Pathfinder cells provide a novel therapeutic intervention for acute kidney injury

Pathfinder cells (PCs) are a novel class of adult-derived cells that facilitate functional repair of host tissue. We used rat PCs to demonstrate that they enable the functional mitigation of ischemia reperfusion (I/R) injury in a mouse model of renal damage. Female C57BL/6 mice were subjected to 30 min of renal ischemia and treated with intravenous (i.v.) injection of saline (control) or male rat pancreas-derived PCs in blinded experimentation. Kidney function was assessed 14 days after treatment by measuring serum creatinine (SC) levels. Kidney tissue was assessed by immunohistochemistry (IHC) for markers of cellular damage, proliferation, and senescence (TUNEL, Ki67, p16ink4a, p21). Fluorescence in situ hybridization (FISH) was performed to determine the presence of any rat (i.e., pathfinder) cells in the mouse tissue. PC-treated animals demonstrated superior renal function at day 14 post-I/R, in comparison to saline-treated controls, as measured by SC levels (0.13 mg/dL vs. 0.23 mg/dL, p<0.001). PC-treated kidney tissue expressed significantly lower levels of p16ink4a in comparison to the control group (p=0.009). FISH analysis demonstrated that the overwhelming majority of repaired kidney tissue was mouse in origin. Rat PCs were only detected at a frequency of 0.02%. These data confirm that PCs have the ability to mitigate functional damage to kidney tissue following I/R injury. Kidneys of PC-treated animals showed evidence of improved function and reduced expression of damage markers. The PCs appear to act in a paracrine fashion, stimulating the host tissue to recover functionally, rather than by differentiating into renal cells. This study demonstrates that pancreatic-derived PCs from the adult rat can enable functional repair of renal damage in mice. It validates the use of PCs to regenerate damaged tissues and also offers a novel therapeutic intervention for repair of solid organ damage in situ

A Minimal Model of Signaling Network Elucidates Cell-to-Cell Stochastic Variability in Apoptosis

Signaling networks are designed to sense an environmental stimulus and adapt to it. We propose and study a minimal model of signaling network that can sense and respond to external stimuli of varying strength in an adaptive manner. The structure of this minimal network is derived based on some simple assumptions on its differential response to external stimuli. We employ stochastic differential equations and probability distributions obtained from stochastic simulations to characterize differential signaling response in our minimal network model. We show that the proposed minimal signaling network displays two distinct types of response as the strength of the stimulus is decreased. The signaling network has a deterministic part that undergoes rapid activation by a strong stimulus in which case cell-to-cell fluctuations can be ignored. As the strength of the stimulus decreases, the stochastic part of the network begins dominating the signaling response where slow activation is observed with characteristic large cell-to-cell stochastic variability. Interestingly, this proposed stochastic signaling network can capture some of the essential signaling behaviors of a complex apoptotic cell death signaling network that has been studied through experiments and large-scale computer simulations. Thus we claim that the proposed signaling network is an appropriate minimal model of apoptosis signaling. Elucidating the fundamental design principles of complex cellular signaling pathways such as apoptosis signaling remains a challenging task. We demonstrate how our proposed minimal model can help elucidate the effect of a specific apoptotic inhibitor Bcl-2 on apoptotic signaling in a cell-type independent manner. We also discuss the implications of our study in elucidating the adaptive strategy of cell death signaling pathways.Comment: 9 pages, 6 figure

A powerful intervention: general practitioners' use of sickness certification in depression

<b>Background</b> Depression is frequently cited as the reason for sickness absence, and it is estimated that sickness certificates are issued in one third of consultations for depression. Previous research has considered GP views of sickness certification but not specifically in relation to depression. This study aimed to explore GPs views of sickness certification in relation to depression.<p></p> <b>Methods</b> A purposive sample of GP practices across Scotland was selected to reflect variations in levels of incapacity claimants and antidepressant prescribing. Qualitative interviews were carried out between 2008 and 2009.<p></p> <b>Results</b> A total of 30 GPs were interviewed. A number of common themes emerged including the perceived importance of GP advocacy on behalf of their patients, the tensions between stakeholders involved in the sickness certification system, the need to respond flexibly to patients who present with depression and the therapeutic nature of time away from work as well as the benefits of work. GPs reported that most patients with depression returned to work after a short period of absence and that it was often difficult to predict which patients would struggle to return to work.<p></p> <b>Conclusions</b> GPs reported that dealing with sickness certification and depression presents distinct challenges. Sickness certificates are often viewed as powerful interventions, the effectiveness of time away from work for those with depression should be subject to robust enquiry

