Multicytokine-producing CD4+ T cells characterize the livers of patients with NASH.

A role of CD4+ T cells during the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) has been suggested, but which polarization state of these cells characterizes this progression and the development of fibrosis remain unclear. In addition, a gut-liver axis has been suggested to play a role in NASH, but the role of CD4+ T cells in this axis has just begun to be investigated. Combining single-cell RNA sequencing and multiple-parameter flow cytometry, we provide the first cell atlas to our knowledge focused on liver-infiltrating CD4+ T cells in patients with NAFLD and NASH, showing that NASH is characterized by a population of multicytokine-producing CD4+ T cells. Among these cells, only those with a Th17 polarization state were enriched in patients with advanced fibrosis. In parallel, we observed that Bacteroides appeared to be enriched in the intestine of NASH patients and to correlate with the frequency of multicytokine-producing CD4+ T cells. In short, we deliver a CD4+ T cell atlas of NAFLD and NASH, providing the rationale to target CD4+ T cells with a Th17 polarization state to block fibrosis development. Finally, our data offer an early indication to test whether multicytokine-producing CD4+ T cells are part of the gut-liver axis characterizing NASH.

Identification of ALK in Thinness.

There is considerable inter-individual variability in susceptibility to weight gain despite an equally obesogenic environment in large parts of the world. Whereas many studies have focused on identifying the genetic susceptibility to obesity, we performed a GWAS on metabolically healthy thin individuals (lowest 6th percentile of the population-wide BMI spectrum) in a uniquely phenotyped Estonian cohort. We discovered anaplastic lymphoma kinase (ALK) as a candidate thinness gene. In Drosophila, RNAi mediated knockdown of Alk led to decreased triglyceride levels. In mice, genetic deletion of Alk resulted in thin animals with marked resistance to diet- and leptin-mutation-induced obesity. Mechanistically, we found that ALK expression in hypothalamic neurons controls energy expenditure via sympathetic control of adipose tissue lipolysis. Our genetic and mechanistic experiments identify ALK as a thinness gene, which is involved in the resistance to weight gain.

Deep Learning and Machine Vision Approaches for Posture Detection of Individual Pigs.

Posture detection targeted towards providing assessments for the monitoring of health and welfare of pigs has been of great interest to researchers from different disciplines. Existing studies applying machine vision techniques are mostly based on methods using three-dimensional imaging systems, or two-dimensional systems with the limitation of monitoring under controlled conditions. Thus, the main goal of this study was to determine whether a two-dimensional imaging system, along with deep learning approaches, could be utilized to detect the standing and lying (belly and side) postures of pigs under commercial farm conditions. Three deep learning-based detector methods, including faster regions with convolutional neural network features (Faster R-CNN), single shot multibox detector (SSD) and region-based fully convolutional network (R-FCN), combined with Inception V2, Residual Network (ResNet) and Inception ResNet V2 feature extractions of RGB images were proposed. Data from different commercial farms were used for training and validation of the proposed models. The experimental results demonstrated that the R-FCN ResNet101 method was able to detect lying and standing postures with higher average precision (AP) of 0.93, 0.95 and 0.92 for standing, lying on side and lying on belly postures, respectively and mean average precision (mAP) of more than 0.93.

Contrast sensitivity and visual acuity under low light conditions in macular telangiectasia type 2.

BACKGROUND/AIM: Macular pigment optical density (MPOD) is centrally depleted early on in macular telangiectasia type 2 (MacTel). Contrast sensitivity (CS) might be related to MPOD, and thus impaired in early MacTel. The effect of low luminance was assessed on both CS and best corrected visual acuity (BCVA). METHODS: This is a cross-sectional study. Pelli-Robson charts were used for CS testing at 1 m in photopic (110 lux) and mesopic (1 lux) conditions. BCVA was tested with ETDRS charts and low luminance visual acuity (LLVA) with a 2.0 log unit neutral density filter. MPOD was obtained with dual-wavelength autofluorescence. RESULTS: One hundred and three eyes of 52 patients with MacTel (mean±SD age 62.9±10.2, range 35-77) were compared with 34 healthy eyes of 17 controls (mean±SD age 65.2±7.4, range 53-78). CS was significantly lower in the eyes with MacTel. This impairment was higher in low light conditions (low light contrast sensitivity (LL-CS)). Eyes at the early stages of MacTel had significantly lower LL-CS than controls, but normal (photopic) CS. The results were similar but less pronounced for BCVA/LLVA. Decrease in CS was correlated with loss of MPOD. CONCLUSIONS: Low light conditions have a detrimental effect on visual performance in MacTel. Impaired CS might correlate with MPOD depletion as a pathognomonic finding in MacTel. Functional impairment might precede structural disintegration, indicating dysfunction at the cellular level. The applied tests might be useful as additional functional assessments in clinical routine and as outcome measures in future interventional clinical trials.

