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Engaging with children and adolescents in mental health settings who are exhibiting behaviours that challenge can often result in the use of seclusion, restraint and coercive practices. It is recognised that more therapeutic ways to engage this population are needed, adopting trauma informed interventions may provide a solution. The aim of this systematic review is to synthesize the evidence in relation to the effect of trauma-informed interventions on coercive practices in child and adolescent residential settings. The review is guided by elements of the Cochrane Handbook for Systematic Reviews of Interventions and reported using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist. Results were synthesized and reported narratively. Nine studies met the eligibility criteria for this review. There was a lack of homogeneity amongst the studies. The trauma-informed interventions used were typically multi-faceted, underpinned by a variety of approaches and sought to bring about changes to clinical practice. Most studies (n = 8) reported significant reductions in the use of restrictive practices following the implementation of a trauma informed approach. The use of a trauma-informed approach, underpinned by an organisational change or implementation strategy, have the potential to reduce coercive practices with children and adolescents. However, the included interventions were insufficiently described to draw strong conclusions.

BackgroundType 2 diabetes (T2D) increases the risk of pancreatic ductal adenocarcinoma (PDAC), which could be due to an epigenetic mechanism.MethodsWe explored the association between T2D and whole pancreas methylation in 141 individuals, of which 28 had T2D, using Illumina MethylationEPIC 850K BeadChip arrays. We performed downstream functional assessment in the rat acinar pancreas cell line AR42J. To further understand the role of our candidate gene in humans, we tested whether null variants were associated with T2D and related traits using the UK biobank.ResultsMethylation analysis identified one significant CpG associated with T2D: hypermethylation in an enhancer inPNLIPRP1, an acinar-specific gene.PNLIPRP1expression was decreased in T2D individuals. Using a rat acinar cell line, we 1/ confirmed decreasedPnliprp1in response to a diabetogenic treatment, and 2/ inPnliprp1knockdown, an up-regulation of cholesterol biosynthesis, cell cycle down-regulation, decreased expression of acinar markers and increased expression of ductal markers pointing towards acinar-to-ductal metaplasia (ADM), a hallmark of PDAC initiation. Using exome data from UK Biobank, we show that rarePNLIPRP1null variants associated with increased glucose, BMI and LDL-cholesterol.Conclusions/interpretationWe present evidence that an epigenetically-regulated gene associates with T2D risk, and might promote ADM and PDAC progression, opening new insights into early prevention of PDAC.

In developing countries, mental health literacy (MHL) still needs to be improved due to the high prevalence of mental disorders. It is widely recognized that MHL can improve health outcomes for both individuals and populations. Healthcare professionals' development in MHL is crucial to the prevention of mental disorders. The aim of this study was to assess MHL of primary healthcare (PHC) workers in South Africa (SA) and Zambia and determinants thereof. Limited evidence is available on the levels of MHL among PHC workers in the sub-Saharan Africa region, which faces a large burden of mental disorders.The study population for this cross-sectional survey comprised PHC workers (n = 250) in five provinces of SA and Zambia. MHL was measured with the Mental Health Literacy Scale (MHLS). We conducted a multivariate analysis to explore determinants of MHL.Results showed moderate MHL among PHC professionals, but with a wide range from low to high MHL. Knowledge-related items had a greater dispersion than other attributes of MHL. PHC workers with more education showed a greater ability to recognize mental health-related disorders. Those who had experience in the use of mental health-related assessment scales or screening tools reported a higher total MHL. The results confirmed strong internal consistency for the MHLS.The results highlighted varying mental health perceptions and knowledge in PHC. Implementation of specifically developed formal training programs and interventions to improve MHL in PHC workers to strengthen their competence may help bridge the treatment gap.

Aquaporin-8 (AQP8) is a peroxiporin, a transmembrane water and hydrogen peroxide (H2O2) transport protein expressed in the mitochondrial and plasma membranes of pancreatic β-cells. AQP8 protein expression is low under physiological conditions, but it increases after cytokine exposure both, in vitro and in vivo, possibly related to a NF-κB consensus sequence in the promoter. AQP8 knockdown (KD) insulin-producing RINm5F cells are particularly susceptible to cytokine-mediated oxidative stress. Cytokine (a mixture of IL-1β, TNF-α, and IFN-γ) treated AQP8 KD cells exhibited pronounced sensitivity to reactive oxygen and nitrogen species (ROS and RNS), resulting in a significant loss of β-cell viability due to enhanced toxicity of the increased concentrations of H2O2 and hydroxyl radicals (●OH) in mitochondria of AQP8 KD cells. This viability loss went along with increased caspase activities, reduced nitrite concentration (representative of nitric oxide (NO●) accumulation) and increased lipid peroxidation. The explanation for the increased toxicity of the proinflammatory cytokines in AQP8 KD cells resides in the fact that efflux of the H2O2 generated during oxidative stress in the β-cell mitochondria is hampered through the loss of the peroxiporin channels in the mitochondrial membranes of the AQP8 KD cells. The increased proinflammatory cytokine toxicity due to loss of AQP8 expression in the KD β-cell mitochondria is thus the result of increased rates of apoptosis. This decreased cell viability is caused by increased levels of oxidative stress along with a ferroptosis-mediated cell death component due to decreased NO● generation.

The sun bear Helarctos malayanus is one of the most endangered ursids, and to date classification of sun bear populations has been based almost exclusively on geographic distribution and morphology. The very few molecular studies focusing on this species were limited in geographic scope. Using archival and non-invasively collected sample material, we have added a substantial number of complete or near-complete mitochondrial genome sequences from sun bears of several range countries of the species’ distribution. We here report 32 new mitogenome sequences representing sun bears from Cambodia, Thailand, Peninsular Malaysia, Sumatra and Borneo. Reconstruction of phylogenetic relationships revealed two matrilines that diverged ∼290 thousand years ago: one restricted to portions of mainland Indochina (China, Cambodia, Thailand; “Mainland clade”), and one comprising bears from Borneo, Sumatra, Peninsular Malaysia but also Thailand (“Sunda clade”). Generally recent coalescence times in the mitochondrial phylogeny suggest that recent or historical demographic processes have resulted in a loss of mtDNA variation. Additionally, analysis of our data in conjunction with shorter mtDNA sequences revealed that the Bornean sun bear, classified as a distinct subspecies (H. m. euryspilus), does not harbour a distinctive matriline. Further molecular studies of H. malayanus are needed, which should ideally include data from nuclear loci.

