Microbiota-Induced Type I Interferons Instruct a Poised Basal State of Dendritic Cells.

Environmental signals shape host physiology and fitness. Microbiota-derived cues are required to program conventional dendritic cells (cDCs) during the steady state so that they can promptly respond and initiate adaptive immune responses when encountering pathogens. However, the molecular underpinnings of microbiota-guided instructive programs are not well understood. Here, we report that the indigenous microbiota controls constitutive production of type I interferons (IFN-I) by plasmacytoid DCs. Using genome-wide analysis of transcriptional and epigenetic regulomes of cDCs from germ-free and IFN-I receptor (IFNAR)-deficient mice, we found that tonic IFNAR signaling instructs a specific epigenomic and metabolic basal state that poises cDCs for future pathogen combat. However, such beneficial biological function comes with a trade-off. Instructed cDCs can prime T cell responses against harmless peripheral antigens when removing roadblocks of peripheral tolerance. Our data provide fresh insights into the evolutionary trade-offs that come with successful adaptation of vertebrates to their microbial environment.

Lipid-Droplet Formation Drives Pathogenic Group 2 Innate Lymphoid Cells in Airway Inflammation.

Innate lymphoid cells (ILCs) play an important role in the control and maintenance of barrier immunity. However, chronic activation of ILCs results in immune-mediated pathology. Here, we show that tissue-resident type 2 ILCs (ILC2s) display a distinct metabolic signature upon chronic activation. In the context of allergen-driven airway inflammation, ILC2s increase their uptake of both external lipids and glucose. Externally acquired fatty acids are transiently stored in lipid droplets and converted into phospholipids to promote the proliferation of ILC2s. This metabolic program is imprinted by interleukin-33 (IL-33) and regulated by the genes Pparg and Dgat1, which are both controlled by glucose availability and mTOR signaling. Restricting dietary glucose by feeding mice a ketogenic diet largely ablated ILC2-mediated airway inflammation by impairing fatty acid metabolism and the formation of lipid droplets. Together, these results reveal that pathogenic ILC2 responses require lipid metabolism and identify ketogenic diet as a potent intervention strategy to treat airway inflammation.

Mitochondrial Dysfunction Contributes to Impaired Cytokine Production of CD56bright Natural Killer Cells From Human Immunodeficiency Virus-Infected Individuals Under Effective Antiretroviral Therapy.

Human immunodeficiency virus (HIV) infection is associated with impaired natural killer (NK) cell activity, which is only incompletely restored under antiretroviral therapy. Analyzing the bioenergetics profiles of oxygen consumption, we observed that several parameters were significantly reduced in HIV+ NK cells, indicating a mitochondrial defect. Accordingly, we found HIV+ CD56bright NK cells to display a decreased mitochondrial membrane potential and mitochondrial mass. Both parameters were positively correlated with interferon gamma (IFN-γ) production of NK cells. Finally, we demonstrated that stimulation of HIV+ NK cells with MitoTEMPO, a mitochondria-targeting antioxidant, significantly improved IFN-γ production. We identified mitochondrial dysfunction as a mechanism that contributes to impaired NK cell function.

Impact of stimulus format and reward value on quantity discrimination in capuchin and squirrel monkeys.

Quantity discrimination abilities are seen in a diverse range of species with similarities in performance patterns, suggesting common underlying cognitive mechanisms. However, methodological factors that impact performance make it difficult to draw broad phylogenetic comparisons of numerical cognition across studies. For example, some Old World monkeys selected a higher quantity stimulus more frequently when choosing between inedible (pebbles) than edible (food) stimuli. In Experiment 1 we presented brown capuchin (Cebus [Sapajus] paella) and squirrel monkeys (Saimiri sciureus) with the same two-choice quantity discrimination task in three different stimulus conditions: edible, inedible, and edible replaced (in which choice stimuli were food items that stood in for the same quantity of food items that were given as a reward). Unlike Old World monkeys, capuchins selected the higher quantity stimulus more in the edible condition and squirrel monkeys showed generally poor performance across all stimulus types. Performance patterns suggested that differences in subjective reward value might motivate differences in choice behavior between and within species. In Experiment 2 we manipulated the subjective reinforcement value of the reward by varying reward type and delay to reinforcement and found that delay to reinforcement had no impact on choice behavior, while increasing the value of the reward significantly improved performance by both species. The results of this study indicate that species presented with identical tasks may respond differently to methodological factors such as stimulus and reward types, resulting in significant differences in choice behavior that may lead to spurious suggestions of species differences in cognitive abilities.

