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We addressed the role of interleukin-23 (IL-23) in driving the intestinal T helper type 17 (Th17) response during obesity and metabolic syndrome progression induced by a high-fat diet (HFD). Diet-induced obese and lean mice received HFD or control diet (CTD), respectively, for 20 weeks. The nutritional, metabolic and immune parameters were examined at weeks 9 and 20. Gene and protein IL-23p19 and IL-23 receptor expression was increased in the ileum of obese wild-type mice (WT) fed the HFD for 9 weeks. Mice lacking IL-23 and fed the HFD exhibited greater weight gain, higher fat accumulation, adipocyte hypertrophy and hepatic steatosis. Notably, these mice had more glucose intolerance, insulin resistance and associated metabolic alterations, such as hyperinsulinaemia and hyperlipidaemia. IL-23 deficiency also significantly reduced protein levels of IL-17, CCL20 and neutrophil elastase in the ileum and reduced Th17 cell expansion in the mesenteric lymph nodes of the HFD mice. Of importance, IL-23-deficient mice exhibited increased gut permeability and blood bacterial translocation compared with WT mice fed HFD. Finally, metagenomics analysis of gut microbiota revealed a dramatic outgrowth of Bacteroidetes over Firmicutes phylum with the prevalence of Bacteroides genera in the faeces of IL-23-deficient mice after HFD. In summary, IL-23 appears to maintain the Th17 response and neutrophil migration into the intestinal mucosa, minimizing the gut dysbiosis and protecting against obesity and metabolic disease development in mice.

Diagnosing the causes of low back pain is a challenging task, prone to errors. A novel approach to increase diagnostic accuracy in medical decision making is collective intelligence, which refers to the ability of groups to outperform individual decision makers in solving problems. We investigated whether combining the independent ratings of chiropractors, chiropractic radiologists and medical radiologists can improve diagnostic accuracy when interpreting diagnostic images of the lumbosacral spine. Evaluations were obtained from two previously published studies: study 1 consisted of 13 raters independently rating 300 lumbosacral radiographs; study 2 consisted of 14 raters independently rating 100 lumbosacral magnetic resonance images. In both studies, raters evaluated the presence of “abnormalities”, which are indicators of a serious health risk and warrant immediate further examination. We combined independent decisions of raters using a majority rule which takes as final diagnosis the decision of the majority of the group. We compared the performance of the majority rule to the performance of single raters. Our results show that with increasing group size (i.e., increasing the number of independent decisions) both sensitivity and specificity increased in both data-sets, with groups consistently outperforming single raters. These results were found for radiographs and MR image reading alike. Our findings suggest that combining independent ratings can improve the accuracy of lumbosacral diagnostic image reading.

DNA profiles can be used as evidence to distinguish between possible donors of a crime stain. In some cases, both the prosecution and the defence claim that the cell material was left by the suspect but they dispute which cell type was left behind. For example, in sexual offense cases the prosecution could claim that the sample contains semen cells where the defence argues that the sample contains skin cells. In these cases, traditional methods (e.g. a phosphatase test) can be used to examine the cell type contained in the sample. However, there are some drawbacks when using these methods. For instance, many of these techniques need to be carried out separately for each cell type and each of them requires part of the available sample, which reduces the amount that can be used for DNA analysis. Another option is messenger RNA (mRNA) evidence. mRNA expression levels vary among cell types and can be used to make (probability) statements about the cell type(s) present in a sample. Existing methods for the interpretation of RNA profiles as evidence for the presence of certain cell types aim at making categorical statements. Such statements limit the possibility to report the associated uncertainty. Some of these existing methods will be discussed. Most notably, a method based on a 'n/2' scoring rule (Lindenbergh et al. [2]) and a method using marker values and cell type scoring thresholds (Roeder et al. [3]). From a statistical point of view, a probabilistic approach is the most obvious choice. Two approaches (multinomial logistic regression and naïve Bayes') are suggested. All methods are compared, using two different datasets and several criteria regarding their ability to assess the evidential value of RNA profiles. We conclude that both the naïve Bayes' method and a method based on multinomial logistic regression, that produces a probabilistic statement as measure of the evidential value, are an important improvement of the existing methods. Besides a better performance, they are flexible and can be adapted to other situations. For example, they could potentially assist in the combination of RNA with DNA evidence.