Encounters between individuals with a mental disorder and police forces can be harmful and dangerous for both parties involved. Previous research explored mostly police officers’ subjective experience of these encounters and focused on their recommendations. The present study takes the perspective of individuals with a mental disorder and investigates their subjective experience of dealing with the police. Thirteen semi-structural interviews were conducted with individuals with a history of mental health problems who have had encounters with the police and experienced contact-based anti-stigmatization interventions as consultants. Interviews revolved around the subjective experience of these police encounters. Questionnaires were used to inquire about context factors, individuals’ perceptions of police officers, and their sense of security during these encounters. Furthermore, individuals were asked to rate police officers’ ability to recognize signs and symptoms of ill mental health and give recommendations in regard to adequate communication strategies, interventions, and police training. The results indicate that encounters were experienced predominantly as positive and non-threatening. Participants emphasized the importance of communication strategies with a focus on empathy and respect. Keeping personal space and satisfying basic needs was recommended. Contact-based anti-stigmatization interventions were regarded as an effective approach to reduce stigma. Empathy and respect are perceived as key strategies for police officers when dealing with individuals with a mental disorder. To promote these strategies, trialogical anti-stigmatization interventions and crisis intervention training, including communication skills and face-to-face contact, are promising approaches.

Free-ranging cheetahs (Acinonyx jubatus) are generally healthy, whereas cheetahs under human care, such as those in zoological gardens, suffer from ill-defined infectious and degenerative pathologies. These differences are only partially explained by husbandry management programs because both groups share low genetic diversity. However, mounting evidence suggests that physiological differences between populations in different environments can be tracked down to differences in epigenetic signatures. Here, we identified differentially methylated regions (DMRs) between free-ranging cheetahs and conspecifics in zoological gardens and prospect putative links to pathways relevant to immunity, energy balance and homeostasis. Comparing epigenomic DNA methylation profiles obtained from peripheral blood mononuclear cells (PBMCs) from eight free-ranging female cheetahs from Namibia and seven female cheetahs living in zoological gardens within Europe, we identified DMRs of which 22 were hypermethylated and 23 hypomethylated. Hypermethylated regions in cheetahs under human care were located in the promoter region of a gene involved in host-pathogen interactions (KLC1) and in an intron of a transcription factor relevant for the development of pancreatic β-cells, liver, and kidney (GLIS3). The most canonical mechanism of DNA methylation in promoter regions is assumed to repress gene transcription. Taken together, this could indicate that hypermethylation at the promoter region of KLC1 is involved in the reduced immunity in cheetahs under human care. This approach can be generalized to characterize DNA methylation profiles in larger cheetah populations under human care with a more granular longitudinal data collection, which, in the future, could be used to monitor the early onset of pathologies, and ultimately translate into the development of biomarkers with prophylactic and/or therapeutic potential.

Background Many felid species are of high conservation concern, and with increasing human disturbance the situation is worsening. Small isolated populations are at risk of genetic impoverishment decreasing within-species biodiversity. Movement is known to be a key behavioural trait that shapes both demographic and genetic dynamics and affects population survival. However, we have limited knowledge on how different manifestations of movement behaviour translate to population processes. In this study, we aimed to 1) understand the potential effects of movement behaviour on the genetic diversity of small felid populations in heterogeneous landscapes, while 2) presenting a simulation tool that can help inform conservation practitioners following, or considering, population management actions targeting the risk of genetic impoverishment. Methods We developed a spatially explicit individual-based population model including neutral genetic markers for felids and applied this to the example of Eurasian lynx. Using a neutral landscape approach, we simulated reintroductions into a three-patch system, comprising two breeding patches separated by a larger patch of differing landscape heterogeneity, and tested for the effects of various behavioural movement syndromes and founder population sizes. We explored a range of movement syndromes by simulating populations with various movement model parametrisations that range from ‘shy’ to ‘bold’ movement behaviour. Results We find that movement syndromes can lead to a higher loss of genetic diversity and an increase in between population genetic structure for both “bold” and “shy” movement behaviours, depending on landscape conditions, with larger decreases in genetic diversity and larger increases in genetic differentiation associated with bold movement syndromes, where the first colonisers quickly reproduce and subsequently dominate the gene pool. In addition, we underline the fact that a larger founder population can offset the genetic losses associated with subpopulation isolation and gene pool dominance. Conclusions We identified a movement syndrome trade-off for population genetic variation, whereby bold-explorers could be saviours - by connecting populations and promoting panmixia, or sinks - by increasing genetic losses via a ‘founder takes all’ effect, whereas shy-stayers maintain a more gradual genetic drift due to their more cautious behaviour. Simulations should incorporate movement behaviour to provide better projections of long-term population viability and within-species biodiversity, which includes genetic diversity. Simulations incorporating demographics and genetics have great potential for informing conservation management actions, such as population reintroductions or reinforcements. Here, we present such a simulation tool for solitary felids.

External temperature change has been shown to modify epigenetic patterns, such as DNA methylation, which regulates gene expression. DNA methylation is heritable, and as such provides a mechanism to convey environmental information to subsequent generations. Studies on epigenetic response to temperature increase are still scarce in wild mammals, even more so studies that compare tissue-specific epigenetic responses. Here, we aim to address differential epigenetic responses on a gene and gene pathway level in two organs, liver and testis. We chose these organs, because the liver is the main metabolic and thermoregulation organ, and epigenetic modifications in testis are potentially transmitted to the F2 generation. We focused on the transmission of DNA methylation changes to naive male offspring after paternal exposure to an ambient temperature increase of 10 °C, and investigated differential methylated regions of sons sired before and after the paternal exposure using Reduced Representation Bisulfite Sequencing. We detected both a highly tissue-specific epigenetic response, reflected in genes involved in organ-specific metabolic pathways, and a more general regulation of single genes epigenetically modified in both organs. We conclude that genomes are context-specifically differentially epigenetically regulated in response to temperature increase. These findings emphasize the epigenetic relevance in cell differentiation, which is essential for the specific function(s) of complex organs, and is represented in a diverse molecular regulation of genes and gene pathways. The results also emphasize the paternal contribution to adaptive processes. Electronic supplementary material The online version of this article (10.1007/s00335-020-09832-6) contains supplementary material, which is available to authorized users.