Applications of high-resolution magic angle spinning MRS in biomedical studies II-Human diseases.

High-resolution magic angle spinning (HRMAS) MRS is a powerful method for gaining insight into the physiological and pathological processes of cellular metabolism. Given its ability to obtain high-resolution spectra of non-liquid biological samples, while preserving tissue architecture for subsequent histopathological analysis, the technique has become invaluable for biochemical and biomedical studies. Using HRMAS MRS, alterations in measured metabolites, metabolic ratios, and metabolomic profiles present the possibility to improve identification and prognostication of various diseases and decipher the metabolomic impact of drug therapies. In this review, we evaluate HRMAS MRS results on human tissue specimens from malignancies and non-localized diseases reported in the literature since the inception of the technique in 1996. We present the diverse applications of the technique in understanding pathological processes of different anatomical origins, correlations with in vivo imaging, effectiveness of therapies, and progress in the HRMAS methodology.

Do monkeys compare themselves to others?

Social comparisons are a fundamental characteristic of human behaviour, yet relatively little is known about their evolutionary foundations. Adapting the co-acting paradigm from human research (Seta in J Pers Soc Psychol 42:281-291, 1982. doi: 10.1037//0022-3514.42.2.281), we examined how the performance of a partner influenced subjects' performance in long-tailed macaques (Macaca fascicularis). Using parallel testing in touch screen setups in which subjects had to discriminate familiar and novel photographs of men and women, we investigated whether accuracy and reaction time were influenced by partner performance and relationship quality (affiliate vs. non-affiliate). Auditory feedback about the alleged performance of the co-actor was provided via playback; partner performance was either moderately or extremely better or worse than subject performance. We predicted that subjects would assimilate to moderately different comparison standards as well as to affiliates and contrast away from extreme standards and non-affiliates. Subjects instantly generalized to novel pictures. While accuracy was not affected by any of the factors, long reaction times occurred more frequently when subjects were tested with a non-affiliate who was performing worse, compared to one who was doing better than them (80% quantile worse: 5.1, better: 4.3 s). For affiliate co-actors, there was no marked effect (worse: 4.4, better: 4.6 s). In a control condition with no auditory feedback, subjects performed somewhat better in the presence of affiliates (M = 77.8% correct) compared to non-affiliates (M = 71.1%), while reaction time was not affected. Apparently, subjects were sensitive to partner identity and performance, yet variation in motivation rather than assimilation and contrast effects may account for the observed effects.

Biomechanical Analysis of the Modified Kessler, Lahey, Adelaide, and Becker Sutures for Flexor Tendon Repair.

