Dermal fibroblasts (dFBs) resist infection by locally differentiating into adipocytes and producing cathelicidin antimicrobial peptide in response to Staphylococcus aureus (S. aureus). Here, we show ...that neonatal skin was enriched with adipogenic dFBs and immature dermal fat that highly expressed cathelicidin. The pool of adipogenic and antimicrobial dFBs declined after birth, leading to an age-dependent loss of dermal fat and a decrease in adipogenesis and cathelidicin production in response to infection. Transforming growth factor beta (TGF-β), which acted on uncommitted embryonic and adult dFBs and inhibited their adipogenic and antimicrobial function, was identified as a key upstream regulator of this process. Furthermore, inhibition of the TGF-β receptor restored the adipogenic and antimicrobial function of dFBs in culture and increased resistance of adult mice to S. aureus infection. These results provide insight into changes that occur in the skin innate immune system between the perinatal and adult periods of life.
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•Neonatal skin is enriched with immature fat and adipogenic dermal fibroblasts•Dermal immature fat and adipogenic-antimicrobial dFBs are lost with age•TGF-β pathway promotes the age-related adipogenic-to-fibrotic switch of dFBs•Inhibition of TGFBR restores antimicrobial function of dFBs in adult mice
Dermal immature adipocytes fight against Staphylococcus aureus infection by secreting antimicrobial peptides during adipogenesis. Zhang et al. demonstrate that activation of the TGF-β pathway suppresses the adipogenic potential of dermal fibroblasts and therefore leads to an age-dependent loss of antimicrobial protection from dermal fat.
The field of genomics has benefited greatly from its "openness" approach to data sharing. However, with the increasing volume of sequence information being created and stored and the growing number ...of international genomics efforts, the equity of openness is under question. The United Nations Convention of Biodiversity aims to develop and adopt a standard policy on access and benefit-sharing for sequence information across signatory parties. This standardization will have profound implications on genomics research, requiring a new definition of open data sharing. The redefinition of openness is not unwarranted, as its limitations have unintentionally introduced barriers of engagement to some, including Indigenous Peoples. This commentary provides an insight into the key challenges of openness faced by the researchers who aspire to protect and conserve global biodiversity, including Indigenous flora and fauna, and presents immediate, practical solutions that, if implemented, will equip the genomics community with both the diversity and inclusivity required to respectfully protect global biodiversity.
We report the combined use of steady-state fluorescence resonance energy transfer (FRET) experiments and molecular dynamics (MD) simulations to investigate conformational distributions of the prion ...protein (PrP) repeat system. FRET was used for the first time to probe the distance, as a function of temperature and pH, between a donor Trp residue and an acceptor dansyl group attached to the N-terminus in seven model peptides containing one to three repeats of the second decarepeat of PrP from marsupial possum (PHPGGSN
WGQ)
nG, and one and two human PrP consensus octarepeats (PHGGG
WGQ)
nG. In multirepeat peptides, single-Trp mutants were made by replacing other Trp(s) with Phe. As previous work has shown PrP repeats do not adopt a single preferred stable conformation, the FRET values are averages reflecting heterogeneity in the donor-acceptor distances. The
T-dependence of the conformational distributions, and derived average dansyl-Trp distances, were obtained directly from MD simulation of the marsupial dansyl-PHPGGSN
WGQG peptide. The results show excellent agreement between the FRET and MD
T-dependent distances, and demonstrate the remarkable sensitivity and reproducibility of the FRET method in this first-time use for a set of disordered peptides. Based on the results, we propose a model involving cation-
π or
π-
π His-Trp interactions to explain the
T- (5–85°C) and pH- (6.0, 7.2) dependencies on distance, with HW
i,
i
+
4 or WH
i,
i
+
4 separations in sequence being more stable than HW
i,
i
+
6 or WH
i,
i
+
6 separations. The model has peptides adopting loosely folded conformations, with dansyl-Trp distances very much less than estimates for fully extended conformations, for example, ∼16 vs. 33, ∼21 vs. 69, and ∼22 vs. 106
Å for 1–3 decarepeats, and ∼14 vs. 25 and ∼19 vs. 54
Å for 1–2 octarepeats, respectively. The study demonstrates the usefulness of combining FRET with MD, a combination reported only once previously. Initial “mapping” of the conformational distribution of flexible peptides by simulation can assist in designing and interpreting experiments using steady-state intensity methods, and indicating how time-resolved or anisotropy methods might be used.