Social epigenomics is a new field of research that studies how the social environment shapes the epigenome and how in turn the epigenome modulates behavior. We focus on describing known gene–environment interactions (GEIs) and epigenetic mechanisms in different mammalian social systems. To illustrate how epigenetic mechanisms integrate GEIs, we highlight examples where epigenetic mechanisms are associated with social behaviors and with their maintenance through neuroendocrine, locomotor, and metabolic responses. We discuss future research trajectories and open questions for the emerging field of social epigenomics in nonmodel and naturally occurring social systems. Finally, we outline the technological advances that aid the study of epigenetic mechanisms in the establishment of GEIs and vice versa.

Free-ranging cheetahs (

Species of the mustelid subfamily Guloninae inhabit diverse habitats on multiple continents, and occupy a variety of ecological niches. They differ in feeding ecologies, reproductive strategies and morphological adaptations. To identify candidate loci associated with adaptations to their respective environments, we generated a de novo assembly of the tayra (Eira barbara), the earliest diverging species in the subfamily, and compared this with the genomes available for the wolverine (Gulo gulo) and the sable (Martes zibellina). Our comparative genomic analyses included searching for signs of positive selection, examining changes in gene family sizes and searching for species-specific structural variants. Among candidate loci associated with phenotypic traits, we observed many related to diet, body condition and reproduction. For example, for the tayra, which has an atypical gulonine reproductive strategy of aseasonal breeding, we observed species-specific changes in many pregnancy-related genes. For the wolverine, a circumpolar hypercarnivore that must cope with seasonal food scarcity, we observed many changes in genes associated with diet and body condition. All types of genomic variation examined (single nucleotide polymorphisms, gene family expansions, structural variants) contributed substantially to the identification of candidate loci. This argues strongly for consideration of variation other than single nucleotide polymorphisms in comparative genomics studies aiming to identify loci of adaptive significance.

The Asian elephant population is continuously declining due to several extrinsic reasons in their range countries, but also due to diseases in captive populations worldwide. One of these diseases, the elephant endotheliotropic herpesvirus (EEHV) hemorrhagic disease, is very impactful because it particularly affects Asian elephant calves. It is commonly fatal and presents as an acute and generalized hemorrhagic syndrome. Therefore, having reference values of coagulation parameters, and obtaining such values for diseased animals in a very short time, is of great importance. We analyzed prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen concentrations using a portable and fast point-of-care analyzer (VetScan Pro) in 127 Asian elephants from Thai camps and European captive herds. We found significantly different PT and aPTT coagulation times between elephants from the two regions, as well as clear differences in fibrinogen concentration. Nevertheless, these alterations were not expected to have biological or clinical implications. We have also sequenced the coagulation factor VII gene of 141 animals to assess the presence of a previously reported hereditary coagulation disorder in Asian elephants and to investigate the presence of other mutations. We did not find the previously reported mutation in our study population. Instead, we discovered the presence of several new single nucleotide polymorphisms, two of them being considered as deleterious by effect prediction software.

The LEW.1AR1-iddm rat is an animal model of human type 1 diabetes (T1D). Previously, we have shown that combination with anti-TCR/anti-TNF-α antibody-based therapy re-established normoglycemia and increased proteinic arginine-dimethylation in the spleen, yet not in the pancreas. High blood glucose is often associated with elevated formation of advanced glycation end-products (AGEs) which act via their receptor (RAGE). Both anti-TCR and anti-TNF-α are inhibitors of RAGE. The aim of the present work was to investigate potential biochemical changes of anti-TCR/anti-TNF-α therapy in the LEW.1AR1-iddm rat. We determined by stable-isotope dilution gas chromatography-mass spectrometry (GC-MS) the content of free and proteinic AGEs and the Nε-monomethylation of lysine (Lys) residues in proteins of pancreas, kidney, liver, spleen and lymph nodes of normoglycemic control (ngCo, n = 6), acute diabetic (acT1D, n = 6), chronic diabetic (chT1D, n = 4), and cured (cuT1D, n = 4) rats after anti-TCR/anti-TNF-α therapy. Analyzed biomarkers included Lys and its metabolites Nε-carboxymethyl lysine (CML), furosine and Nε-monomethyl lysine (MML). Other amino acids were also determined. Statistical methods including ANOVA, principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to evaluate the effects. Most statistical differences between the study groups were observed for spleen, pancreas and kidney, with liver and lymph nodes showing no such differences. In the pancreas, the groups differed with respect to proteinic furosine (p = 0.0289) and free CML (p = 0.0023). In the kidneys, the groups differed with respect to proteinic furosine (p = 0.0076) and CML (p = 0.0270). In the spleen, group differences were found for proteinic furosine (p = 0.0114) and free furosine (p = 0.0368), as well as for proteinic CML (p = 0.0502) and proteinic MML (p = 0.0191). The acT1D rats had lower furosine, CML and MML levels in the spleen than the rats in all other groups. This observation corresponds to the lower citrullination levels previously measured in these rats. PCA revealed diametric associations between PC1 and PC2 for spleen (r = −0.8271, p < 0.0001) compared to pancreas (r = 0.5805, p = 0.0073) and kidney (r = 0.8692, p < 0.0001). These findings underscore the importance of the spleen in this animal model of human T1D. OPLS-DA showed that in total sixteen amino acids differed in the experimental groups.

The Asian elephant population is continuously declining due to several extrinsic reasons in their range countries, but also due to diseases in captive populations worldwide. One of these diseases, the elephant endotheliotropic herpesvirus (EEHV) hemorrhagic disease, is very impactful because it particularly affects Asian elephant calves. It is commonly fatal and presents as an acute and generalized hemorrhagic syndrome. Therefore, having reference values of coagulation parameters, and obtaining such values for diseased animals in a very short time, is of great importance. We analyzed prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen concentrations using a portable and fast point-of-care analyzer (VetScan Pro) in 127 Asian elephants from Thai camps and European captive herds. We found significantly different PT and aPTT coagulation times between elephants from the two regions, as well as clear differences in fibrinogen concentration. Nevertheless, these alterations were not expected to have biological or clinical implications. We have also sequenced the coagulation factor VII gene of 141 animals to assess the presence of a previously reported hereditary coagulation disorder in Asian elephants and to investigate the presence of other mutations. We did not find the previously reported mutation in our study population. Instead, we discovered the presence of several new single nucleotide polymorphisms, two of them being considered as deleterious by effect prediction software.