PURPOSE: To compare the biomechanical properties of the modified Kessler, Lahey, Adelaide, and Becker repairs, which are marked by either a locking-loop or a cross-lock configuration. METHODS: Ninety-six lacerated porcine flexor tendons were repaired using the respective core suture and an epitendinous repair. Biomechanical testing was conducted under static and cyclic loads. Parameters of interest were 2-mm gap formation force, displacement during different loads, stiffness, maximum force, and mode of failure. RESULTS: The meaningful gap formation occurred in all 4 repairs at similar tension loads without any significant differences. Maximum force was highest in the Becker repair with a considerable difference compared with the modified Kessler and Lahey sutures. The Adelaide repair showed the highest stiffness. Overall, the displacement during cyclic loading demonstrated similar results with an exception between the Lahey and the Adelaide repairs at 10 N load. Failure by suture pull-out occurred in 42% in the modified Kessler, in 38% in the Lahey, and in 4% in the Adelaide repairs. The Becker repair failed only by suture rupture. CONCLUSIONS: The results of our study suggest that the difference between the 4-strand repairs with a cross-lock or a locking-loop configuration is minor in regard to gap formation. A strong epitendinous suture and the application of core suture pretension might prevent differences in gapping. However, the modified Kessler and Lahey repairs had an inferior maximum tensile strength and were prone to early failure caused by the narrow locking loops with their limited locking power. CLINICAL RELEVANCE: We suggest that surgeons should use pre-tension in repaired tendons to improve gap resistance and should avoid narrow locking loop anchoring to the tendon.

Monkeys perform as well as apes and humans in a size discrimination task.

Whether the cognitive competences of monkeys and apes are rather similar or whether the larger-brained apes outperform monkeys in cognitive experiments is a highly debated topic. Direct comparative analyses are therefore essential to examine similarities and differences among species. We here compared six primate species, including humans, chimpanzees, bonobos, gorillas (great apes), olive baboons, and long-tailed macaques (Old World monkeys) in a task on fine-grained size discrimination. Except for gorillas, subjects of all taxa (i.e. humans, apes, and monkeys) were able to discriminate three-dimensional cubes with a volume difference of only 10 % (i.e. cubes of 50 and 48 mm side length) and performed only slightly worse when the cubes were presented successively. The minimal size discriminated declined further with increasing time delay between presentations of the cubes, highlighting the difficulty to memorize exact size differences. The results suggest that differences in brain size, as a proxy for general cognitive abilities, did not account for variation in performance, but that differential socio-ecological pressures may better explain species differences. Our study highlights the fact that differences in cognitive abilities do not always map neatly onto phylogenetic relationships and that in a number of cognitive experiments monkeys do not fare significantly worse than apes, casting doubt on the assumption that larger brains per se confer an advantage in such kinds of tests.

Machine learning models for predicting severe COVID-19 outcomes in hospitals.

The aim of this observational retrospective study is to improve early risk stratification of hospitalized Covid-19 patients by predicting in-hospital mortality, transfer to intensive care unit (ICU) and mechanical ventilation from electronic health record data of the first 24 h after admission. Our machine learning model predicts in-hospital mortality (AUC = 0.918), transfer to ICU (AUC = 0.821) and the need for mechanical ventilation (AUC = 0.654) from a few laboratory data of the first 24 h after admission. Models based on dichotomous features indicating whether a laboratory value exceeds or falls below a threshold perform nearly as good as models based on numerical features. We devise completely data-driven and interpretable machine-learning models for the prediction of in-hospital mortality, transfer to ICU and mechanical ventilation for hospitalized Covid-19 patients within 24 h after admission. Numerical values of. CRP and blood sugar and dichotomous indicators for increased partial thromboplastin time (PTT) and glutamic oxaloacetic transaminase (GOT) are amongst the best predictors.

Role of HIPEC after Complete Cytoreductive Surgery (CRS) in Peritoneal Recurrence of Platinum-Sensitive Recurrent Ovarian Cancer (OC): The Aim for Standardization at Two Reference Centers for CRS.