Aim
We consider the opportunities and challenges comparative phylogeography (CP) faces in the genomic age to determine: (1) how we can maximise the potential of big CP analyses to advance ...biogeographic and macroevolutionary theory; and (2) what we can, and will struggle, to achieve using CP approaches in this era of genomics.
Location
World‐wide.
Taxon
All.
Methods
We review the literature to discuss the future of CP ‐ particularly examining CP insights enabled by genomics that may not be possible for single species and/or few molecular markers. We focus on how geography and species' natural histories interact to yield congruent and incongruent patterns of neutral and adaptive processes in the context of both historical and recent rapid evolution. We also consider how CP genomic data are being stored, accessed, and shared.
Results
With the widespread availability of genomic data, the shift from a single‐ to a multi‐locus perspective is resulting in detailed historical inferences and an improved statistical rigour in phylogeography. However, the time and effort required for collecting co‐distributed species and accruing species‐specific ecological knowledge continue to be limiting factors. Bioinformatic skills and user‐friendly analytical tools, alongside the computational infrastructure required for big data, can also be limiting.
Main conclusions
Over the last ~35 years, there has been much progress in understanding how intraspecific genetic variation is geographically distributed. The next major steps in CP will be to incorporate evolutionary processes and community perspectives to account for patterns and responses among co‐distributed species and across temporal scales, including those related to anthropogenic change. However, the full potential of CP will only be realised if we employ robust study designs within a sound comparative framework. We advocate that phylogeographers adopt such consistent approaches to enhance future comparisons to present‐day findings.
Hemorrhage is the leading cause of preventable death in trauma, and hemorrhage from noncompressible junctional anatomic sites is particularly difficult to control. The current standard is QuikClot ...Combat Gauze packing, which requires 3 min of compression. We have created a novel dressing with calcium carbonate microparticles that can disperse and self-propel upstream against flowing blood. We loaded these microparticles with thrombin and tranexamic acid and tested their efficacy in a swine arterial bleeding model without wound compression. Anesthetized immature female swine received 5 mm femoral arteriotomies to induce severe junctional hemorrhage. Wounds were packed with kaolin-based QuikClot Combat Gauze (KG), propelled thrombin-microparticles with protonated tranexamic acid (PTG), or a non-propelling formulation of the same thrombin-microparticles with non-protonated tranexamic acid (NPTG). Wounds were not compressed after packing. Each animal then received one 15 mL/kg bolus of hydroxyethyl starch solution followed by Lactated Ringer as needed for hypotension (maximum: 100 mL/kg) for up to 3 h. Survival was improved with PTG (3-h survival: 8/8, 100%) compared with KG (3/8, 37.5%) and NPTG (2/8, 25%) (P <0.01). PTG animals maintained lower serum lactate and higher hemoglobin concentrations than NPTG (P <0.05) suggesting PTG decreased severity of subsequent hemorrhagic shock. However, total blood loss, Lactated Ringer infusion volumes, and mean arterial pressures of surviving animals were not different between groups (P >0.05). Thus, in this swine model of junctional arterial hemorrhage, gauze with self-propelled, prothrombotic microparticles improved survival and 2 indicators of hemorrhagic shock when applied without compression, suggesting this capability may enable better treatment of non-compressible junctional wounds.
Background: Hypoglycemia remains a concern for insulin-treated individuals living with diabetes. SSTR2a increases the endogenous glucagon counterregulatory response during hypoglycemia in rodent ...models of diabetes, but its impact on OGT is unclear. We examined the impact of SSTR2a on OGT in a rodent model of T2D maintained on basal insulin therapy.
Methods: High fat fed (HFF), low dose streptozotocin (35 mg/kg) T2D rats received SSTR2a treatment (ZT-01 3 mg/kg) or vehicle (N=8-9/group) immediately before a fasted OGT test (OGTT, 2 g/kg). Glycemia, glucagon and c-peptide levels were measured pre- and post-dose and monitored for 120 minutes.