The LEW.1AR1

Previous molecular studies of the wide-ranging Eurasian lynx Lynx lynx focused mainly on its northern Palearctic populations, with the consequence that the reconstruction of this species' evolutionary history did not include genetic variation present in its southern Palearctic distribution. We sampled a previously not considered Asian subspecies (L. l. dinniki), added published data from another Asian subspecies (L. l. isabellinus), and reassessed the Eurasian lynx mtDNA phylogeny along with previously published data from northern Palearctic populations. Our mitogenome-based analyses revealed the existence of three major clades (A: Central Asia, B: SE Europe/SW Asia, C: Europe and Northern Asia) and at least five lineages, with diversification in Lynx lynx commencing at least 28kyr earlier than hitherto estimated. The subspecies L. l. isabellinus harbors the most basal matriline, consistent with the origin of Lynx lynx in this subspecies' current range. L. l. dinniki harbors the second most basal matriline, which is related to, and may be the source of, the mtDNA diversity of the critically endangered Balkan lynx L. l. balcanicus. Our results suggest that the Anatolian peninsula was a glacial refugium for Eurasian lynx, with previously unconsidered implications for the colonization of Europe by this species. RSGF [11447-1]; DAAD grant; Leibniz-IZW research grant; TUB.ITAK MAM-NCNP project [109G016] Accommodation for DM in Nallihan was partially provided by Nallihan Turizm Gonulluleri Dernegi and per diems by the General Directorate of Nature Conservation and National Parks (NCNP), Turkish Ministry of Agriculture and Forestry. Sample collection in Ankara was supported by the RSGF 11447-1 project. DM was also supported by a DAAD grant and a Leibniz-IZW research grant. Support for field work in Antalya was provided by the TUB.ITAK MAM-NCNP project 109G016 for Conservation and Management of Large Mammals in Turkey. WOS:000689079800001 2-s2.0-85112472155 PubMed: 34440390

Species of the mustelid subfamily Guloninae inhabit diverse habitats on multiple continents, and occupy a variety of ecological niches. They differ in feeding ecologies, reproductive strategies and morphological adaptations. To identify candidate loci associated with adaptations to their respective environments, we generated a de novo assembly of the tayra (Eira barbara), the earliest diverging species in the subfamily, and compared this with the genomes available for the wolverine (Gulo gulo) and the sable (Martes zibellina). Our comparative genomic analyses included searching for signs of positive selection, examining changes in gene family sizes, as well as searching for species-specific structural variants (SVs). Among candidate loci associated with phenotypic traits, we observed many related to diet, body condition and reproduction. For example, for the tayra, which has an atypical gulonine reproductive strategy of aseasonal breeding, we observe species-specific changes in many pregnancy-related genes. For the wolverine, a circumpolar hypercarnivore that must cope with seasonal food scarcity, we observed many changes in genes associated with diet and body condition. All types of genomic variation examined contributed substantially to the identification of candidate loci. This strongly argues for consideration of variation other than single nucleotide polymorphisms in comparative genomics studies aiming to identify loci of adaptive significance.

The recognition of certain mental health conditions is important as this requires police officers to communicate and behave in an adjusted manner with affected individuals. The objective of the present study was to test police officers’ knowledge about mental health symptoms as a component of their mental health literacy (MHL) and to examine if police officers’ perceived knowledge corresponds with their actual knowledge. A questionnaire was used to assess for MHL representing mental health conditions which occur frequently in police requests (schizophrenia, bipolar disorder, depression, post-traumatic stress disorders, and emotionally unstable personality disorder). Furthermore, the questionnaire assessed the frequency of police requests, the officers’ perceived knowledge regarding mental disorders and their sense of feeling sufficiently trained to deal with these kinds of requests. Eighty-two police officers participated in the study. Police officers’ actual knowledge about mental health conditions did not correspond with their perceived knowledge. Participants revealed a moderately high level of overall knowledge which differed with regard to symptoms of each of the five mental health conditions. The mental status of a paranoid schizophrenia was best identified by the police officers and the majority correctly allocated the symptoms. Post-traumatic stress disorders and manic episodes were only identified by a minority of police offers. Police training geared to prepare for requests involving individuals with mental disorders should expand this limited knowledge transfer and focus on a broader variety of mental health conditions that police officers frequently encounter in requests.

Approximately 10% of patients with type 2 diabetes suffer from latent autoimmune diabetes in adults (LADA). This study provides a systematic assessment of the pathology of the endocrine pancreas of patients with LADA and for comparison in a first rat model mimicking the characteristics of patients with LADA. Islets in human and rat pancreases were analyzed by immunohistochemistry for immune cell infiltrate composition, by in situ RT-PCR and quantitative real-time PCR of laser microdissected islets for gene expression of proinflammatory cytokines, the proliferation marker proliferating cell nuclear antigen (PCNA), the anti-inflammatory cytokine interleukin (IL) 10, and the apoptosis markers caspase 3 and TUNEL as well as insulin. Human and rat LADA pancreases showed differences in areas of the pancreas with respect to immune cell infiltration and a changed ratio between the number of macrophages and CD8 T cells toward macrophages in the islet infiltrate. Gene expression analyses revealed a changed ratio due to an increase of IL-1β and a decrease of tumor necrosis factor-α. IL-10, PCNA, and insulin expression were increased in the LADA situation, whereas caspase 3 gene expression was reduced. The analyses into the underlying pathology in human as well as rat LADA pancreases provided identical results, allowing the conclusion that LADA is a milder form of autoimmune diabetes in patients of an advanced age.

The LEW.1AR1-iddm rat is an animal model of human type 1 diabetes (T1D). We determined by GC-MS the extent of asymmetric dimethylation (prADMA) and citrullination (prCit) of L-arginine residues in organ proteins (pr) of normoglycaemic control (ngCo, n = 6), acutely diabetic (acT1D, n = 6), chronically diabetic (chT1D, n = 4), and cured (cuT1D, n = 4) rats after anti-TCR/anti-TNF-α therapy. Pancreatic prCit and prADMA did not differ between the groups but were correlated (r = 0.728, P = 0.0003, n = 20). acT1D rats had lower prCit levels in spleen and kidney than ngCo rats. cuT1D rats had higher prADMA levels than chT1D rats only in the spleen. Combination therapy re-established normoglycaemia and increased prADMA in the spleen without altering pancreatic prADMA and prCit. Western blotting demonstrated the presence of different prADMA pattern, especially an ≈ 50-kDa prADMA in spleen and pancreas, and an ≈ 25-kDa prADMA in the pancreas only, with the kidney showing only a very faint and small prADMA. Besides the changes in the pancreas during different metabolic states, the spleen may play a stronger role for the recognition of metabolic changes in T1D than thought thus far.