Stereoscopic Vision in Macular Telangiectasia Type 2.

PURPOSE: To investigate stereoscopic vision in patients with macular telangiectasia (MacTel) type 2 and correlate paracentral sensitivity loss to reduced stereoscopic function. METHODS: In a prospective single-center study, 50 patients with MacTel type 2 and 25 age-matched controls were investigated. Stereoscopic function was evaluated with Lang I, Titmus, and TNO tests. Sensitivity of the central 16° was tested using fundus-controlled perimetry (microperimetry). Functional loss was quantified as depth, size, and localization of scotomata. RESULTS: Both the Titmus and the TNO test revealed significantly reduced stereoscopic vision in patients compared to controls (p < 0.0001 for both). This applied even to patients with only relative or monocular paracentral scotoma. A strong correlation was observed for reduced stereoscopic vision with horizontal scotoma size and with the distance of scotomata from the foveal center. CONCLUSIONS: The results indicate that stereoscopic vision is impaired early in patients with MacTel type 2. A paracentral sensitivity loss, even if mild and limited to one eye, may considerably interfere with stereoscopic function despite normal visual acuity. Projection of paracentral scotomata within the patient's central visual field plays an important role in stereoscopic vision and should be considered when interpreting stereoscopic test results.

Macular Pigment Distribution as Prognostic Marker for Disease Progression in Macular Telangiectasia Type 2.

PURPOSE: To evaluate macular pigment distribution pattern as a prognostic marker for disease progression in patients with macular telangiectasia type 2 (MacTel). DESIGN: Retrospective cohort study. METHODS: In this single-center study, 90 eyes of 47 patients were analyzed. Macular pigment optical density (MPOD) was measured with dual-wavelength fundus autofluorescence. Eyes were graded into MPOD distribution classes 1 to 3 with increasing loss of macular pigment and grading was performed masked by 2 independent graders. Best-corrected visual acuity, reading acuity, total scotoma size in fundus-controlled perimetry (microperimetry), and break of the ellipsoid zone (EZ) in optical coherence tomography (en face measurement) were defined as functional and morphologic outcome parameters and evaluated at baseline and after 60 months. RESULTS: After a mean review period of 59.6 months (±standard deviation 5.2 months), no change between MPOD classes was observed compared to baseline. Morphologic and functional deficits were limited to the area of MPOD loss. At last follow-up, a significant mean decrease of visual acuity and reading acuity as well as a significant mean increase of scotoma size and EZ break were observed in eyes assigned to MPOD classes 2 and 3, while outcome parameters remained stable in eyes of class 1. CONCLUSIONS: The results indicate that MPOD and its distribution may serve as a prognostic marker for disease progression and functional impairment in patients with MacTel.

Fungaemia caused by obstructive renal candida bezoars leads to bilateral chorioretinitis: a case report.

BACKGROUND: Renal fungal bezoars are remarkably rare and mostly occur in immunodeficient patients. Only a small number of cases with immunocompetent patients have been published so far. The published treatment approaches comprised systemic antimycotic therapy and surgical or minimal invasive removal of the fungal balls. In some cases irrigation of the renal duct system with amphotericin B was performed. By obstruction of the urinary tract bezoars can lead to infected hydronephrosis and severe urosepsis with high lethality. Fungaemia can cause fungal colonization in different distant organs. Fulminant chorioretinitis and irreversible visual impairment can be the consequence of ocular fundus colonization. The following report highlights that a co-operation between urologists and ophthalmologists is absolutely indispensible in case of fungaemia. CASE PRESENTATION: Hereinafter we describe a case of an immunocompetent 56 years old woman, presenting with flank pain and shivering. The diagnosis turned out to be difficult due to initially negative urine culture. The fungaemia caused by obstructive nephropathy led to bilateral candida chorioretinitis. The patient was treated with intravenous amphotericin b and the bezoar was removed by percutaneous "nephrolitholapaxy". After two months, a follow up revealed the patient felt well, chorioretinal lesions regressed and urine culture did not show any fungal growth. CONCLUSION: To the best of our knowledge, this is the first case reporting on obstructive renal bezoars, which lead to haematogenous fungus spread and bilateral chorioretinitis. It points out that extensive ophthalmologic examination should be performed in case of fungaemia even if the patient is not suffering from any visual impairment.