Results: The OGTT resulted in comparable rises in blood glucose levels in both groups, consistent with an animal model of T2D. Glucagon levels rose within 15 minutes of SSTR2a and glucose administration (120 ± 70 vs 4.8 ± 3, p=0.006) and remained higher than controls for the duration of the OGTT. C-peptide levels also increased from baseline by 116 ± 77% in SSTR2a-treated animals compared to 28.9 ± 70% in controls.
Conclusion: SSTR2a treatment increases glucagon and c-peptide levels following oral glucose ingestion in this rat model of T2D. These preliminary findings suggest that the use of the SSTR2a should not adversely impact glucose control around meals if used as a preventive therapy against insulin-induced hypoglycemia.
Disclosure
N. C. D'souza: None. M. C. Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Indigo Diabetes, Consultant; Lilly Diabetes, Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Novo Nordisk, Sanofi, Stock/Shareholder; Supersapiens, Zucara Therapeutics. N. Aleali: None. D. Shakeri: None. E. G. Hoffman: None. S. C. Atherley: None. S. Champsi: None. M. El-zahed: None. R. Liggins: Employee; Zucara Therapeutics, Stock/Shareholder; Zucara Therapeutics. O. Chan: None.
Funding
GlycoNet (CD-85)
Phyto-oestrogens: where are we now? Bingham, S A; Atkinson, C; Liggins, J ...
British journal of nutrition,
05/1998, Letnik:
79, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Phyto-oestrogens have emerged from their esoteric role in animal husbandry following the hypothesis that the human Western diet is relatively deficient in these substances compared with societies ...where large amounts of plant foods and legumes are eaten. Evidence is beginning to accrue that they may begin to offer protection against a wide range of human conditions, including breast, bowel, prostate and other cancers, cardiovascular disease, brain function, alcohol abuse, osteoporosis and menopausal symptoms. Of the two main classes of these weak oestrogens, the isoflavones are under intensive investigation due to their high levels in soyabean. Like the 'anti-oestrogen' Tamoxifen, these seem to have oestrogenic effects in human subjects in the cardiovascular system and bone. Although previously only available from food, isoflavones are now being marketed in health-food supplements or drinks, and tablets may soon be available over the counter as 'natural' hormone-replacement therapy. In cancer, anti-oestrogenic effects are thought to be important, although genistein especially has been shown to induce wide-ranging anti-cancer effects in cell lines independent of any hormone-related influence. There are few indications of harmful effects at present, although possible proliferative effects have been reported. In infants, the effects of high levels in soya milk formulas are uncertain. The second group, lignans, have been less investigated despite their known antioestrogenic effects and more widespread occurrence in foods. Investigation of the possible benefits of phyto-oestrogens is hampered by lack of analytical standards and, hence, inadequate methods for the measurement of low levels in most foods. This problem may prove to be a major dilemma for regulatory authorities, clinicians and others wishing to advise the general public on whether these compounds really do have the health benefits attributed to them.
A controlled release delivery system for paclitaxel was developed using poly(L-lactic acid) to provide local delivery to the peritoneal cavity. Microspheres were made in 1-40 and 30-120 microm size ...ranges. In an in vitro release study, 30-120 microm microspheres loaded with 10, 20 and 30% paclitaxel exhibited a burst phase of release for 3 days followed by an apparently zero-order phase of release. At all loadings, 20-25% of the original load of paclitaxel was released after 30 days. The effect of microsphere size on retention in the peritoneal cavity was assessed. Control 1-40 microm microspheres were injected intraperitoneally in rats. The rats received either insufflation of the peritoneal cavity using 11 mmHg CO2 or no further treatment. After sacrifice, microspheres with diameters less than 24 microm were observed in the lymphatic system after being cleared from the peritoneal cavity through fenestrations in the diaphragm. Insufflation of the peritoneal cavity had no effect on the size of microspheres that were cleared. Efficacy studies were carried out using 30-120 microm microspheres that were of sufficient size to be retained in the peritoneal cavity. In a model of a tumor cell spill after a cecotomy repair, 100 mg of 30-120 microm microspheres containing 30% paclitaxel were effective in preventing growth of tumors in the peritoneal cavity at both 2 and 6 weeks post-surgery. No gross or histologically evident tumor growth was observed on any peritoneal surfaces or in the surgical wound site. Rats receiving control microspheres all showed tumor cell implantation and growth after 2 weeks.
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