Literature indicates a high prevalence and burden of mental illness in youths world-wide, which may be even higher in low- and middle-income countries (LMIC), such as South Africa and Zambia. Additionally, there is a lack of knowledge regarding youth depression amongst many primary health care (PHC) practitioners. The principal goal of the MEGA project is to provide youth with better access to mental health services and appropriate care, by developing a mental health screening mobile application tool to be used in PHC settings in South Africa and Zambia. In this study, we will use a mixed methods multi-center study design. In phase one, we will investigate the mental health literacy of PHC practitioners to identify areas in need of development. Based on the needs identified, we will develop and test a mobile health application to screen for common youth mental health problems in phase two. In phase three, we will implement and evaluate a tiered education and training program in the use of the m-health application. In the final phase, we will evaluate the acceptability and feasibility of the m-health application in PHC centres across South Africa and Zambia. Evidence suggests that PHC practitioners should routinely consider mental illness when assessing youth. However, common psychiatric disorders remain largely undetected and untreated in PHC settings. By identifying limitations in PHC workers knowledge with regard to youth mental health, we aspire to improve the depression care provided to youth in Southern Africa and Zambia by developing and implementing a locally relevant m-health application.

Differentiation of human pluripotent stem cells into insulin-producing stem cell-derived beta cells harbors great potential for research and therapy of diabetes. SOX9 plays a crucial role during development of the pancreas and particularly in the development of insulin-producing cells as SOX9+ cells form the source for NEUROG3+ endocrine progenitor cells. For the purpose of easy monitoring of differentiation efficiencies into pancreatic progenitors and insulin-producing cells, we generated new reporter lines by knocking in a P2A-H-2Kk-F2A-GFP2 reporter gene into the SOX9-locus and a P2A-mCherry reporter gene into the INS-locus mediated by CRISPR/CAS9-technology. The knock-ins enabled co-expression of the endogenous and reporter genes and report on the endogenous gene expression. Furthermore, FACS and MACS enabled the purification of pancreatic progenitors and insulin-producing cells. Using these cell lines, we established a new differentiation protocol geared towards SOX9+ cells to efficiently drive human pluripotent stem cells into glucose-responsive beta cells. Our new protocol offers an alternative route towards stem cell-derived beta cells, pointing out the importance of Wnt/beta-catenin inhibition and the efficacy of EGF for the development of pancreatic progenitors, as well as the significance of 3D culture for the functionality of the generated beta cells. Graphic Abstract

Emerging infectious diseases may become serious threats to wildlife, a prominent example being the white-nose disease (WND). In case of WND, the cold-loving fungus Pseudogymnoascus destructans colonizes bats during hibernation, invades the skin and has already lead to the death of millions of bats in North America. P. destructans most likely originated from Europe, where it also causes lesions but without associated mortalities. However, it is still unclear how European bats cope with the fungus. Hence, it is important to have tools that precisely characterise disease progression. Because hibernation is a physiological state during which bats are vulnerable to disturbance, in-situ assessments of the clinical status should be carried out minimal-invasively to avoid detrimental impacts on bats. However, currently available disease assessment methods require handling/touching bats and are therefore invasive: i) UV-light trans-illumination of wing membranes to detect lesions and ii) a qPCR-based quantification of fungal material from wing membrane swabs. Since P. destructans (‘Pd') becomes visible on all furless skin with distinct distribution patterns, we investigated the use of visible symptoms to assess levels of infections without handling/touching bats. We introduce a technique which we termed ‘Visual Pd-score’ (a visual classification scheme), which can be applied without disturbing the animals. To assess its reliability, we used P. destructans infected greater mouse-eared bats (Myotis myotis) to compare the novel method with the two existing golden-standard techniques. Our results show that infection levels obtained from all three techniques are correlated. Importantly, the information carried by the Visual Pd-score is most similar to a composite index combining the information from the qPCR-based and UV-light quantification methods. We conclude that the Visual Pd-score represents a promising index to better characterise disease severity as it is simultaneously representative for fungal colonization and wing damage. We discuss advantages and disadvantages of the applied techniques and conclude that the Visual Pd-score is particularly useful for routine hibernacula counts or large-scale P. destructans-surveillance. In combination with the lesion detection technique the new method is also applicable to immunological studies where both fungal colonization and associated damage have to be investigated, while qPCRs from swabs of all body parts are especially useful if it is necessary to detect cryptic infections, e.g. during the early hibernation period.

A unique set of mouse outbred lines has been generated through selective breeding in the longest selection experiment ever conducted on mice. Over the course of >140 generations, selection on the control line has given rise to two extremely fertile lines (>20 pups per litter each), two giant growth lines (one lean, one obese) and one long-distance running line. Genomic analysis revealed line-specific patterns of genetic variation among lines and high levels of homozygosity within lines as a result of long-term intensive selection, genetic drift and isolation. Detection of line-specific patterns of genetic differentiation and structural variation revealed multiple candidate genes behind the improvement of the selected traits. We conclude that the genomes of these lines are rich in beneficial alleles for the respective selected traits and represent an invaluable resource for unraveling the polygenic basis of fertility, obesity, muscle growth and endurance fitness.

Differentiation of human pluripotent stem cells into insulin-producing stem cell-derived beta cells harbors great potential for research and therapy of diabetes. The SOX9 gene plays a crucial role during development of the pancreas and particularly in the development of insulin-producing cells as SOX9+ cells form the source for NEUROG3+ endocrine progenitor cells. For the purpose of easy monitoring of differentiation efficiencies into pancreatic progenitors and insulin-producing cells, we generated new reporter lines by knocking in a P2A-H-2Kk-F2A-GFP2 reporter genes into theSOX9locus and a P2A-mCherry reporter gene into theINSlocus mediated by CRISPR/CAS9-technology. The knock-ins enable co-expression of the endogenous genes and reporter genes, report the endogenous gene expression and enable the purification of pancreatic progenitors and insulin-producing cells using FACS or MACS. Using these cell lines we established a new differentiation protocol geared towards SOX9+ cells to efficiently drive human pluripotent stem cells into glucose-responsive beta cells.