BACKGROUND: This bicentric study evaluated cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for platinum-sensitive recurrent ovarian cancer patients. METHODS: The data of 88 patients with the first peritoneal recurrence of platinum-sensitive epithelial ovarian cancer who underwent CRS and HIPEC from a prospective HIPEC registry were retrospectively investigated. Endpoints were feasibility, chemotherapeutic compound, time of exposure, complications, and overall survival. RESULTS: The median follow-up was 4.7 years (95%-CI 4.6-5.5). The median age was 55.8 years (IQR: 50.3-66.2). Eighty-four patients (95.5%) had high-grade serous histology. The median peritoneal cancer index was 12.0 (IQR: 7.0-20.5). Sixty-five patients (73.9%) had complete cytoreduction (CCR 0). Thirty-eight patients (43.2%) received HIPEC for 60 min, and fifty patients (56.8%) for 90 min. Eighteen patients (20.5%) had grade III to IV complications. One patient (1.1%) died perioperatively. The overall median survival was 43.1 months (95%-CI 34.1-52.2), and the 5-year survival rate was 39.7%. Only 90 min HIPEC and cisplatin were associated with survival. CONCLUSION: In well-selected patients with platinum-sensitive recurrent ovarian cancer, survival may correlate with complete CRS and 90 min cisplatin-based HIPEC. We confirmed the results of primary OC studies; therefore, this combination should be used for further analysis in the recurrent situation.

Enhanced l-Malic Acid Production by Aspergillus oryzae DSM 1863 Using Repeated-Batch Cultivation.

l-Malic acid is a C4-dicarboxylic acid and a potential key building block for a bio-based economy. At present, malic acid is synthesized petrochemically and its major market is the food and beverages industry. In future, malic acid might also serve as a building block for biopolymers or even replace the commodity chemical maleic anhydride. For a sustainable production of l-malic acid from renewable resources, the microbial synthesis by the mold Aspergillus oryzae is one possible route. As CO2 fixation is involved in the biosynthesis, high yields are possible, and at the same time greenhouse gases can be reduced. In order to enhance the production potential of the wild-type strain Aspergillus oryzae DSM 1863, process characteristics were studied in shake flasks, comparing batch, fed-batch, and repeated-batch cultivations. In the batch process, a prolonged cultivation time led to malic acid consumption. Keeping carbon source concentration on a high level by pulsed feeding could prolong cell viability and cultivation time, however, did not result in significant higher product levels. In contrast, continuous malic acid production could be achieved over six exchange cycles and a total fermentation time of 19 days in repeated-batch cultivations. Up to 178 g/L l-malic acid was produced. The maximum productivity (0.90 ± 0.05 g/L/h) achieved in the repeated-batch cultivation had more than doubled than that achieved in the batch process and also the average productivity (0.42 ± 0.03 g/L/h for five exchange cycles and 16 days) was increased considerably. Further repeated-batch experiments confirmed a positive effect of regular calcium carbonate additions on pH stability and malic acid synthesis. Besides calcium carbonate, nitrogen supplementation proved to be essential for the prolonged malic acid production in repeated-batch. As prolonged malic acid production was only observed in cultivations with product removal, product inhibition seems to be the major limiting factor for malic acid production by the wild-type strain. This study provides a systematic comparison of different process strategies under consideration of major influencing factors and thereby delivers important insights into natural l-malic acid production.

Inferential reasoning and modality dependent discrimination learning in olive baboons (Papio hamadryas anubis).

Apes use inferential reasoning by exclusion to locate food both in the visual and auditory domain. To test whether olive baboons (Papio hamadryas anubis) show similar abilities as the apes object choice experiments with differing information about food located in 1 of 2 cups were conducted in the visual and auditory modality. Although all baboons (N = 7) were able to locate the reward when they had previously seen it, they failed to make use of auditory cues or arbitrary acoustic signals. When only partial information was given (i.e., only 1 cup was opened) 4 of the baboons were apparently able to infer the location of the reward by reasoning, whereas the other 3 may have adopted an alternative strategy ("avoid the empty cup"). In addition, 3 of the baboons were able to use arbitrary visual markers to locate the food reward. The results suggest that inferential reasoning is not restricted to apes but is shared with Old World monkeys. Furthermore, they also highlight some important differences in the processing of auditory versus visual information in operant conditioning settings.

Adiponectin Limits IFN-γ and IL-17 Producing CD4 T Cells in Obesity by Restraining Cell Intrinsic Glycolysis.

