Summary Background Women with gestational diabetes are at increased risk of developing type 2 diabetes, but the risk and time of onset have not been fully quantified. We therefore did a comprehensive ...systematic review and meta-analysis to assess the strength of association between these conditions and the effect of factors that might modify the risk. Methods We identified cohort studies in which women who had developed type 2 diabetes after gestational diabetes were followed up between Jan 1, 1960, and Jan 31, 2009, from Embase and Medline. 205 relevant reports were hand searched. We selected 20 studies that included 675 455 women and 10 859 type 2 diabetic events. We calculated and pooled unadjusted relative risks (RRs) with 95% CIs for each study using a random-effects model. Subgroups analysed were the number of cases of type 2 diabetes, ethnic origin, duration of follow-up, maternal age, body-mass index, and diagnostic criteria. Findings Women with gestational diabetes had an increased risk of developing type 2 diabetes compared with those who had a normoglycaemic pregnancy (RR 7·43, 95% CI 4·79–11·51). Although the largest study (659 164 women; 9502 cases of type 2 diabetes) had the largest RR (12·6, 95% CI 12·15–13·19), RRs were generally consistent among the subgroups assessed. Interpretation Increased awareness of the magnitude and timing of the risk of type 2 diabetes after gestational diabetes among patients and clinicians could provide an opportunity to test and use dietary, lifestyle, and pharmacological interventions that might prevent or delay the onset of type 2 diabetes in affected women. Funding None.
Interleukin-35 (IL-35) is an immunosuppressive cytokine composed of Epstein-Barr-virus-induced protein 3 (Ebi3) and IL-12α chain (p35) subunits, yet the forms that IL-35 assume and its role in ...peripheral tolerance remain elusive. We induce CBA-specific, IL-35-producing T regulatory (Treg) cells in TregEbi3WT C57BL/6 reporter mice and identify IL-35 producers by expression of Ebi3TdTom gene reporter plus Ebi3 and p35 proteins. Curiously, both subunits of IL-35 are displayed on the surface of tolerogen-specific Foxp3+ and Foxp3neg (iTr35) T cells. Furthermore, IL-35 producers, although rare, secrete Ebi3 and p35 on extracellular vesicles (EVs) targeting a 25- to 100-fold higher number of T and B lymphocytes, causing them to acquire surface IL-35. This surface IL-35 is absent when EV production is inhibited or if Ebi3 is genetically deleted in Treg cells. The unique ability of EVs to coat bystander lymphocytes with IL-35, promoting exhaustion in, and secondary suppression by, non-Treg cells identifies a novel mechanism of infectious tolerance.
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•IL-35 subunits Ebi3 and p35 are secreted as components of CD81+ EVs•IL-35+ EVs secreted by a small number of Treg cells target a higher number of lymphocytes•EV coating of bystander lymphocytes with IL-35 promotes infectious tolerance
Sullivan et al. show that while many factors and cytokines contribute to primary immunosuppression, EV-associated IL-35 uniquely promotes “infectious” tolerance not only by inducing IL-35 production in non-Treg cells but also by causing an immunosuppressive phenotype in EV-acquiring T and B cells, leading to secondary suppression of immune responses.
During pregnancy, the immune systems of mother and offspring are challenged by their close adjacency to balance tolerance and rejection. After birth the neonate has to continue this balance towards ...its new environment by tolerating commensals while rejecting pathogens and towards its developing tissues to avoid inflammatory damage while overcoming immunosuppression. Our group was the first to link immunosuppressive features of myeloid derived suppressor cells (MDSC) to materno-fetal tolerance, neonatal susceptibility to infection and inflammation control. Here we summarize recent advances in this dynamic field.
Forest trees are exposed to a myriad of single and combined stresses with varying strength and duration throughout their lifetime, and many of the simultaneous and successive stress factors strongly ...interact. While much progress has been achieved in understanding the effects of single stresses on tree performance, multiple interacting stress effects cannot be adequately assessed from combination of single factor analyses. In particular, global change brings about novel combinations of severity and timing of different stresses, the effects of which on tree performance are currently hard to predict. Furthermore, the combinations of stresses commonly sustained by trees change during tree ontogeny. In addition, tree photosynthesis and growth rates decline with increasing tree age and size, while support biomass in roots, stem and branches accumulates and the concentrations of non-structural carbohydrates increase, collectively resulting in an enhancement of non-structural carbon pools. In this review, tree physiological responses to key environmental stress factors and their combinations are analyzed from seedlings to mature trees. The key conclusions of this analysis are that combined stresses can influence survival of large trees even more than chronic exposure to a single predictable stress such as drought. In addition, tree tolerance to many environmental stresses increases throughout the ontogeny as the result of accumulation of non-structural carbon pools, implying major change in sensing, response and acclimation to single and multiple stresses in trees of different size and age.