In violent crimes, adhesive tapes such as duct tape are often used by perpetrators e.g. to tie up a victim. In the forensic examination of such tapes many different types of traces can be found, such as finger marks and human biological traces. These traces are first interpreted at source level. However, even when it is certain that a trace was donated by the suspect this does not necessarily mean that he donated the trace while taping the victim, as he could have e.g. used the tape roll from which the pieces came previous to the crime. Therefore, the trace can also be interpreted at activity level. For this, factors such as transfer, persistence and recovery, as well as the position of the trace as it would have been on the original roll have to be taken into consideration. In this study, we have developed a Bayesian network which can aid the forensic practitioner in his interpretation. From a sensitivity analysis, we have concluded that it would be most desirable to set up further studies to determine the most likely positions of DNA on tape rolls if there has only been innocent contact.

Stressed gut epithelium gets some relief Immunoglobulin A (IgA) is the most abundantly expressed antibody isotype and can be found at various mucosal surfaces in the body, including the gastrointestinal (GI) tract. IgA is polyreactive and can coat and restrain both commensal bacteria and enteric pathogens. Grootjans et al. found that endoplasmic reticulum (ER) stress in the intestinal epithelial cells of mice induced the T cell– and microbiota-independent expansion of peritoneal B1b cells, which secrete IgA. Similarly, human subjects homozygous for a variant of an autophagy gene ( ATG16L1 ) known to cause ER stress showed increased numbers of GI IgA + cells compared with controls. Thus, epithelial ER stress serves as an advantageous “eustress” response that can functionally antagonize its well-characterized role in promoting inflammation. Science , this issue p. 993

This article aims at presenting and discussing problems and difficulties that a translator of Kagi – a novel written in 1956 by the Japanese author Tanizaki Jun’ichirō (1886–1965) may face in translating from Japanese to Polish. By providing specific examples from the Japanese text, decisions that sometimes the translator must take are explained; these decisions derive from situations when the translator is confronted with the problem of untranslatability or cultural context of two such distant cultures as the Japanese and Polish ones. Operating between two such different cultures, the translator in fact intentionally becomes an intercultural intermediary – as Soliński suggests, and a cultural advisor – as Jabłoński claims. While focusing on lexical, grammatical, contextual and technical (distinctive features of the Japanese language e.g. writing systems) aspects of untranslatability, some excerpts of the Japanese text are analysed and examples of Polish equivalents are provided. It should be added that it is difficult to analyse the translation of a text that has not been published yet and officially does not exist. However, it seems the comments and solutions suggested here might be helpful or useful for those who will translate Japanese literature in the future in general, as some of these observations can be applicable not only to Kagi . The proposed solutions are certainly not perfect, thay can be a starting point for further discussions. Finally, the approach described above also provides an opportunity to consider certain technical aspects of the translation in order to demonstrate problems encountered by translators of literature in general. Artykuł na podstawie wybranych fragmentów jeszcze nieprzetłumaczonej na język polski powieści japońskiego pisarza Tanizakiego Jun’ichirō Kagi (1956) przedstawia w zarysie najważniejsze problemy, jakie może napotkać potencjalny tłumacz nowożytnej literatury japońskiej na język polski. Stając się pośrednikiem międzykulturowym – jak nazywa to Wojciech Soliński, czy też doradcą kulturowym – jak wskazuje Arkadiusz Jabłoński, musi zmierzyć się z kwestiami, takimi jak kontekst kulturowy, ograniczona przekładalność czy brak pokrewieństwa między językiem polskim a japońskim. Jakie rozwiązania wówczas zaproponować i jak dokonać przekładu, by w tekście docelowym nie pozostały wyczuwalne ślady zmagań tłumacza z tekstem, ale przede wszystkim, by wszystkie sensy zostały kreatywnie przekazane i by przekład zaistniał?

Many methods have been suggested for evaluating the evidential value of a matching Y-chromosomal DNAprofile obtained from a biological stain associated with a crime scene and the Y-chromosomal DNA profile of asuspect. Most of these methods are based on estimating the population frequency of the Y-profile. The commonindependence assumption between loci for autosomal DNA profiles cannot be used for Y-chromosomal DNAprofiles. In this paper we reconsider the problem of population frequency estimation by application of Bayesian networks and the Chow-Liu algorithm to model dependencies between loci. We found that the method based on the Chow-Liu algorithm performs almost as well as the discrete Laplace method. We have also made comparisons to the independence model and we have demonstrated once again that the independence method foY-profiles cannot be supported.