SEX STEROIDS AND MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: To investigate the relationship between macular telangiectasia Type 2 and systemic levels of sex steroids or their antagonization. METHODS: In a prospective single-center study, 90 patients with macular telangiectasia Type 2 were investigated. Female patients were evaluated for previous surgical (e.g., ovariectomy) and/or pharmacological (e.g., aromatase inhibitors, tamoxifen) therapy resulting in reduced action of sex steroids. In males, free serum testosterone levels were assessed in patients and controls. RESULTS: Fourteen of 49 (29%) female patients had a history of pharmacological suppression of sex steroids and/or ovariectomy. These patients were younger at disease onset when compared with those without such medical history (mean ± SD: 47.1 ± 7.8, range: 38-59, versus 60.1 ± 7.6, range: 45-76; P < 0.0001). Male patients showed significantly lower free serum testosterone levels compared with controls at younger age (P < 0.0001 and 0.04 in the first and second age quartiles, respectively), as opposed to nonsignificant differences in older patients. In men ≤ 60 years of age, a biochemical hypogonadism (free serum testosterone < 0.05 ng/mL) was present in 53% (8/15) and 4% (2/49) of patients and controls, respectively (P < 0.0001). CONCLUSION: The results indicate that steroidal sex hormones might be involved in the presumably multifactorial pathophysiology of macular telangiectasia Type 2.

Natural history and effect of therapeutic interventions on subretinal fluid causing foveal detachment in macular telangiectasia type 2.

AIM: To report the natural history of subretinal fluid (SRF) causing foveal detachment in macular telangiectasia type 2 (MacTel) and our experience of therapeutic intervention with intravitreal steroids or antivascular endothelial growth factor inhibitor (anti-VEGF) agents in some cases. METHODS: Retrospective case series. Three of the MacTel study's largest registries were searched to identify eyes with foveal detachment. RESULTS: We identified 7 eyes from 6 exclusively female patients. The prevalence of foveal detachment was low, present in 1.4% of the assessed MacTel population. Age at presentation ranged from 50 to 66 years. Follow-up ranged from 2 to 8 years. There was late-phase leakage on fluorescein angiography from what was presumed to be ectatic capillaries. The SRF fluctuated without a rapid decline in visual acuity in cases that were not treated. When they were, intravitreal anti-VEGF and steroid therapy in general reduced SRF, at least temporarily, but did not halt the gradual long-term decrease in visual acuity. In one case, optical coherence tomography angiography showed significant reduction in the extent of the predominantly deep intraretinal vascular complex 1 month after anti-VEGF therapy. DISCUSSION AND CONCLUSIONS: As the natural history of this unusual MacTel phenotype is not characterised by rapid visual decline, intervention with intravitreal anti-VEGF or steroid therapy may not be necessary.

From Cabling the Atlantic to Wiring the World: A Review Essay on the 150th Anniversary of the Atlantic Telegraph Cable of 1866.

The year 2016 witnesses the 150th anniversary of laying the first successful transatlantic telegraph cables. This review essay offers a critical rereading of existing scholarship while simultaneously suggesting new perspectives for research. Telegraphy = globalization, the history of wiring the world commencing with the Atlantic cable of 1866 seems to suggest. At the same time, this essay argues, this equation should make scholars uneasy and cautious of a possible technological determinism retracing its steps back into the middle of scholarly debates on globalization. More attention needs to be paid to whose globalization we are talking about, what the globalization of politics, markets, and media means in connection to communication, and whether the cables really started something radically new. 150 years after laying the "first" Atlantic cable, there is still room for research. New spaces, theories, and methodologies, as well as alternate user groups including women and subalterns, offer avenues to test established scholarship on global communications.

Low-dose Actinomycin-D treatment re-establishes the tumoursuppressive function of P53 in RELA-positive ependymoma.

