyzed in 57 patients with Goodpasture's disease, and kidney-bound antibodies were analyzed in 14 patients with Goodpasture's disease and 2 patients with Alport's post-transplantation nephritis. The molecular architecture of key epitope regions was deduced with the use of chimeric molecules and a three-dimensional model of the alpha345NC1 hexamer. RESULTS: In patients with Goodpasture's disease, both autoantibodies to the alpha3NC1 monomer and antibodies to the alpha5NC1 monomer (and fewer to the alpha4NC1 monomer) were bound in the kidneys and lungs, indicating roles for the alpha3NC1 and alpha5NC1 monomers as autoantigens. High antibody titers at diagnosis of anti-GBM disease were associated with ultimate loss of renal function. The antibodies bound to distinct epitopes encompassing region E(A) in the alpha5NC1 monomer and regions E(A) and E(B) in the alpha3NC1 monomer, but they did not bind to the native cross-linked alpha345NC1 hexamer. In contrast, in patients with Alport's post-transplantation nephritis, alloantibodies bound to the E(A) region of the alpha5NC1 subunit in the intact hexamer, and binding decreased on dissociation. CONCLUSIONS: The development of Goodpasture's disease may be considered an autoimmune "conformeropathy" that involves perturbation of the quaternary structure of the alpha345NC1 hexamer, inducing a pathogenic conformational change in the alpha3NC1 and alpha5NC1 subunits, which in turn elicits an autoimmune response. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)

EGFR signaling promotes TGFß-dependent renal fibrosis.

The mechanisms by which angiotensin II (Ang II) promotes renal fibrosis remain incompletely understood. Ang II both stimulates TGFß signaling and activates the EGF receptor (EGFR), but the relative contribution of these pathways to renal fibrogenesis is unknown. Using a murine model with EGFR-deficient proximal tubules, we demonstrate that upstream activation of EGFR-dependent ERK signaling is critical for mediating sustained TGFß expression in renal fibrosis. Persistent activation of the Ang II receptor stimulated ROS-dependent phosphorylation of Src, leading to sustained EGFR-dependent signaling for TGFß expression. Either genetic or pharmacologic inhibition of EGFR significantly decreased TGFß-mediated fibrogenesis. We conclude that TGFß-mediated tissue fibrosis relies on a persistent feed-forward mechanism of EGFR/ERK activation through an unexpected signaling pathway, highlighting EGFR as a potential therapeutic target for modulating tissue fibrogenesis.

The Effectiveness of Student-Led Musculoskeletal and Vascular Ultrasound Workshops at a Single Institution: A Retrospective Survey Analysis.

Introduction Point-of-care ultrasound (POCUS) is a rapidly evolving field of diagnostic medicine as its low cost, portability, and versatility have made handheld ultrasound (US) probes an invaluable tool for many modern physicians. Despite US's benefits as a bedside evaluative tool, many medical schools have not integrated POCUS into their pre-clerkship medical education due to a lack of equipment and faculty. The first objective of our study was to determine whether student tutors (STs) would be effective resources to teach musculoskeletal (MSK) and vascular US to preclinical medical students. The second objective of our study was to determine whether students who previously attended ST-run MSK US workshops perform better in vascular US than those who did not. Methods Six POCUS workshops were led by STs after approval from experienced US faculty. These included US workshops on gastrointestinal structures, forearm structures, joint structures, basic echocardiography, and US-guided IV access. We collected data from two of our six workshops. We developed surveys to gauge the confidence and ability of students to perform US after an MSK workshop and US-guided IV access workshop led by STs. We also measured students' US abilities and collected student feedback after our US-guided IV access workshop. We evaluated students' US competency in US-guided IV access via their ability to correctly position the US probe, angle the needle of insertion, move the probe with the needle, and access the vein based on the accuracy of the movements. We divided student results into two groups: students who previously attended the MSK workshop before attending the US-guided IV access workshop and students who did not attend the MSK workshop before attending the US-guided IV access workshop. We used averages, frequencies, and two-tailed t-tests to analyze the survey responses and US-guided IV access skill assessments. Results Fifty percent of first- and second-year surveyed students "agreed," and 32.4% "strongly agreed" that they felt confident using US after an ST-run MSK workshop. About 29.4% of surveyed students "agreed" and 41.2% "strongly agreed" that they felt comfortable explaining basic US concepts, such as proper probe positioning and echogenicity. The group of students who attended the MSK workshop prior to the peripheral IV workshop scored similarly to the students who did not attend the MSK workshop (14.33±1.03 versus 14.20±0.84 points). Both groups of students had an average of over 94% accuracy in technique, positioning, angling, moving the US probe, and achieving US-guided venous access after being taught by STs. Qualitative surveying noted positive student feedback, such as "Teacher was great at guiding us through the procedure." Survey responses also included suggestions on adding and diversifying equipment, such as "[It would be useful to have a] different type of needle to see the difference on ultrasound." Conclusion Based on the high percentages of accuracy and confidence, we found that STs were effective resources to teach MSK and vascular POCUS and that students who attended previous MSK ST-run US workshops had stronger vascular US ability over time compared to those who did not. Our data support the use of STs as US educational resources, especially in institutions without an existing pre-clerkship US curriculum and limited US resources.

Body fluid dynamics: back to the future.

