Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine-gingipain inhibitor COR388.

COR388, a small-molecule lysine-gingipain inhibitor, is currently being investigated in a Phase 2/3 clinical trial for Alzheimer's disease (AD) with exploratory endpoints in periodontal disease. Gingipains are produced by two species of bacteria, Porphyromonas gingivalis and Porphyromonas gulae, typically associated with periodontal disease and systemic infections in humans and dogs, respectively. P. gulae infection in dogs is associated with periodontal disease, which provides a physiologically relevant model to investigate the pharmacology of COR388. In the current study, aged dogs with a natural oral infection of P. gulae and periodontal disease were treated with COR388 by oral administration for up to 90 days to assess lysine-gingipain target engagement and reduction of bacterial load and downstream pathology. In a 28-day dose-response study, COR388 inhibited the lysine-gingipain target and reduced P. gulae load in saliva, buccal cells, and gingival crevicular fluid. The lowest effective dose was continued for 90 days and was efficacious in continuous reduction of bacterial load and downstream periodontal disease pathology. In a separate histology study, dog brain tissue showed evidence of P. gulae DNA and neuronal lysine-gingipain, demonstrating that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of P. gingivalis in humans. Together, the pharmacokinetics and pharmacodynamics of COR388 lysine-gingipain inhibition, along with reduction of bacterial load and periodontal disease in naturally occurring P. gulae infection in the dog, support the use of COR388 in targeting lysine-gingipain and eliminating P. gingivalis infection in humans

The Interstellar Medium In Galaxies Seen A Billion Years After The Big Bang

Evolution in the measured rest frame ultraviolet spectral slope and ultraviolet to optical flux ratios indicate a rapid evolution in the dust obscuration of galaxies during the first 3 billion years of cosmic time (z>4). This evolution implies a change in the average interstellar medium properties, but the measurements are systematically uncertain due to untested assumptions, and the inability to measure heavily obscured regions of the galaxies. Previous attempts to directly measure the interstellar medium in normal galaxies at these redshifts have failed for a number of reasons with one notable exception. Here we report measurements of the [CII] gas and dust emission in 9 typical (~1-4L*) star-forming galaxies ~1 billon years after the big bang (z~5-6). We find these galaxies have >12x less thermal emission compared with similar systems ~2 billion years later, and enhanced [CII] emission relative to the far-infrared continuum, confirming a strong evolution in the interstellar medium properties in the early universe. The gas is distributed over scales of 1-8 kpc, and shows diverse dynamics within the sample. These results are consistent with early galaxies having significantly less dust than typical galaxies seen at z<3 and being comparable to local low-metallicity systems.Comment: Submitted to Nature, under review after referee report. 22 pages, 4 figures, 4 Extended Data Figures, 5 Extended Data table

Oral tolerance to cancer can be abrogated by T regulatory cell inhibition

Oral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue – JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups - this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut

Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re‐emerging phenotype is associated with graft function

Islet transplantation is an effective therapy for life‐threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet‐specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty‐eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet‐specific T cell responses was not significantly different over time (pre‐Tx: 59%; 1–6 m posttransplant: 38%; 7–12 m: 44%; 13–24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN‐γ–dominated response in the pretransplant group replaced by IL‐10–dominated response in the 1–6 m posttransplant group, reverting to predominantly IFN‐γ–oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN‐γ and IL‐10 phenotypes, respectively. IL‐10–oriented posttransplant response was associated with relatively low graft function. Recipients within the IL‐10+ cluster had a significant decline in C‐peptide levels in the period preceding the IL‐10 response, but stable graft function following the response. In contrast, an IFN‐γ response was associated with subsequently decreased C‐peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet‐specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function

Study of B -> \rho \pi decays at Belle

This paper describes a study of B meson decays to the pseudoscalar-vector final state \rho\pi using 31.9\times 10^6 B\bar{B} events collected with the Belle detector at KEKB. The branching fractions B(B^+ \to \rho^0\pi^+) = (8.0^{+2.3+0.7}_{-2.0-0.7}) \times 10^{-6} and B(B^0 -> \rho^{+-} \pi^{-+}) = (20.8^{+6.0+2.8}_{-6.3-3.1}) \times 10^{-6} are obtained. In addition, a 90% confidence level upper limit of B(B^0 \to \rho^0\pi^0) < 5.3 \times 10^{-6}is reported.Comment: 14 pages, 3 figures, to be submitted to Phys. Lett.

A new method to quantify and compare the multiple components of fitness-A study case with kelp niche partition by divergent microstage adaptations to Temperature

Point 1 Management of crops, commercialized or protected species, plagues or life-cycle evolution are subjects requiring comparisons among different demographic strategies. The simpler methods fail in relating changes in vital rates with changes in population viability whereas more complex methods lack accuracy by neglecting interactions among vital rates. Point 2 The difference between the fitness (evaluated by the population growth rate.) of two alternative demographies is decomposed into the contributions of the differences between the pair-wised vital rates and their interactions. This is achieved through a full Taylor expansion (i.e. remainder = 0) of the demographic model. The significance of each term is determined by permutation tests under the null hypothesis that all demographies come from the same pool. Point 3 An example is given with periodic demographic matrices of the microscopic haploid phase of two kelp cryptic species observed to partition their niche occupation along the Chilean coast. The method provided clear and synthetic results showing conditional differentiation of reproduction is an important driver for their differences in fitness along the latitudinal temperature gradient. But it also demonstrated that interactions among vital rates cannot be neglected as they compose a significant part of the differences between demographies. Point 4 This method allows researchers to access the effects of multiple effective changes in a life-cycle from only two experiments. Evolutionists can determine with confidence the effective causes for changes in fitness whereas population managers can determine best strategies from simpler experimental designs.CONICYT-FRENCH EMBASSADY Ph.D. gran