Compared to the innate immune system, the contribution of the adaptive immune response during obesity and insulin resistance is still not completely understood. Here we demonstrate that high fat diet (HFD) increases the frequencies of activated CD4+ and CD8+ T cells and frequencies of T cells positive for IFN-γ and IL-17 in the adipose tissue. The adipocyte-derived soluble factor adiponectin reduces IFN-γ and IL-17 positive CD4+ T cells from HFD mice and dampens the differentiation of naïve T cells into Th1 cells and Th17 cells. Adiponectin reduces Th17 cell differentiation and restrains glycolysis in an AMPK dependent fashion. Treatment with adult worm extracts of the rodent filarial nematode Litomosoides sigmodontis (LsAg) reduces adipose tissue Th1 and Th17 cell frequencies during HFD and increases adiponectin levels. Stimulation of T cells in the presence of adipocyte-conditioned media (ACM) from LsAg-treated mice reduces Th1 and Th17 frequencies and this effect was abolished when ACM was treated with an adiponectin neutralizing antibody. Collectively, these data reveal a novel role of adiponectin in controlling pro-inflammatory CD4+ T cells during obesity and suggest that the beneficial role of helminth infections and helminth-derived products on obesity and insulin resistance may be in part mediated by adiponectin.

Establishing an infrastructure for collaboration in primate cognition research.

Inferring the evolutionary history of cognitive abilities requires large and diverse samples. However, such samples are often beyond the reach of individual researchers or institutions, and studies are often limited to small numbers of species. Consequently, methodological and site-specific-differences across studies can limit comparisons between species. Here we introduce the ManyPrimates project, which addresses these challenges by providing a large-scale collaborative framework for comparative studies in primate cognition. To demonstrate the viability of the project we conducted a case study of short-term memory. In this initial study, we were able to include 176 individuals from 12 primate species housed at 11 sites across Africa, Asia, North America and Europe. All subjects were tested in a delayed-response task using consistent methodology across sites. Individuals could access food rewards by remembering the position of the hidden reward after a 0, 15, or 30-second delay. Overall, individuals performed better with shorter delays, as predicted by previous studies. Phylogenetic analysis revealed a strong phylogenetic signal for short-term memory. Although, with only 12 species, the validity of this analysis is limited, our initial results demonstrate the feasibility of a large, collaborative open-science project. We present the ManyPrimates project as an exciting opportunity to address open questions in primate cognition and behaviour with large, diverse datasets.

Hand preferences in Barbary macaques (Macaca sylvanus).

Nearly 90% of humans are right-handed, raising the question of the evolutionary origins of this trait. While lateralisation of certain actions appears to be widespread in vertebrates, the question of whether nonhuman primates exhibit hand preferences at the population level is often contested. We observed Barbary macaques (Macaca sylvanus) living in the outdoor enclosure "La Forêt des Singes" at Rocamadour, France, while performing simple unimanual and coordinated bimanual tasks. For the unimanual task, we recorded continuously which hand they used reaching for grains. For the coordinated bimanual tasks, a semi-transparent box and a tube baited with peanut butter were presented to the macaques and the hand used to open the box or reach into the tube, respectively, was recorded. We found no significant hand preference in any of the tasks at the population level, but found individual hand preferences, the extent of which varied among individuals. For the unimanual, but not the bimanual task, we found that the handedness index increased with age. Our results add to the growing body of evidence that monkeys do not show hand preference at the population level.

Metabolic tumour volume of anal carcinoma on (18)FDG PET/CT before combined radiochemotherapy is the only independant determinant of recurrence free survival.