Pioneering investigations conducted over a half century ago on tonicity, transcapillary fluid exchange, and the distribution of water and solute serve as a foundation for understanding the physiology of body fluid spaces. With passage of time, however, some of these concepts have lost their connectivity to more contemporary information. Here we examine the physical forces determining the compartmentalization of body fluid and its movement across capillary and cell membrane barriers, drawing particular attention to the interstitium operating as a dynamic interface for water and solute distribution rather than as a static reservoir. Newer work now supports an evolving model of body fluid dynamics that integrates exchangeable Na(+) stores and transcapillary dynamics with advances in interstitial matrix biology.

Effect of recommendations from reviewers suggested or excluded by authors.

The Journal of the American Society of Nephrology (JASN) gives authors submitting original research the option of suggesting qualified reviewers or those they wish to exclude. This historical habit often leaves us wondering whether author preferences correlate with reviewer recommendations and whether differences related to reviewer selection affect decisions by editors. In a self-study presented here, we found that author-suggested reviewers, as a group, make more positive recommendations than editor-suggested reviewers (P = 0.01), although the difference disappears when recommendations are compared with those of editor-suggested reviewers of the same manuscript (P = 0.081). The distribution of recommendations by author-excluded reviewers, as a group, did not differ from those by editor-suggested reviewers; however, author-excluded reviewers impart significantly more negative recommendations than other reviewers of the same manuscript (P = 0.029). We further explored whether such differences result from individual reviewer tendencies to give generally more positive or more negative recommendations than editor-suggested reviewers and found no such tendency. Finally, editorial decisions on manuscripts reviewed by author-suggested or author-excluded reviewers do not differ from those decisions on manuscripts assigned but not reviewed by them. JASN's policy of editors making decisions independent from individual reviewer recommendations minimizes the effect of selection bias on publication decisions.

Volume depletion versus dehydration: how understanding the difference can guide therapy.

Although often used interchangeably, dehydration and volume depletion are not synonyms. Dehydration refers to loss of total-body water, producing hypertonicity, which now is the preferred term in lieu of dehydration, whereas volume depletion refers to a deficit in extracellular fluid volume. In particular, hypertonicity implies intracellular volume contraction, whereas volume depletion implies blood volume contraction. Using a case of hyperglycemic hypertonic nonketosis as an example, we examine the changing composition of body fluid spaces to explore the distinction between dehydration and hypertonicity from volume depletion.

Risk of natural disturbances makes future contribution of Canada's forests to the global carbon cycle highly uncertain.

A large carbon sink in northern land surfaces inferred from global carbon cycle inversion models led to concerns during Kyoto Protocol negotiations that countries might be able to avoid efforts to reduce fossil fuel emissions by claiming large sinks in their managed forests. The greenhouse gas balance of Canada's managed forest is strongly affected by naturally occurring fire with high interannual variability in the area burned and by cyclical insect outbreaks. Taking these stochastic future disturbances into account, we used the Carbon Budget Model of the Canadian Forest Sector (CBM-CFS3) to project that the managed forests of Canada could be a source of between 30 and 245 Mt CO(2)e yr(-1) during the first Kyoto Protocol commitment period (2008-2012). The recent transition from sink to source is the result of large insect outbreaks. The wide range in the predicted greenhouse gas balance (215 Mt CO(2)e yr(-1)) is equivalent to nearly 30% of Canada's emissions in 2005. The increasing impact of natural disturbances, the two major insect outbreaks, and the Kyoto Protocol accounting rules all contributed to Canada's decision not to elect forest management. In Canada, future efforts to influence the carbon balance through forest management could be overwhelmed by natural disturbances. Similar circumstances may arise elsewhere if global change increases natural disturbance rates. Future climate mitigation agreements that do not account for and protect against the impacts of natural disturbances, for example, by accounting for forest management benefits relative to baselines, will fail to encourage changes in forest management aimed at mitigating climate change.

Mechanisms of tubulointerstitial fibrosis.

The pathologic paradigm for renal progression is advancing tubulointerstitial fibrosis. Whereas mechanisms underlying fibrogenesis have grown in scope and understanding in recent decades, effective human treatment to directly halt or even reverse fibrosis remains elusive. Here, we examine key features mediating the molecular and cellular basis of tubulointerstitial fibrosis and highlight new insights that may lead to novel therapies. How to prevent chronic kidney disease from progressing to renal failure awaits even deeper biochemical understanding.

Fibroblast expression of an IκB dominant-negative transgene attenuates renal fibrosis.

It is not clear whether interstitial fibroblasts or tubular epithelial cells are primarily responsible for the profibrotic effects of NF-κB activation during renal fibrogenesis. Here, we crossed mice carrying a conditional IκB dominant-negative transgene (IκBdN) with mice transgenic for cell-specific FSP1.Cre (FSP1(+) fibroblasts) or γGT.Cre (proximal tubular epithelia) and challenged all progeny with unilateral ureteral obstruction. We determined NF-κB activation by nuclear localization of phosphorylated p65 ((p)p65) in renal tissues after 7 days. We observed inhibition of NF-κB activation in interstitial cells and tubular epithelia in obstructed kidneys of FSP1.Cre;IκBdN and γGT.Cre;IκBdN mice, respectively, compared with IκBdN controls (P < 0.05). Deposition of extracellular matrix, however, was significantly lower in the obstructed kidneys of FSP1.Cre;IκBdN mice but not in γGT.Cre;IκBdN mice (P < 0.05). In addition, levels of mRNA encoding the profibrotic PAI-1, fibronectin-EIIIA, and type I (α1) procollagen were significantly lower in obstructed kidneys of FSP1.Cre;IκBdN mice compared with γGT.Cre;IκBdN mice (P < 0.05). Taken together, these data support a profibrotic role for fibroblasts, but not proximal tubular epithelial cells, in modulating NF-κB activation during renal fibrogenesis.