When two or more crimes show specific similarities, such as a very distinct modus operandi, the probability that they were committed by the same offender becomes of interest. This probability depends on the degree of similarity and distinctiveness. We show how Bayesian networks can be used to model different evidential structures that can occur when linking crimes, and how they assist in understanding the complex underlying dependencies. That is, how evidence that is obtained in one case can be used in another and vice versa. The flip side of this is that the intuitive decision to "unlink" a case in which exculpatory evidence is obtained leads to serious overestimation of the strength of the remaining cases.

STUDY DESIGN: A cross-sectional diagnostic accuracy study was conducted in 2 sessions.OBJECTIVE: It is important to know whether it is possible to accurately detect "specific findings" on lumbosacral magnetic resonance (MR) images and whether the results of different observers are comparable.SUMMARY OF BACKGROUND DATA: Health care providers frequently use magnetic resonance imaging in the diagnostic process of patients with low back pain. The use of MR scans is increasing. This leads to an increase in costs and to an increase in risk of inaccurately labeling patients with an anatomical diagnosis that might not be the actual cause of symptoms.METHODS: A set of 300 blinded MR images was read by medical radiologists, chiropractors, and chiropractic radiologists in 2 sessions. Each assessor read 100 scans in round 1 and 50 scans in round 2. The reference test was an expert panel.For all analyses, the magnetic resonance imaging findings were dichotomized into "specific findings" or "no specific findings." For the agreement, percentage agreement and κ values were calculated and for validity, sensitivity, and specificity. Sensitivity analysis was done for classifications A and B (prevalence of 31% and 57%, respectively).RESULTS: The intraobserver κ values for chiropractors, chiropractic radiologists, and medical radiologists were 0.46, 0.49, and 0.69 for A and 0.55, 0.75, and 0.64 for B, respectively.The interobserver κ values were lowest for chiropractors (0.28 for A, 0.37 for B) and highest for chiropractic radiologists (0.50 for A, 0.49 for B).The sensitivities of the medical radiologists, chiropractors, and chiropractic radiologists were 0.62, 0.71, and 0.75 for A and 0.70, 0.74, 0.84 for B, respectively.The specificities of medical radiologists, chiropractic radiologists, and chiropractors were 0.82, 0.77, and 0.70 for A and 0.74, 0.52, and 0.61 for B, respectively.CONCLUSION: Agreement and validity of MR image readings of chiropractors and chiropractic and medical radiologists is modest at best. This study supports recommendations in clinical guidelines against routine use of magnetic resonance imaging in patients with low back pain.LEVEL OF EVIDENCE: 3.

Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 (IL15) and human signal regulatory protein alpha (SIRPA) knock-in mouse on a Rag2-/- Il2rg-/- background (SRG-15). Transplantation of human hematopoietic stem and progenitor cells into SRG-15 mice dramatically improved the development and functional maturation of circulating and tissue-resident human NK and CD8+ T cells and promoted the development of tissue-resident innate lymphoid cell (ILC) subsets. Profiling of human NK cell subsets by mass cytometry revealed a highly similar expression pattern of killer inhibitory receptors and other candidate molecules in NK cell subpopulations between SRG-15 mice and humans. In contrast to nonobese diabetic severe combined immunodeficient Il2rg-/- (NSG) mice, human NK cells in SRG-15 mice did not require preactivation but infiltrated a Burkitt's lymphoma xenograft and efficiently inhibited tumor growth following treatment with the therapeutic antibody rituximab. Our humanized mouse model may thus be useful for preclinical testing of novel human NK cell-targeted and combinatory cancer immunotherapies and for studying how they elicit human antitumor immune responses in vivo.

Rotavirus, a leading cause of severe gastroenteritis and diarrhoea in young children, accounts for around 215,000 deaths annually worldwide. Rotavirus specifically infects the intestinal epithelial cells in the host small intestine and has evolved strategies to antagonize interferon and NF-κB signalling, raising the question as to whether other host factors participate in antiviral responses in intestinal mucosa. The mechanism by which enteric viruses are sensed and restricted in vivo, especially by NOD-like receptor (NLR) inflammasomes, is largely unknown. Here we uncover and mechanistically characterize the NLR Nlrp9b that is specifically expressed in intestinal epithelial cells and restricts rotavirus infection. Our data show that, via RNA helicase Dhx9, Nlrp9b recognizes short double-stranded RNA stretches and forms inflammasome complexes with the adaptor proteins Asc and caspase-1 to promote the maturation of interleukin (Il)-18 and gasdermin D (Gsdmd)-induced pyroptosis. Conditional depletion of Nlrp9b or other inflammasome components in the intestine in vivo resulted in enhanced susceptibility of mice to rotavirus replication. Our study highlights an important innate immune signalling pathway that functions in intestinal epithelial cells and may present useful targets in the modulation of host defences against viral pathogens.