AIM: to determine whether [(18)F]2-fluoro-2-deoxyglucose (FDG) positron emission tomography and X-ray computed tomography (PET/CT) findings and metabolic parameters before combined chemo- and radiotherapy (CRT) have a prognostic value in patients with anal carcinoma. MATERIALS AND METHODS: 45 patients with anal cancer who underwent pre-treatment FDG-PET/CT were included. Metabolic parameters, recurrence and anal carcinoma specific survival were analyzed. RESULTS: SUV max and metabolic volume of the primary tumour were significantly higher in patients with lymph node or distant metastases than in those with locally confined disease (p=0.020 and p=0.015, respectively). The extent of disease (local tumour only, lymph node or distant metastases) was highly predictive of both for recurrence free and disease specific survival (p=0.010 and p<0.001, respectively). Recurrence free (p=0.010) and anal carcinoma specific survival (p=0.006) differed significantly between patients with a metabolic volume ≤45ml and >45ml. Multivariate analysis revealed that a metabolic volume >45ml was the only significant independent determinant (p=0.19) for recurrence free survival whereas for anal carcinoma specific survival the extent of disease was identified as the only significant independent determinant (p=0.002). CONCLUSIONS: the extent of disease on FDG PET/CT before combined radio-chemotherapy is strongly predictive of prognosis in anal cancer. Furthermore, patients with a large metabolic volume of the primary tumour (>45ml) are at significantly higher risk of recurrence.

Critical role of fatty acid metabolism in ILC2-mediated barrier protection during malnutrition and helminth infection.

Innate lymphoid cells (ILC) play an important role in many immune processes, including control of infections, inflammation, and tissue repair. To date, little is known about the metabolism of ILC and whether these cells can metabolically adapt in response to environmental signals. Here we show that type 2 innate lymphoid cells (ILC2), important mediators of barrier immunity, predominantly depend on fatty acid (FA) metabolism during helminth infection. Further, in situations where an essential nutrient, such as vitamin A, is limited, ILC2 sustain their function and selectively maintain interleukin 13 (IL-13) production via increased acquisition and utilization of FA. Together, these results reveal that ILC2 preferentially use FAs to maintain their function in the context of helminth infection or malnutrition and propose that enhanced FA usage and FA-dependent IL-13 production by ILC2 could represent a host adaptation to maintain barrier immunity under dietary restriction.

Bayesian Cure Rate Modeling of Local Tumor Control: Evaluation in Stereotactic Body Radiation Therapy for Pulmonary Metastases.

PURPOSE: Most radiobiological models for prediction of tumor control probability (TCP) do not account for the fact that many events could remain unobserved because of censoring. We therefore evaluated a set of TCP models that take into account this censoring. METHODS AND MATERIALS: We applied 2 fundamental Bayesian cure rate models to a sample of 770 pulmonary metastasis treated with stereotactic body radiation therapy at German, Austrian, and Swiss institutions: (1) the model developed by Chen, Ibrahim and Sinha (the CIS99 model); and (2) a mixture model similar to the classic model of Berkson and Gage (the BG model). In the CIS99 model the number of clonogens surviving the radiation treatment follows a Poisson distribution, whereas in the BG model only 1 dominant recurrence-competent tissue mass may remain. The dose delivered to the isocenter, tumor size and location, sex, age, and pretreatment chemotherapy were used as covariates for regression. RESULTS: Mean follow-up time was 15.5 months (range: 0.1-125). Tumor recurrence occurred in 11.6% of the metastases. Delivered dose, female sex, peripheral tumor location and having received no chemotherapy before RT were associated with higher TCP in all models. Parameter estimates of the CIS99 were consistent with the classical Cox proportional hazards model. The dose required to achieve 90% tumor control after 15.5 months was 146 (range: 114-188) Gy10 in the CIS99 and 133 (range: 101-164) Gy10 in the BG model; however, the BG model predicted lower tumor control at long (≳20 months) follow-up times and gave a suboptimal fit to the data compared to the CIS99 model. CONCLUSIONS: Biologically motivated cure rate models allow adding the time component into TCP modeling without being restricted to the follow-up period which is the case for the Cox model. In practice, application of such models to the clinical setting could allow for adaption of treatment doses depending on whether local control should be achieved in the short or longer term.