Background & Aims Reserve intestinal stem cells (rISCs) are quiescent/slowly cycling under homeostatic conditions, allowing for their identification with label-retention assays. rISCs mediate ...epithelial regeneration after tissue damage by converting to actively proliferating stem cells (aISCs) that self renew and demonstrate multipotency, which are defining properties of stem cells. Little is known about the genetic mechanisms that regulate the production and maintenance of rISCs. High expression levels of the transcription factor Sox9 (Sox9high ) are associated with rISCs. This study investigates the role of SOX9 in regulating the rISC state. Methods We used fluorescence-activated cell sorting to isolate cells defined as aISCs ( Lgr5high ) and rISCs ( Sox9high ) from Lgr5EGFP and Sox9EGFP reporter mice. Expression of additional markers associated with active and reserve ISCs were assessed in Lgr5 high and Sox9 high populations by single-cell gene expression analyses. We used label-retention assays to identify whether Sox9high cells were label-retatining cells (LRCs). Lineage-tracing experiments were performed in Sox9 -CreERT2 mice to measure the stem cell capacities and radioresistance of Sox9 -expressing cells. Conditional SOX9 knockout mice and inducible-conditional SOX9 knockout mice were used to determine whether SOX9 was required to maintain LRCs and rISC function. Results Lgr5high and a subset of crypt-based Sox9high cells co-express markers of aISC and rISC ( Lgr5 , Bmi1 , Lrig1 , and Hopx ). LRCs express high levels of Sox9 and are lost in SOX9-knockout mice. SOX9 is required for epithelial regeneration after high-dose irradiation. Crypts from SOX9-knockout mice have increased sensitivity to radiation, compared with control mice, which could not be attributed to impaired cell-cycle arrest or DNA repair. Conclusions SOX9 limits proliferation in LRCs and imparts radiation resistance to rISCs in mice.
•MDSC are induced by biological stress, such as tissue damage and inflammation.•MDSC suppress over-reactive immune response, maintain immunotolerance and homeostasis.•Chronic exposure to inflammation ...bases the transition from protective to harmful MDSC.•In chronic inflammation and neoplastic conditions, MDSC worsen disease.•Understanding the underlying process in the transition may help for therapeutics.
MDSC are a heterogeneous population of immature myeloid cells that are released by biological stress such as tissue damage and inflammation. Conventionally, MDSC are known for their detrimental role in chronic inflammation and neoplastic conditions. However, their intrinsic functions in immunoregulation, wound healing, and angiogenesis are intended to protect from over-reactive immune responses, maintenance of immunotolerance, tissue repair, and homeostasis. Paradoxically, under certain conditions, MDSC can impair protective immune responses and exacerbate the disease. The transition from protective to harmful MDSC is most likely driven by environmental and epigenetic mechanisms induced by prolonged exposure to unresolved inflammatory triggers. Here, we review several examples of the dual impact of MDSC in conditions such as maternal-fetal tolerance, self-antigens immunotolerance, obesity-associated cancer, sepsis and trauma. Moreover, we also highlighted the evidence indicating that MDSC have a role in COVID-19 pathophysiology. Finally, we have summarized the evidence indicating epigenetic mechanisms associated with MDSC function.
Several yeasts, which are eukaryotic microorganisms, have long been used in different industries due to their potential applications, both for fermentation and for the production of specific ...metabolites. Kluyveromyces marxianus is one of the most auspicious nonconventional yeasts, generally isolated from wide-ranging natural habitats such as fermented traditional dairy products, kefir grain, sewage from sugar industries, sisal leaves, and plants. This is a food-grade yeast with various beneficial traits, such as rapid growth rate and thermotolerance that make it appealing for different industrial food and biotechnological applications. K. marxianus is a respiro-fermentative yeast likely to produce energy by either respiration or fermentation pathways. It generates a wide-ranging specific metabolites and could contribute to a variety of different food and biotechnological industries. Although Saccharomyces cerevisiae is the most widely used dominant representative in all aspects, many applications of K. marxianus in biotechnology, food and environment have only started to emerge nowadays; some of the most promising applications are reviewed here. The general physiology of K. marxianus is outlined, and then the different applications are discussed: first, the applications of K. marxianus in biotechnology, and then the recent advances and possible applications in food, feed and environmental industries. Finally, this review provides a discussion of the main challenges and some perspectives for targeted applications of K. marxianus in the modern food technology and applied biotechnology in order to exploit the full potential of this yeast which can be used as a cell factory with great efficiency.
•Kluyveromyces marxianus as emerging yeast for food and biotechnology applications.•Kluyveromyces marxianus as efficient cell factory for valuable metabolites production.•Kluyveromyces marxianus for food waste valorization.•Kluyveromyces marxianus can be used to minimize waste from food and biotechnology industry.
The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply, With a predominant role in innate ...immunity, the liver is enriched with various innate immune cells, among which natural killer （NK） cells play important roles in host defense and in maintaining immune balance, Hepatic NK cells were first described as ＇pit cells＇ in the rat liver in the 1970s, Recent studies of NK cells in mouse and human livers have shown that two distinct NK cell subsets, liver-resident NK cells and conventional NK （cNK） cells, are present in this organ, Here, we review liver NK cell subsets in different species, revisiting rat hepatic pit ceils and highlighting recent progress related to resident NK cells in mouse and human livers, and also discuss the dual roles of NK cells in liver immunity,
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