Inflammasomes play a central role in regulating intestinal barrier function and immunity during steady state and disease. Because the discoveries of a passenger mutation and a colitogenic microbiota in the widely used caspase-1-deficient mouse strain have cast doubt on previously identified direct functions of caspase-1, we reassessed the role of caspase-1 in the intestine. To this end, we generated Casp1(-/-) and Casp11(-/-) mice and rederived them into an enhanced barrier facility to standardize the microbiota. We found that caspase-11 does not influence caspase-1-dependent processing of IL-18 in homeostasis and during DSS colitis. Deficiency of caspase-1, but not caspase-11, ameliorated the severity of DSS colitis independent of microbiota composition. Ablation of caspase-1 in intestinal epithelial cells was sufficient to protect mice against DSS colitis. Moreover, Casp1(-/-) mice developed fewer inflammation-induced intestinal tumors than control mice. These data show that canonical inflammasome activation controls caspase-1 activity, contributing to exacerbation of chemical-induced colitis.

Objective To assess the clinical benefits of joint mobilization for ankle sprains. Data Sources MEDLINE, MEDLINE In-Process, Embase, AMED, PsycINFO, CINAHL, Cochrane Library, PEDro, Scopus, SPORTDiscus, and Dissertations and Theses were searched from inception to June 2017. Study Selection Studies investigating humans with grade I or II lateral or medial sprains of the ankle in any pathologic state from acute to chronic, who had been treated with joint mobilization were considered for inclusion. Any conservative intervention was considered as a comparator. Commonly reported clinical outcomes were considered such as ankle range of movement, pain, and function. After screening of 1530 abstracts, 56 studies were selected for full-text screening, and 23 were eligible for inclusion. Eleven studies on chronic sprains reported sufficient data for meta-analysis. Data Extraction Data were extracted using the participants, interventions, comparison, outcomes, and study design approach. Clinically relevant outcomes (dorsiflexion range, proprioception, balance, function, pain threshold, pain intensity) were assessed at immediate, short-term, and long-term follow-up points. Data Synthesis Methodological quality was assessed independently by 2 reviewers, and most studies were found to be of moderate quality, with no studies rated as poor. Meta-analysis revealed significant immediate benefits of joint mobilization compared with comparators on improving posteromedial dynamic balance (P=.0004), but not for improving dorsiflexion range (P=.16), static balance (P=.96), or pain intensity (P=.45). Joint mobilization was beneficial in the short-term for improving weight-bearing dorsiflexion range (P=.003) compared with a control. Conclusions Joint mobilization appears to be beneficial for improving dynamic balance immediately after application, and dorsiflexion range in the short-term. Long-term benefits have not been adequately investigated.

SummaryThe mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify a mechanism by which mitochondria and downstream proapoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a proinflammatory type of cell death.

Inflammasomes are large cytosolic protein complexes that detect infection and stress-associated signals and promote immediate inflammatory responses. In the intestine, activation of the inflammasome leads to an inflammatory response that is important for controlling enteric infections but can also result in pathological tissue damage. Recent studies have suggested that the inflammasome also regulates intestinal homeostasis through its effects on the intestinal microbiota. Notably, many conflicting studies have been published regarding the effect of inflammasome deficiencies on intestinal homeostasis. Here, we attempt to reconcile these contrasting data by highlighting the many ways that the inflammasome contributes to intestinal homeostasis and pathology and exploring the potential role of alterations in the microbiota in these conflicting studies.

Neck pain, whether from a traumatic event such as a motor vehicle crash or of a non-traumatic nature, is a leading cause of worldwide disability. This narrative review evaluated the evidence from systematic reviews, recent randomised controlled trials, clinical practice guidelines, and other relevant studies for the effects of rehabilitation approaches for chronic neck pain. Rehabilitation was defined as the aim to restore a person to health or normal life through training and therapy and as such, passive interventions applied in isolation were not considered. The results of this review found that the strongest treatment effects to date are those associated with exercise. Strengthening exercises of the neck and upper quadrant have a moderate effect on neck pain in the short-term. The evidence was of moderate quality at best, indicating that future research will likely change these conclusions. Lower quality evidence and smaller effects were found for other exercise approaches. Other treatments, including education/advice and psychological treatment, showed only very small to small effects, based on low to moderate quality evidence. The review also provided suggestions for promising future directions for clinical practice and research.