BackgroundDynamic interactions between the host and gastrointestinal microbiota play an important role for local and systemic immune homeostasis. Helminthic parasites modulate the host immune response, resulting in protection against autoimmune disease but also increased susceptibility to pathogen infection. The underlying mechanisms remain largely unknown.ResultsWe showed that the type 2 immune response to enteric Nippostrongylus brasiliensis infection in mice was associated with altered intestinal mucin and AMP expression and shifts in microbiota composition. Most strikingly, infection reduced concentrations of intestinal segmented filamentous bacteria (SFB), known inducers of T helper 17 cells, and IL-17-associated gene expression. Infected mice deficient in IL-13 or STAT6 did not reduce SFB or IL-17, and exogenous IL-25 replicated the effects of parasite infection in wild type mice.ConclusionsOur data show that parasite infection acts through host type 2 immunity to reduce intestinal SFB and expression of IL-17, providing an example of a microbiota-dependent immune modulation by parasites.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-015-0103-8) contains supplementary material, which is available to authorized users.

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f Infection with parasitic nematodes, especially gastrointestinal geohelminths, affects hundreds of millions of people worldwide and thus poses a major risk to global health. The host mechanism of defense against enteric nematode infection remains to be fully understood, but it involves a polarized type 2 immunity leading to alterations in intestinal function that facilitate worm expulsion. We investigated the role of interleukin-25 (IL-25) in host protection against Heligmosomoides polygyrus bakeri infection in mice. Our results showed that Il25 and its receptor subunit, Il17rb, were upregulated during a primary infection and a secondary challenge infection with H. polygyrus bakeri. Genetic deletion of IL-25 (IL-25 ؊/؊ ) led to an attenuated type 2 cytokine response and increased worm fecundity in mice with a primary H. polygyrus bakeri infection. In addition, the full spectrum of the host memory response against a secondary infection with H. polygyrus bakeri was severely impaired in IL-25 ؊/؊ mice, including delayed type 2 cytokine responses, an attenuated functional response of the intestinal smooth muscle and epithelium, diminished intestinal smooth muscle hypertrophy/hyperplasia, and impaired worm expulsion. Furthermore, exogenous administration of IL-25 restored the host protective memory response against H. polygyrus bakeri infection in IL-25 ؊/؊ mice. These data demonstrate that IL-25 is critical for host protective immunity against H. polygyrus bakeri infection, highlighting its potential application as a therapeutic agent against parasitic nematode infection worldwide.A lthough studies using mouse models have advanced our understanding of the molecular and cellular mechanisms underlying host protection against nematode infection, many of the details remain to be fully elucidated. Infection with gastrointestinal nematode parasites induces a polarized Th2 immune response featuring elevated levels of production of interleukin-4 (IL-4), IL-5, and IL-13. IL-4 and IL-13 activate STAT6 signaling pathways, leading to characteristic alterations in intestinal function that facilitate worm expulsion. IL-25, also called IL-17E, is a cytokine member of the IL-17 family that includes IL-17A through IL-17F. Unlike other members of the IL-17 family that are involved in various inflammatory pathologies, IL-25 possesses immune-modulating properties that inhibit Th1/Th17-associated inflammation.It has been observed that intestinal epithelium-derived IL-25 plays a pivotal role in the initiation of the host protective immune cascade against nematode infection. In particular, intestinal epithelial tuft cells produce IL-25 (1, 2) in response to early-stage worm infection, leading to the expansion and activation of type 2 innate lymphoid cells (ILC2), a recently identified noncytotoxic innate lymphoid cell (ILC) family member that has a classic lymphoid cell morphology but that lacks the expression of cell surface markers of other known immune lymphocytes (3, 4). The activated ILC2 then release Th2-associated cytokines IL-5 a...

Background: Bilateral renal agenesis (BRA) is a lethal congenital anomaly caused by the failure of normal development of both kidneys early in embryonic development. Oligohydramnios upon fetal ultrasonography reveals BRA. Although exact causes are not clear, BRA is associated with mutations in many renal development genes. However, molecular diagnostics cannot pick up many clinical cases. Nephronectin (NPNT) may be a candidate protein for widening diagnosis. It is essential in kidney development and knockout of Npnt in mice frequently leads to kidney agenesis or hypoplasia. Methods: A consanguineous Han family experienced three cases of induced abortion in the second trimester of pregnancy due to suspicion of BRA. Whole-exome sequencing-(WES)-:based homozygosity mapping detected underlying genetic factors, and a knock-in mouse model confirmed the renal agenesis phenotype. Results: WES and evaluation of homozygous regions in II-3 and II-4 revealed a pathological homozygous frameshift variant in NPNT (NM_001184690:exon8:c.777dup/p.Lys260*), which leads to a premature stop in the next codon. The truncated NPNT protein exhibited decreased expression, as confirmed in vivo by the overexpression of WT and mutated NPNT. A knock-in mouse model homozygous for the detected Npnt mutation replicated the BRA phenotype. Conclusions: A biallelic loss-of-function NPNT mutation causing an autosomal recessive form of BRA in humans was confirmed by the corresponding phenotype of knock-in mice. Our results identify a novel genetic cause of BRA, revealing a new target for genetic diagnosis, prenatal diagnosis, and preimplantation diagnosis for families with BRA.