Donor insulin use predicts beta‐cell function after islet transplantation

Insulin is routinely used to manage hyperglycaemia in organ donors and during the peri-transplant period in islet transplant recipients. However, it is unknown whether donor insulin use (DIU) predicts beta-cell dysfunction after islet transplantation. We reviewed data from the UK Transplant Registry and the UK Islet Transplant Consortium; all first-time transplants during 2008-2016 were included. Linear regression models determined associations between DIU, median and coefficient of variation (CV) peri-transplant glucose levels and 3-month islet graft function. In 91 islet cell transplant recipients, DIU was associated with lower islet function assessed by BETA-2 scores (β [SE] -3.5 [1.5], P = .02), higher 3-month post-transplant HbA1c levels (5.4 [2.6] mmol/mol, P = .04) and lower fasting C-peptide levels (−107.9 [46.1] pmol/l, P = .02). Glucose at 10 512 time points was recorded during the first 5 days peri-transplant: the median (IQR) daily glucose level was 7.9 (7.0-8.9) mmol/L and glucose CV was 28% (21%-35%). Neither median glucose levels nor glucose CV predicted outcomes post-transplantation. Data on DIU predicts beta-cell dysfunction 3 months after islet transplantation and could help improve donor selection and transplant outcomes

Chronic obstructive pulmonary disease and inhaled steroids alter surfactant protein D (SP-D) levels: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Surfactant protein D (SP-D), an innate immune molecule, plays an important protective role during airway inflammation. Deficiency of this molecule induces emphysematous changes in murine lungs, but its significance in human COPD remains unclear.</p> <p>Methods</p> <p>We collected bronchoalveolar lavage fluid from 20 subjects with varying degrees of COPD (8 former smokers and 12 current smokers) and 15 asymptomatic healthy control subjects (5 never smokers, 3 remote former smokers, and 7 current smokers). All subjects underwent a complete medical history and pulmonary function testing. SP-D was measured by Enzyme-Linked ImmunoSorbent Assay. Statistical analysis was performed using nonparametric methods and multivariable linear regression for control of confounding. The effect of corticosteroid treatment on SP-D synthesis was studied <it>in vitro </it>using an established model of isolated type II alveolar epithelial cell culture.</p> <p>Results</p> <p>Among former smokers, those with COPD had significantly lower SP-D levels than healthy subjects (median 502 and 1067 ng/mL, respectively, p = 0.01). In a multivariable linear regression model controlling for age, sex, race, and pack-years of tobacco, COPD was independently associated with lower SP-D levels (model coefficient -539, p = 0.04) and inhaled corticosteroid use was independently associated with higher SP-D levels (398, p = 0.046). To support the hypothesis that corticosteroids increase SP-D production we used type II alveolar epithelial cells isolated from adult rat lungs. These cells responded to dexamethasone treatment by a significant increase of SP-D mRNA (p = 0.041) and protein (p = 0.037) production after 4 days of culture.</p> <p>Conclusion</p> <p>Among former smokers, COPD is associated with lower levels of SP-D and inhaled corticosteroid use is associated with higher levels of SP-D in the lung. Dexamethasone induced SP-D mRNA and protein expression in isolated epithelial cells <it>in vitro</it>. Given the importance of this molecule as a modulator of innate immunity and inflammation in the lung, low levels may play a role in the pathogenesis and/or progression of COPD. Further, we speculate that inhaled steroids may induce SP-D expression and that this mechanism may contribute to their beneficial effects in COPD. Larger, prospective studies are warranted to further elucidate the role of surfactant protein D in modulating pulmonary inflammation and COPD pathogenesis.</p

Using honey to heal diabetic foot ulcers

Diabetic ulcers seem to be arrested in the inflammatory/proliferative stage of the healing process, allowing infection and inflammation to preclude healing. Antibiotic-resistant bacteria have become a major cause of infections, including diabetic foot infections. It is proposed here that the modern developments of an ancient and traditional treatment for wounds, dressing them with honey, provide the solution to the problem of getting diabetic ulcers to move on from the arrested state of healing. Honeys selected to have a high level of antibacterial activity have been shown to be very effective against antibiotic-resistant strains of bacteria in laboratory and clinical studies. The potent anti-inflammatory action of honey is also likely to play an important part in overcoming the impediment to healing that inflammation causes in diabetic ulcers, as is the antioxidant activity of honey. The action of honey in promotion of tissue regeneration through stimulation of angiogenesis and the growth of fibroblasts and epithelial cells, and its insulin-mimetic effect, would also be of benefit in stimulating the healing of diabetic ulcers. The availability of honey-impregnated dressings which conveniently hold honey in place on ulcers has provided a means of rapidly debriding ulcers and removing the bacterial burden so that good healing rates can be achieved with neuropathic ulcers. With ischemic ulcers, where healing cannot occur because of lack of tissue viability, these honey dressings keep the ulcers clean and prevent infection occurring