Ependymomas in children can arise throughout all compartments of the central nervous system (CNS). Highly malignant paediatric ependymoma subtypes are Group A tumours of the posterior fossa (PF-EPN-A) and RELA-fusion positive (ST-EPN-RELA) tumours in the supratentorial compartment. It was repeatedly reported in smaller series that accumulation of p53 is frequently observed in ependymomas and that immunohistochemical staining correlates with poor clinical outcome, while TP53 mutations are rare. Our TP53 mutation analysis of 130 primary ependymomas identified a mutation rate of only 3%. Immunohistochemical analysis of 398 ependymomas confirmed previous results correlating the accumulation of p53 with inferior outcome. Among the p53-positive ependymomas, the vast majority exhibited a RELA fusion leading to the hypothesis that p53 inactivation might be linked to RELA positivity.In order to assess the potential of p53 reactivation through MDM2 inhibition in ependymoma, we evaluated the effects of Actinomycin-D and Nutlin-3 treatment in two preclinical ependymoma models representing the high-risk subtypes PF-EPN-A and ST-EPN-RELA. The IC-50 of the agent as determined by metabolic activity assays was in the lower nano-molar range (0.2-0.7 nM). Transcriptome analyses of high-dose (100 nM), low-dose (5 nM) and non-treated cells revealed re-expression of p53 dependent genes including p53 upregulated modulator of apoptosis (PUMA) after low-dose treatment. At the protein level, we validated the Actinomycin-D induced upregulation of PUMA, and of p53 interaction partners MDM2 and p21. Proapoptotic effects of low-dose application of the agent were confirmed by flow cytometry. Thus, Actinomycin-D could constitute a promising therapeutic option for ST-EPN-RELA ependymoma patients, whose tumours frequently exhibit p53 inactivation.

S-100 B Concentrations Are a Predictor of Decreased Survival in Patients with Major Trauma, Independently of Head Injury.

BACKGROUND: Major trauma remains one of the principle causes of disability and death throughout the world. There is currently no satisfactory risk assessment to predict mortality in patients with major trauma. The aim of our study is to examine whether S-100 B protein concentrations correlate with injury severity and survival in patients with major trauma, with special emphasis on patients without head injury. METHODS: Our retrospective data analysis comprised adult patients admitted to our emergency department between 1.12. 2008 and 31.12 2010 with a suspected major trauma. S-100 B concentrations were routinely assessed in major trauma patients. RESULTS: A total of 27.7% (378) of all patients had major trauma. The median ISS was 24.6 (SD 8.4); 16.6% (63/378) of the patients died. S-100 B concentrations correlated overall with the ISS (p<0.0001). Patients who died had significantly higher S-100 B concentrations than survivors (8.2 µg/l versus 2.2 µg/l, p<0.0001). Polytraumatised patients with and without head trauma did not differ significantly with respect to S-100 B concentration (3.2 µg/l (SD 5.3) versus 2.9 µg/l (SD 3.8), respectively, p = 0.63) or with respect to Injury Severity Score (24.8 (SD 8.6) versus 24.2 (SD 8.1), respectively, p = 0.56). S-100 B concentrations correlated negatively with survival (p<0.0001) in all patients and in both subgroups (p = 0.001 and p = 0.006, respectively). CONCLUSIONS: S-100 concentrations on admission correlate positively with greater injury severity and decreased survival in major trauma patients, independently of the presence of a head injury. S-100 B protein levels at admission in patients with major trauma may therefore be used to assess outcome in all polytraumatised patients. These measurements should be subject to further evaluation.

Perception of Haidinger Brushes in Macular Disease Depends on Macular Pigment Density and Visual Acuity.