SCOPUS: ar.j, info:eu-repo/semantics/published

Small-molecule flux in tissue-microdomains is essential for organ function, but knowledge of this process is scant due to the lack of suitable methods. We developed two independent techniques that allow the quantification of advection (flow) and diffusion in individual bile canaliculi and in interlobular bile ducts of intact livers in living mice, namely Fluorescence Loss After Photoactivation (FLAP) and Intravital Arbitrary Region Image Correlation Spectroscopy (IVARICS). The results challenge the prevailing 'mechano-osmotic' theory of canalicular bile flow. After active transport across hepatocyte membranes bile acids are transported in the canaliculi primarily by diffusion. Only in the interlobular ducts, diffusion is augmented by regulatable advection. Photoactivation of fluorescein bis-(5-carboxymethoxy-2-nitrobenzyl)-ether (CMNB-caged fluorescein) in entire lobules demonstrated the establishment of diffusive gradients in the bile canalicular network and the sink function of interlobular ducts. In contrast to the bile canalicular network, vectorial transport was detected and quantified in the mesh of interlobular bile ducts. In conclusion, the liver consists of a diffusion dominated canalicular domain, where hepatocytes secrete small molecules and generate a concentration gradient and a flow-augmented ductular domain, where regulated water influx creates unidirectional advection that augments the diffusive flux.

Background and purposeMost research regarding child and adolescent mental health prevention and promotion in low-and middle-income countries is undertaken in high-income countries. This systematic review set out to synthesise findings from epidemiological studies, published between 2008 and 2020, documenting the prevalence of mental health problems in adolescents from across sub-Saharan Africa.MethodsA systematic search of multiple databases (MEDLINE, PsycINFO, Scopus) and Google Scholar was conducted guided by the Joanna Briggs Institute (JBI) Reviewer's manual for systematic reviews of observational epidemiological studies. Studies included reported prevalence outcomes for adolescents aged 10-19 using either clinical interviews or standardized questionnaires to assess psychopathology. Clinical samples were excluded.ResultsThe search yielded 1 549 records of which 316 studies were assessed for eligibility and 51 met the inclusion criteria. We present a qualitative synthesis of 37 of these 51 included articles. The other 14 studies reporting prevalence rates for adolescents living with HIV are published elsewhere. The prevalence of depression, anxiety disorders, emotional and behavioural difficulties, posttraumatic stress and suicidal behaviour in the general adolescent population and selected at-risk groups in 16 sub-Saharan countries (with a total population of 97 616 adolescents) are reported.

The meerkat, Suricata suricatta, is a highly social member of the mongoose family (Herpestidae) and the only extant species of the genus Suricata. We present the first complete mitochondrial genome of the meerkat, assembled with a seed-and-extend algorithm using three closely related species as references. Phylogenetic analyses using 22 mitochondrial genome sequences confirm the position of meerkat within the Herpestidae family and the Feliformia, a suborder of Carnivora, with high support values. This position is in good agreement with formerly conducted studies based on a small number of mitochondrial and nuclear gene fragments. Our complete mitochondrial genome represents a valuable resource for further phylogenetic studies, especially of the underrepresented members of the Herpestidae family.

Simple Summary An urban environment holds many barriers for mammals with limited mobility such as hedgehogs. These barriers appear often unsurmountable (e.g., rivers, highways, fences) and thus hinder contact between hedgehogs, leading to genetic isolation. In our study we tested whether these barriers affect the hedgehog population of urban Berlin, Germany. As Berlin has many of these barriers, we were expecting a strong genetic differentiation among hedgehog populations. However, when we looked at unrelated individuals, we did not see genetic differentiation among populations. The latter was only detected when we included related individuals too, a ‘family clan’ structure that is referred to as gamodemes. We conclude that the high percentage of greenery in Berlin provides sufficient habitat for hedgehogs to maintain connectivity across the city. Abstract We use the European hedgehog (Erinaceus europaeus), a mammal with limited mobility, as a model species to study whether the structural matrix of the urban environment has an influence on population genetic structure of such species in the city of Berlin (Germany). Using ten established microsatellite loci we genotyped 143 hedgehogs from numerous sites throughout Berlin. Inclusion of all individuals in the cluster analysis yielded three genetic clusters, likely reflecting spatial associations of kin (larger family groups, known as gamodemes). To examine the potential bias in the cluster analysis caused by closely related individuals, we determined all pairwise relationships and excluded close relatives before repeating the cluster analysis. For this data subset (N = 65) both clustering algorithms applied (Structure, Baps) indicated the presence of a single genetic cluster. These results suggest that the high proportion of green patches in the city of Berlin provides numerous steppingstone habitats potentially linking local subpopulations. Alternatively, translocation of individuals across the city by hedgehog rescue facilities may also explain the existence of only a single cluster. We therefore propose that information about management activities such as releases by animal rescue centres should include location data (as exactly as possible) regarding both the collection and the release site, which can then be used in population genetic studies.

Pro-inflammatory cytokines are crucial mediators of beta-cell destruction in type 1 diabetes mellitus (T1DM). The involvement of ferroptosis as a form of oxidative non-apoptotic cell death in T1DM pathogenesis has not been elucidated so far. Moreover, the role of glutathione peroxidase 4 (GPx4) as an antioxidative enzyme and a major regulator of ferroptosis remains elusive. Assessment of GPx4 expression in different pancreatic islet cell types revealed a predominant expression in beta-cells. Silencing of GPx4 by RNA interference and exposure to tert-butyl hydroperoxide (tert-BHP) caused ferroptosis in rat pancreatic beta-cells as evidenced by non-apoptotic cell death in association with increased lipid peroxidation, disturbed ATP synthesis, reduced GSH content, and GPx4 degradation. GPx4 overexpression as well as the ferroptosis inhibitor ferrostatin-1 effectively attenuated beta-cell death induced by tert-BHP. Notably, beta-cell toxic cytokines did not induce ferroptosis although beta-cells underwent cell death. Inhibition of iNOS by Nω-nitro-L-arginine however led to a massive lipid peroxidation upon exposure to pro-inflammatory cytokines. Hence, nitric oxide produced during pro-inflammatory cytokine action prevents the induction of ferroptosis, thereby favouring apoptosis as a primary cell death mechanism. The extraordinarily high abundance of the phospholipid hydroperoxidase GPx4 in beta-cells in contrast to the very low expression in other islet cell types points to a susceptibility of beta-cells to the accumulation of toxic lipid peroxides. Overall, these data strongly suggest that GPx4 is indispensable for beta-cell function under physiological conditions. On the other hand, our results exclude an involvement of ferroptosis as an alternative beta-cell death mode under pro-inflammatory cytokine attack.