Large head metal-on-metal cementless total hip arthroplasty versus 28mm metal-on-polyethylene cementless total hip arthroplasty: design of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Osteoarthritis of the hip is successfully treated by total hip arthroplasty with metal-on-polyethylene articulation. Polyethylene wear debris can however lead to osteolysis, aseptic loosening and failure of the implant. Large head metal-on-metal total hip arthroplasty may overcome polyethylene wear induced prosthetic failure, but can increase systemic cobalt and chromium ion concentrations. The objective of this study is to compare two cementless total hip arthroplasties: a conventional 28 mm metal-on-polyethylene articulation and a large head metal-on-metal articulation. We hypothesize that the latter arthroplasties show less bone density loss and higher serum metal ion concentrations. We expect equal functional scores, greater range of motion, fewer dislocations, fewer periprosthetic radiolucencies and increased prosthetic survival with the metal-on-metal articulation.</p> <p>Methods</p> <p>A randomized controlled trial will be conducted. Patients to be included suffer from non-inflammatory degenerative joint disease of the hip, are aged between 18 and 80 and are admitted for primary cementless unilateral total hip arthroplasty. Patients in the metal-on-metal group will receive a cementless titanium alloy acetabular component with a cobalt-chromium liner and a cobalt-chromium femoral head varying from 38 to 60 mm. Patients in the metal-on-polyethylene group will receive a cementless titanium alloy acetabular component with a polyethylene liner and a 28 mm cobalt-chromium femoral head. We will assess acetabular bone mineral density by dual energy x-ray absorptiometry (DEXA), serum ion concentrations of cobalt, chromium and titanium, self reported functional status (Oxford hip score), physician reported functional status and range of motion (Harris hip score), number of dislocations and prosthetic survival. Measurements will take place preoperatively, perioperatively, and postoperatively (6 weeks, 1 year, 5 years and 10 years).</p> <p>Discussion</p> <p>Superior results of large head metal-on-metal total hip arthroplasty over conventional hip arthroplasty have been put forward by experts, case series and the industry, but to our knowledge there is no randomized controlled evidence.</p> <p>Conclusion</p> <p>This randomized controlled study has been designed to test whether large head metal-on-metal cementless total hip arthroplasty leads to less periprosthetic bone density loss and higher serum metal ion concentrations compared to 28 mm metal-on-polyethylene cementless total hip arthroplasty.</p> <p>Trial registration</p> <p>Netherlands Trial Registry NTR1399</p

Large stocks of peatland carbon and nitrogen are vulnerable to permafrost thaw

This is the final version. Available on open access from the National Academy of Sciences via the DOI in this recordData Availability. The results and peat core data are summarized in Datasets S1–S6. Maps of predicted peatland extent, peat depth, and peat C and N storage (10-km pixels) are archived and freely available for download at https://bolin.su.se/data/hugelius-2020Northern peatlands have accumulated large stocks of organic carbon (C) and nitrogen (N), but their spatial distribution and vulnerability to climate warming remain uncertain. Here, we used machine-learning techniques with extensive peat core data (n > 7,000) to create observation-based maps of northern peatland C and N stocks, and to assess their response to warming and permafrost thaw. We estimate that northern peatlands cover 3.7 ± 0.5 million km2 and store 415 ± 150 Pg C and 10 ± 7 Pg N. Nearly half of the peatland area and peat C stocks are permafrost affected. Using modeled global warming stabilization scenarios (from 1.5 to 6 °C warming), we project that the current sink of atmospheric C (0.10 ± 0.02 Pg C⋅y-1) in northern peatlands will shift to a C source as 0.8 to 1.9 million km2 of permafrost-affected peatlands thaw. The projected thaw would cause peatland greenhouse gas emissions equal to ∼1% of anthropogenic radiative forcing in this century. The main forcing is from methane emissions (0.7 to 3 Pg cumulative CH4-C) with smaller carbon dioxide forcing (1 to 2 Pg CO2-C) and minor nitrous oxide losses. We project that initial CO2-C losses reverse after ∼200 y, as warming strengthens peatland C-sinks. We project substantial, but highly uncertain, additional losses of peat into fluvial systems of 10 to 30 Pg C and 0.4 to 0.9 Pg N. The combined gaseous and fluvial peatland C loss estimated here adds 30 to 50% onto previous estimates of permafrost-thaw C losses, with southern permafrost regions being the most vulnerable.Swedish Research CouncilEuropean UnionEuropean Union Horizon 2020Gordon and Betty and Gordon Moore FoundationNatural Environment Research Council (NERC)National Science FoundationNational Natural Science Foundation of Chin

Exciton Condensation and Perfect Coulomb Drag

Coulomb drag is a process whereby the repulsive interactions between electrons in spatially separated conductors enable a current flowing in one of the conductors to induce a voltage drop in the other. If the second conductor is part of a closed circuit, a net current will flow in that circuit. The drag current is typically much smaller than the drive current owing to the heavy screening of the Coulomb interaction. There are, however, rare situations in which strong electronic correlations exist between the two conductors. For example, bilayer two-dimensional electron systems can support an exciton condensate consisting of electrons in one layer tightly bound to holes in the other. One thus expects "perfect" drag; a transport current of electrons driven through one layer is accompanied by an equal one of holes in the other. (The electrical currents are therefore opposite in sign.) Here we demonstrate just this effect, taking care to ensure that the electron-hole pairs dominate the transport and that tunneling of charge between the layers is negligible.Comment: 12 pages, 4 figure