PURPOSE: To optimize the perceptibility of Haidinger brushes (HB) and to investigate its association with visual acuity and macular pigment density. METHODS: In this prospective cross-sectional study, each subject underwent best-corrected visual acuity (BCVA) testing, funduscopy, and assessment of macular pigment optical density (MPOD) using the two-wavelength fundus autofluorescence method. Haidinger brush visibility was tested with a rotating linear polarizer and a controllable three-color light-emitting diode (LED) panel as light source. A simple model of macular pigment absorption was used to predict HB visibility as a function of stimulus wavelength and MPOD. RESULTS: All control eyes (n = 92) and 34% of the 198 eyes of subjects with macular disease (age-related macular degeneration, n = 40; macular telangiectasia type 2, n = 52; Stargardt disease, n = 58; other retinal dystrophies, n = 48) perceived HB when an optimized test setup (464-nm LED light) was applied. The degree of psychophysical perception and the dependency on different wavelengths were in accordance with the absorptance model. In eyes of subjects with macular disease, minimum thresholds of MPOD and BCVA required for HB perception were identified. Subjects with macular telangiectasia type 2 showed lowest values of MPOD and were mostly unable to perceive HB despite relatively preserved BCVA. CONCLUSIONS: Macular pigment and a relatively preserved foveal function are necessary for the perception of HB. Haidinger brushes are usually not perceived by subjects with macular telangiectasia type 2, likely due to their characteristic foveal depletion of macular pigment.

Trypanosomosis: potential driver of selection in African cattle.

Trypanosomosis is a serious cause of reduction in productivity of cattle in tsetse-fly infested areas. Baoule and other local Taurine cattle breeds in Burkina Faso are trypanotolerant. Zebuine cattle, which are also kept there are susceptible to trypanosomosis but bigger in body size. Farmers have continuously been intercrossing Baoule and Zebu animals to increase production and disease tolerance. The aim of this study was to compare levels of zebuine and taurine admixture in genomic regions potentially involved in trypanotolerance with background admixture of composites to identify differences in allelic frequencies of tolerant and non-tolerant animals. The study was conducted on 214 animals (90 Baoule, 90 Zebu, and 34 composites), genotyped with 25 microsatellites across the genome and with 155 SNPs in 23 candidate regions. Degrees of admixture of composites were analyzed for microsatellite and SNP data separately. Average Baoule admixture based on microsatellites across the genomes of the Baoule- Zebu composites was 0.31, which was smaller than the average Baoule admixture in the trypanosomosis candidate regions of 0.37 (P = 0.15). Fixation index F ST measured in the overall genome based on microsatellites or with SNPs from candidate regions indicates strong differentiation between breeds. Nine out of 23 regions had F ST ≥ 0.20 calculated from haplotypes or individual SNPs. The levels of admixture were significantly different from background admixture, as revealed by microsatellite data, for six out of the nine regions. Five out of the six regions showed an excess of Baoule ancestry. Information about best levels of breed composition would be useful for future breeding ctivities, aiming at trypanotolerant animals with higher productive capacity.

Evaluating the performance of sensory quality control: the case of boar taint.

Detection of malodours referred to as 'boar taint' in entire male pigs is essential for quality control when refraining piglet castration. This study analysed the sensitivity and specificity of sensory evaluation by trained assessors (n=18) compared to chemical analysis of two marker compounds (androstenone, skatole) in backfat (n=794). Taking the measurement uncertainty into consideration, several cut-off thresholds for chemical analysis were exemplarily evaluated. Using the panel average score, sensitivity and specificity of sensory analysis ranged from 61 to 69% and 77 to 85%, respectively. Performance of individual assessors varied highly (sensitivity: 47 to 86%; specificity: 45 to 88%) and correlated to olfactory acuity to the compounds. According to receiver operating characteristic-curves, the average panel performed better than single assessors regardless of the sensory criterion shift. Agreement plots illustrate that high skatole levels are better detected than high androstenone levels (useful for assessor feedback). The agreement between sensory and chemical analyses was moderate. Assessors need to be selected carefully.

The Mount Sinai clinical pathway for the management of pheochromocytoma.

OBJECTIVE: Pheochromocytomas are complex tumors that require a comprehensive and systematic management plan orchestrated by a multidisciplinary team. METHODS: To achieve these ends, The Mount Sinai Adrenal Center hosted an interdisciplinary retreat where experts in adrenal disorders assembled with the aim of developing a clinical pathway for the management of pheochromocytomas. RESULTS: The result was a consensus for the diagnosis, perioperative management, and postoperative management of pheochromocytomas, with specific recommendations from our team of adrenal experts, as well as a review of the current literature. CONCLUSION: Our clinical pathway can be applied by other institutions directly or may serve as a guide for institution-specific management.

Patient and physician gender concordance in preventive care in university primary care settings.