Homotherium was a genus of large-bodied scimitar-toothed cats, morphologically distinct from any extant felid species, that went extinct at the end of the Pleistocene [1-4]. They possessed large, saber-form serrated canine teeth, powerful forelimbs, a sloping back, and an enlarged optic bulb, all of which were key characteristics for predation on Pleistocene megafauna [5]. Previous mitochondrial DNA phylogenies suggested that it was a highly divergent sister lineage to all extant cat species [6-8]. However, mitochondrial phylogenies can be misled by hybridization [9], incomplete lineage sorting (ILS), or sex-biased dispersal patterns [10], which might be especially relevant for Homotherium since widespread mito-nuclear discrepancies have been uncovered in modern cats [10]. To examine the evolutionary history of Homotherium, we generated a -7x nuclear genome and a similar to 38x exome from H. latidens using shotgun and target-capture sequencing approaches. Phylogenetic analyses reveal Homotherium as highly divergent (similar to 22.5 Ma) from living cat species, with no detectable signs of gene flow. Comparative genomic analyses found signatures of positive selection in several genes, including those involved in vision, cognitive function, and energy consumption, putatively consistent with diurnal activity, well-developed social behavior, and cursorial hunting [5]. Finally, we uncover relatively high levels of genetic diversity, suggesting that Homotherium may have been more abundant than the limited fossil record suggests [3, 4, 11-14]. Our findings complement and extend previous inferences from both the fossil record and initial molecular studies, enhancing our understanding of the evolution and ecology of this remarkable lineage.

International audience; Small-molecule flux in tissue-microdomains is essential for organ function, but knowledge of this process is scant due to the lack of suitable methods. We developed two independent techniques that allow the quantification of advection (flow) and diffusion in individual bile canaliculi and in interlobular bile ducts of intact livers in living mice, namely Fluorescence Loss After Photoactivation (FLAP) and Intravital Arbitrary Region Image Correlation Spectroscopy (IVARICS). The results challenge the prevailing 'mechano-osmotic' theory of canalicular bile flow. After active transport across hepatocyte membranes bile acids are transported in the canaliculi primarily by diffusion. Only in the interlobular ducts, diffusion is augmented by regulatable advection. Photoactivation of fluorescein bis-(5-carboxymethoxy-2-nitrobenzyl)-ether (CMNB-caged fluorescein) in entire lobules demonstrated the establishment of diffusive gradients in the bile canalicular network and the sink function of interlobular ducts. In contrast to the bile canalicular network, vectorial transport was detected and quantified in the mesh of interlobular bile ducts. In conclusion, the liver consists of a diffusion dominated canalicular domain, where hepatocytes secrete small molecules and generate a concentration gradient and a flow-augmented ductular domain, where regulated water influx creates unidirectional advection that augments the diffusive flux.

Cannabinoids are known to influence hormone secretion of pancreatic islets via G protein‑coupled cannabinoid receptor type 1 and 2 (CB1 and CB2). The present study was designed to further investigate the impact of cannabinoid receptors on the parameters involved in insulin secretion and blood glucose recognition. To this end, CB1 and CB2 receptor knockout mice (10&ndash, 12 week old, both sexes) were characterised at basal state and compared to wild-type mice. The elimination of cannabinoid receptor signalling resulted in alterations of blood glucose concentrations, body weights and insulin levels. Changes were dependent on the deleted receptor type and on the sex. Analyses at mRNA and protein levels provided evidence for the impact of cannabinoid receptor deficiency on the glucose sensing apparatus in the pancreas. Both receptor knockout mouse lines showed decreased mRNA and protein amounts of glucose transporters Glut1 and Glut2, combined with alterations in immunostaining. In addition, pancreatic glucokinase expression was elevated and immunohistochemical labelling was modified in the pancreatic islets. Taken together, CB1 and CB2 signalling pathways seem to influence glucose sensing in &beta, cells by affecting glucose transporters and glucokinase. These alterations were more pronounced in CB2 knockout mice, resulting in higher blood glucose and lower plasma insulin levels.

Over the past ~40 years, several attempts were made to reintroduce Eurasian lynx to suitable habitat within their former distribution range in Western Europe. In general, limited numbers of individuals have been released to establish new populations. To evaluate the effects of reintroductions on the genetic status of lynx populations we used 12 microsatellite loci to study lynx populations in the Bohemian–Bavarian and Vosges–Palatinian forests. Compared with autochthonous lynx populations, these two reintroduced populations displayed reduced genetic diversity, particularly the Vosges–Palatinian population. Our genetic data provide further evidence to support the status of ‘endangered’ and ‘critically endangered’ for the Bohemian–Bavarian and Vosges–Palatinian populations, respectively. Regarding conservation management, we highlight the need to limit poaching, and advocate additional translocations to bolster genetic variability.

Abstract Proinflammatory cytokines released from the pancreatic islet immune cell infiltrate in type 1 diabetes (T1D) cause insulinopenia as a result of severe beta cell loss due to apoptosis. Diabetes prevention strategies targeting different cytokines with antibodies in combination with a T cell antibody, anti-TCR, have been assessed for therapy success in the LEW.1AR1-iddm (IDDM) rat, an animal model of human T1D. Immediately after diabetes manifestation, antibody combination therapies were initiated over 5 days with anti-TNF-α (tumour necrosis factor), anti-IL-1β (interleukin), or anti-IFN-γ (interferon) together with anti-TCR for the reversal of the diabetic metabolic state in the IDDM rat. Anti-TCR alone showed only a very limited therapy success with respect to a reduction of immune cell infiltration and beta cell mass regeneration. Anti-TCR combinations with anti-IL-1β or anti-IFN-γ were also not able to abolish the increased beta cell apoptosis rate and the activated immune cell infiltrate leading to a permanent beta cell loss. In contrast, all anti-TCR combinations with anti-TNF-α provided sustained therapy success over 60 to 360 days. The triple combination of anti-TCR with anti-TNF-α plus anti-IL-1β was most effective in regaining sustained normoglycaemia with an intact islet structure in a completely infiltration-free pancreas and with a normal beta cell mass. Besides the triple combination, the double antibody combination of anti-TCR with anti-TNF-α proved to be the most suited therapy for reversal of the T1D metabolic state due to effective beta cell regeneration in an infiltration free pancreas. Key messages Anti-TCR is a cornerstone in combination therapy for autoimmune diabetes reversal. The combination of anti-TCR with anti-TNF-α was most effective in reversing islet immune cell infiltration. Anti-TCR combined with anti-IL-1β was not effective in this respect. The combination of anti-TCR with anti-TNF-α showed a sustained effect over 1 year.