CuInS2 Quantum Dot and Polydimethylsiloxane Nanocomposites for All-Optical Ultrasound and Photoacoustic Imaging

Dual-modality imaging employing complementary modalities, such as all-optical ultrasound and photoacoustic imaging, is emerging as a well-suited technique for guiding minimally invasive surgical procedures. Quantum dots are a promising material for use in these dual-modality imaging devices as they can provide wavelength-selective optical absorption. The first quantum dot nanocomposite engineered for co-registered laser-generated ultrasound and photoacoustic imaging is presented. The nanocomposites developed, comprising CuInS2 quantum dots and medical-grade polydimethylsiloxane (CIS-PDMS), are applied onto the distal ends of miniature optical fibers. The films exhibit wavelength-selective optical properties, with high optical absorption (> 90%) at 532 nm for ultrasound generation, and low optical absorption (< 5%) at near-infrared wavelengths greater than 700 nm. Under pulsed laser irradiation, the CIS-PDMS films generate ultrasound with pressures exceeding 3.5 MPa, with a corresponding bandwidth of 18 MHz. An ultrasound transducer is fabricated by pairing the coated optical fiber with a Fabry–Pérot (FP) fiber optic sensor. The wavelength-selective nature of the film is exploited to enable co-registered all-optical ultrasound and photoacoustic imaging of an ink-filled tube phantom. This work demonstrates the potential for quantum dots as wavelength-selective absorbers for all-optical ultrasound generation

The inflammatory microenvironment in colorectal neoplasia

Peer reviewedPublisher PD

The development and characterisation of porphyrin isothiocyanate–monoclonal antibody conjugates for photoimmunotherapy

A promising approach to increase the specificity of photosensitisers used in photodynamic therapy has been through conjugation to monoclonal antibodies (MAb) directed against tumour-associated antigens. Many of the conjugations performed to date have relied on the activated ester method, which can lead to impure conjugate preparations and antibody crosslinking. Here, we report the development of photosensitiser–MAb conjugates utilising two porphyrin isothiocyanates. The presence of a single reactive isothiocyanate allowed facile conjugation to MAb FSP 77 and 17.1A directed against internalising antigens, and MAb 35A7 that binds to a non-internalising antigen. The photosensitiser–MAb conjugates substituted with 1–3 mol of photosensitiser were characterised in vitro. No appreciable loss of immunoreactivity was observed and binding specificity was comparable to that of the unconjugated MAb. Substitution with photosensitiser had a minimal effect on antibody biodistribution in vivo for the majority of the conjugates, although a decreased serum half-life was observed using a cationic photosensitiser at the higher loading ratios. Tumour-to-normal tissue ratios as high as 33.5 were observed using MAb 35A7 conjugates. The internalising conjugate showed a higher level of phototoxicity as compared with the non-internalising reagent, using a cell line engineered to express both target antigens. These data demonstrate the applicability of the isothiocyanate group for the development of high-quality conjugates, and the use of internalising MAb to significantly increase the photodynamic efficiency of conjugates during photoimmunotherapy

Optimized DNA isolation from marine sponges for natural sampler DNA metabarcoding

Marine sponges have recently been recognized as natural samplers of environmental DNA (eDNA) due to their effective water filtration and their ubiquitous, sessile, and regenerative nature. However, laboratory workflows for metabarcoding of sponge tissue have not been optimized to ensure that these natural samplers achieve their full potential for community survey. We used a phased approach to investigate the influence of DNA isolation procedures on the biodiversity information recovered from sponges. In Phase 1, we compared three treatments of residual ethanol preservative in sponge tissue alongside five DNA extraction protocols. The results of Phase 1 informed which ethanol treatment and DNA extraction protocol should be used in Phase 2, where we assessed the effect of starting tissue mass on extraction success and whether homogenization of sponge tissue is required. Phase 1 results indicated that ethanol preservative may contain unique and/or additional biodiversity information to that present in sponge tissue, but blotting tissue dry generally recovered more taxa and generated more sequence reads from the wild sponge species. Tissue extraction protocols performed best in terms of DNA concentration, taxon richness, and proportional read counts, but the non-commercial tissue protocol was selected for Phase 2 due to cost-efficiency and greater recovery of target taxa. In Phase 2 overall, we found that homogenization may not be required for sponge tissue and more starting material does not necessarily improve taxon detection. These results combined provide an optimized DNA isolation procedure for sponges to enhance marine biodiversity assessment using natural sampler DNA metabarcoding