OBJECTIVE: To assess the quality of preventive care according to physician and patient gender in a country with universal health care coverage. METHODS: We assessed a retrospective cohort study of 1001 randomly selected patients aged 50-80 years followed over 2 years (2005-2006) in 4 Swiss university primary care settings (Basel, Geneva, Lausanne, Zürich). We used indicators derived from RAND's Quality Assessment Tools and examined percentages of recommended preventive care. Results were adjusted using hierarchical multivariate logistic regression models. RESULTS: 1001 patients (44% women) were followed by 189 physicians (52% women). Female patients received less preventive care than male patients (65.2% vs. 72.1%, p<0.001). Female physicians provided significantly more preventive care than male physicians (p=0.01) to both female (66.7% vs. 63.6%) and male patients (73.4% vs. 70.7%). After multivariate adjustment, differences according to physician (p=0.02) and patient gender (p<0.001) remained statistically significant. Female physicians provided more recommended cancer screening than male physicians (78.4 vs. 71.9%, p=0.01). CONCLUSIONS: In Swiss university primary care settings, female patients receive less preventive care than male patients, with female physicians providing more preventive care than male physicians. Greater attention should be paid to female patients in preventive care and to why female physicians tend to provide better preventive care.

Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man.

Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, the two conditions do not always coincide and the molecular determinants of "healthy" versus "unhealthy" obesity remain ill-defined. Chronic metabolic inflammation (metaflammation) is believed to be pivotal. Here, we tested a hypothesized anti-inflammatory role for heme oxygenase-1 (HO-1) in the development of metabolic disease. Surprisingly, in matched biopsies from "healthy" versus insulin-resistant obese subjects we find HO-1 to be among the strongest positive predictors of metabolic disease in humans. We find that hepatocyte and macrophage conditional HO-1 deletion in mice evokes resistance to diet-induced insulin resistance and inflammation, dramatically reducing secondary disease such as steatosis and liver toxicity. Intriguingly, cellular assays show that HO-1 defines prestimulation thresholds for inflammatory skewing and NF-κB amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease.

STAT1ß is not dominant negative and is capable of contributing to gamma interferon-dependent innate immunity.

The transcription factor STAT1 is essential for interferon (IFN)-mediated immunity in humans and mice. STAT1 function is tightly regulated, and both loss- and gain-of-function mutations result in severe immune diseases. The two alternatively spliced isoforms, STAT1α and STAT1ß, differ with regard to a C-terminal transactivation domain, which is absent in STAT1ß. STAT1ß is considered to be transcriptionally inactive and to be a competitive inhibitor of STAT1α. To investigate the functions of the STAT1 isoforms in vivo, we generated mice deficient for either STAT1α or STAT1ß. As expected, the functions of STAT1α and STAT1ß in IFN-α/ß- and IFN-λ-dependent antiviral activity are largely redundant. In contrast to the current dogma, however, we found that STAT1ß is transcriptionally active in response to IFN-γ. In the absence of STAT1α, STAT1ß shows more prolonged IFN-γ-induced phosphorylation and promoter binding. Both isoforms mediate protective, IFN-γ-dependent immunity against the bacterium Listeria monocytogenes, although with remarkably different efficiencies. Our data shed new light on the potential contributions of the individual STAT1 isoforms to STAT1-dependent immune responses. Knowledge of STAT1ß's function will help fine-tune diagnostic approaches and help design more specific strategies to interfere with STAT1 activity.

Conditional ablation of TYK2 in immunity to viral infection and tumor surveillance.

Tyrosine kinase 2 (TYK2) has a pivotal role in immunity to infection and tumor surveillance. It is associated with several cytokine receptor chains including type I interferon (IFN) receptor 1 (IFNAR1), interleukin- (IL-) 12 receptor beta 1 (IL-12Rb1) and IL-10R2. We have generated a mouse with a conditional Tyk2 null allele and proved integrity of the conditional Tyk2 locus. TYK2 was successfully removed by the use of ubiquitous and tissue-specific Cre-expressing mouse strains. Myeloid TYK2 was found to critically contribute to the defense against murine cytomegalovirus. Ubiquitous TYK2 ablation severely impaired tumor immunosurveillance, while deletion in myeloid, dendritic or T cells alone showed no effect. The conditional Tyk2 mouse strain will be instrumental to further dissect TYK2 functions in infection, inflammation and cancer.