BackgroundPancreatic cancer causes tremendous mortality across the globe mainly due to late diagnosis and unavailability of efficient chemotheruptic agents. In the current study the anticancer potential of a plant derived alkaloid, Mahanimbine, was examined against a panel of pancreatic cancer cells.Material/MethodsThe cell proliferation was determined by MTT assay. Annexin V/PI and DAPI staining were performed to detect apoptosis. Cell cycle distribution was investigated by flow cytometery. Cell migration was detected by wound healing assay and protein expression was checked by western blotting.ResultsThe results revealed that Mahanimbine could inhibit the proliferation of the all the pancreatic cancer cells with lower cytoxicity against the normal cells. The IC50 ranged from 3.5 to 64 μM against the pancreatic cancer cell lines. The lowest IC50 of 3.5 μM was observed tor the Capan-2 and SW119 pancreatic cancer cell lines. The anticancer activity of Mahanimbine against the Capan-2 and SW119 cells was found to be due to G0/G1 cell cycle arrest and induction of apoptosis. Mahanimbine prompted apoptosis was also associated with decline in Bcl-2 and enhancement of the Bax expression. Further, it was observed that Mahanimbine could inhibit the AKT/mTOR and STAT3 signalling pathways in the Capan-2 and SW119 pancreatic cancer cells. The effects of the Mahanimbine were also examined on the migration of the Capan-2 and SW119 pancreatic cancer cells. It was found that Mahanimbine could inhibit the motility and migration of both the pancreatic cancer cell lines.ConclusionsWe found that Mahanimbine inhibits the proliferation of pancreatic cancer cells and as such Mahanimbine may prove beneficial in the management of pancreatic cancer.

Objective To determine the effect of mid‐trimester emergency cerclage in women with twin pregnancies with cervical dilation and prolapsed membranes, and to identify risk factors predicting spontaneous preterm birth (sPTB) before 28 weeks, after cerclage. Methods Retrospective analysis of twin gestations with cervical dilation and prolapsed membranes treated with emergency cerclage or expectant management (2015–2020). The primary outcomes were the rate of sPTB before 28 weeks and the gestational latency. Multiple logistic regression analysis was used to determine the factors associated with sPTB before 28 weeks, after cerclage. Results Ninety‐seven women were included, cerclage (n = 58) or no cerclage (n = 39). Cerclage placement was associated with significantly lower incidence of sPTB before 28 weeks of pregnancy (34.5% vs 82.1%) and prolongation of the gestational latency (46.71 ± 27.52 vs 10.95 ± 11.71 days). Positive cervical culture (odds ratio [OR] 10.69, 95% confidence interval [CI] 1.82–62.95), pregnancy duration at diagnosis less than 22 weeks (OR 9.42; 95% CI 1.69–52.69) and cervical dilation at least 4 cm (OR 7.92; 95% CI 1.40–44.71) were found to be independent risk factors for sPTB before 28 weeks, after cerclage. Conclusion Emergency cerclage in women with twin pregnancies with cervical dilation and prolapsed membranes was associated with an overall 40% decrease in sPTB before 28 weeks and a prolongation of latency by 5 weeks. The strongest predictor of sPTB before 28 weeks after cerclage was a positive cervical culture.

Objective: To evaluate the use of tourniquet and forceps to reduce bleeding during surgical treatment of severe placenta accreta spectrum (placenta increta and placenta percreta).Methods: A tourniquet was used in the lower part of the uterus during surgical treatment of severe placenta accreta spectrum. Severe placenta accreta spectrum was classified into two types according to the relative position of the placenta and tourniquet during surgery: upper-tourniquet type, in which the entire placenta was above the tourniquet, and lower-tourniquet type, in which part or all of the placenta was below the tourniquet. The surgical effects of the two types were retrospectively compared. We then added forceps to the lower-tourniquet group to achieve further bleeding reduction. Finally, the surgical effects of the two types were prospectively compared.Results: During the retrospective phase, patients in the lower-tourniquet group experienced more severe symptoms than did patients in the upper-tourniquet group, based on mean intraoperative blood loss (upper-tourniquet group 787.5 ml, lower-tourniquet group 1434.4 ml) intensive care unit admission rate (upper-tourniquet group 1.0%, lower-tourniquet group 33.3%), and length of hospital stay (upper-tourniquet group 10.2d, lower-tourniquet group 12.1d). During the prospective phase, after introduction of the revised surgical method involving forceps (in the lower-tourniquet group), the lower-tourniquet group exhibited improvements in the above indicators (intraoperative average blood loss 722.9 ml, intensive care unit admission rate 4.3%, hospital stays 9.0d). No increase in the rate of complications was observed.Conclusion: The relative positions of the placenta and tourniquet may influence the perioperative risk of severe placenta accreta spectrum. The method using a tourniquet (and forceps if necessary) can improve the surgical effect in cases of severe placenta accreta spectrum.

To investigate the heterogeneity of decidual stromal cells (DSCs) and their functional alterations during delivery, we conducted single-cell RNA sequencing analysis to characterize the transcriptomic profiles of DSCs before and after labor onset. According to their transcriptomic profiles, DSCs (6382 cells) were clustered into five subgroups with different functions. Similar to stromal cells, cells in cluster 1 were involved in cell substrate adhesion. On the other hand, cells in clusters 2 and 3 were enriched in signal transduction-related genes. Labor onset led to significant alterations in many pathways, including the activator protein 1 pathway (all clusters), as well as in the response to lipopolysaccharide (clusters 1–3). The downregulated genes were involved in coagulation, ATP synthesis, and oxygen homeostasis, possibly reflecting the oxygen and energy balance during delivery. Our findings highlight that peripartum DSCs are heterogeneous and play multiple roles in labor.