Rat models of human type 1 diabetes have been shown to be of great importance for the elucidation of the mechanisms underlying the development of autoimmune diabetes. The three major well-established spontaneous rat models are the BioBreeding (BB) diabetes-prone rat, the Komeda diabetes-prone (KDP) rat, and the IDDM (LEW.1AR1-iddm) rat. Their distinctive features are described with special reference to their pathology, immunology, and genetics and compared with the situation in patients with type 1 diabetes mellitus. For all three established rat models, a distinctive genetic mutation has been identified that is responsible for the manifestation of the diabetic syndrome in these rat strains.

Background The cytokine IL-17 is a key player in autoimmune processes, while the cytokine IL-6 is responsible for the chronification of inflammation. However, their roles in type 1 diabetes development are still unknown. Methods Therefore, therapies for 5 days with anti-IL-17A or anti-IL-6 in combination with a T cell-specific antibody, anti-TCR, or in a triple combination were initiated immediately after disease manifestation to reverse the diabetic metabolic state in the LEW.1AR1-iddm (IDDM) rat, a model of human type 1 diabetes. Results Monotherapies with anti-IL-6 or anti-IL-17 showed no sustained anti-diabetic effects. Only the combination therapy of anti-TCR with anti-IL-6 or anti-IL-17 at starting blood glucose concentrations up to 12 mmol/l restored normoglycaemia. The triple antibody combination therapy was effective even up to very high initial blood glucose concentrations (17 mmol/l). The β cell mass was raised to values of around 6 mg corresponding to those of normoglycaemic controls. In parallel, the apoptosis rate of β cells was reduced and the proliferation rate increased as well as the islet immune cell infiltrate was strongly reduced in double and abolished in triple combination therapies. Conclusions The anti-TCR combination therapy with anti-IL-17 preferentially raised the β cell mass as a result of β cell proliferation while anti-IL-6 strongly reduced β cell apoptosis and the islet immune cell infiltrate with a modest increase of the β cell mass only. The triple combination therapy achieved both goals in a complimentary anti-autoimmune and anti-inflammatory action resulting in sustained normoglycaemia with normalized serum C-peptide concentrations.

Despite the progress made in HIV treatment and prevention, HIV remains a major cause of adolescent morbidity and mortality in sub-Saharan Africa. As perinatally infected children increasingly survive into adulthood, the quality of life and mental health of this population has increased in importance. This review provides a synthesis of the prevalence of mental health problems in this population and explores associated factors. A systematic database search (Medline, PsycINFO, Scopus) with an additional hand search was conducted. Peer-reviewed studies on adolescents (aged 10–19), published between 2008 and 2019, assessing mental health symptoms or psychiatric disorders, either by standardized questionnaires or by diagnostic interviews, were included. The search identified 1461 articles, of which 301 were eligible for full-text analysis. Fourteen of these, concerning HIV-positive adolescents, met the inclusion criteria and were critically appraised. Mental health problems were highly prevalent among this group, with around 25% scoring positive for any psychiatric disorder and 30–50% showing emotional or behavioral difficulties or significant psychological distress. Associated factors found by regression analysis were older age, not being in school, impaired family functioning, HIV-related stigma and bullying, and poverty. Social support and parental competence were protective factors. Mental health problems among HIV-positive adolescents are highly prevalent and should be addressed as part of regular HIV care.

Type 1 diabetes (T1D) is an autoimmune disease where pancreatic β-cells are destroyed by islet-infiltrating T cells. Although a role for β-cell defects has been suspected, β-cell abnormalities are difficult to demonstrate. We show a β-cell DNA damage response (DDR), presented by activation of the 53BP1 protein and accumulation of p53, in biopsy and autopsy material from patients with recently diagnosed T1D as well as a rat model of human T1D. The β-cell DDR is more frequent in islets infiltrated by CD45+ immune cells, suggesting a link to islet inflammation. The β-cell toxin streptozotocin (STZ) elicits DDR in islets, both in vivo and ex vivo, and causes elevation of the proinflammatory molecules IL-1β and Cxcl10. β-Cell–specific inactivation of the master DNA repair gene ataxia telangiectasia mutated (ATM) in STZ-treated mice decreases the expression of proinflammatory cytokines in islets and attenuates the development of hyperglycemia. Together, these data suggest that β-cell DDR is an early event in T1D, possibly contributing to autoimmunity.

Impaired salt and water absorption is a hallmark of diarrhea in IBD. In the present study, the therapeutic effect of continuous anti-TNFα treatment on the progression of inflammation and colonic transport dysfunction during chronic dextran sulfate sodium (DSS)-induced colitis was investigated. Chronic colitis was induced by three DSS exposure cycles. Mice received TNFα monoclonal antibody treatment twice weekly after the end of the first 5-day DSS drinking period. Mice developed chronic DSS-induced colitis characterized by a typical immune cell infiltration composed of CD3+ T cells and CD68+ macrophages, both expressing high levels of the pro-inflammatory cytokines IL-1β and TNFα, a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and a decrease of colonic fluid absorption in vivo, measured by colonic single pass perfusion. Concomitant anti-TNFα treatment resulted in a significant reduction of mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα. It also resulted in a normalization of NHE3-mediated fluid absorption and a restoration of NHE3 and PDZK1 location in the apical and subapical region of the enterocytes. Here, we show for the first time that in this chemically induced murine colitis model, anti-TNFα treatment significantly decreased inflammatory activity, improved mucosal integrity and restored transport function despite an ongoing inflammatory insult. Anti-TNFα treatment may therefore be beneficial in patients with IBD even in spite of an absence of complete mucosal healing.