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Despite increasing interest in using Artificial Intelligence (AI) and Machine Learning (ML) models for drug development, effectively interpreting their predictions remains a challenge, which limits their impact on clinical decisions. We address this issue by providing a practical guide to SHapley Additive exPlanations (SHAP), a popular feature‐based interpretability method, which can be seamlessly integrated into supervised ML models to gain a deeper understanding of their predictions, thereby enhancing their transparency and trustworthiness. This tutorial focuses on the application of SHAP analysis to standard ML black‐box models for regression and classification problems. We provide an overview of various visualization plots and their interpretation, available software for implementing SHAP, and highlight best practices, as well as special considerations, when dealing with binary endpoints and time‐series models. To enhance the reader's understanding for the method, we also apply it to inherently explainable regression models. Finally, we discuss the limitations and ongoing advancements aimed at tackling the current drawbacks of the method.

Understanding the evolution of intelligence rests on comparative analyses of brain sizes as well as the assessment of cognitive skills of different species in relation to potential selective pressures such as environmental conditions and social organization. Because of the strong interest in human cognition, much previous work has focused on the comparison of the cognitive skills of human toddlers to those of our closest living relatives, i.e. apes. Such analyses revealed that apes and children have relatively similar competencies in the physical domain, while human children excel in the socio-cognitive domain; in particular in terms of attention sharing, cooperation, and mental state attribution. To develop a full understanding of the evolutionary dynamics of primate intelligence, however, comparative data for monkeys are needed. We tested 18 Old World monkeys (long-tailed macaques and olive baboons) in the so-called Primate Cognition Test Battery (PCTB) (Herrmann et al. 2007, Science). Surprisingly, our tests revealed largely comparable results between Old World monkeys and the Great apes. Single comparisons showed that chimpanzees performed only better than the macaques in experiments on spatial understanding and tool use, but in none of the socio-cognitive tasks. These results question the clear-cut relationship between cognitive performance and brain size and--prima facie--support the view of an accelerated evolution of social intelligence in humans. One limitation, however, is that the initial experiments were devised to tap into human specific skills in the first place, thus potentially underestimating both true nonhuman primate competencies as well as species differences.

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 (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.

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 CO 2 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.

Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate that delivers a cytotoxic microtubule inhibitor monomethyl auristatin E (MMAE) payload to c-Met-expressing tumor cells. It received accelerated approval from the US FDA for the treatment of adults with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with high c-Met protein overexpression (≥ 50% of tumor cells with strong [3+] staining) at a dose of 1.9 mg/kg every 2 weeks (Q2W; maximum 190 mg for patients ≥ 100 kg) as an intravenous infusion. Population pharmacokinetic (PK) modeling used pooled data from a phase 1 (N = 35) and phase 2 study (N = 269) to describe the Teliso-V conjugate and unconjugated MMAE PK and evaluate the impact of intrinsic and extrinsic factors on exposures in patients with solid tumors. Body weight, race, albumin, and anti-drug antibody status were identified as significant covariates on Teliso-V conjugate clearance, but did not result in clinically meaningful changes in exposure. The exposure-response evaluations for efficacy (based on the pivotal phase 2 study) showed significant correlations between conjugate exposure and overall response rates. Higher conjugate exposures were also correlated with improved progression-free survival and overall survival, demonstrating meaningful clinical benefit with the 1.9 mg/kg Q2W dosing regimen. Exposure-safety evaluations showed significant relationships between conjugate exposures and grade ≥ 2 and grade ≥ 3 peripheral neuropathy, and grade ≥ 2 corneal epitheliopathy. Unconjugated MMAE payload exposures were correlated with a greater probability of grade ≥ 3 treatment-emergent adverse events. The 1.9 mg/kg Q2W dose maximized efficacy while balancing adverse events in patients with c-Met overexpressing NSCLC.

Background: Stannous ions and polyphenols are effective substances in preventive dentistry. The present study’s aim was to investigate whether a combination of these substance groups can achieve increased efficacy. Methods: Initial biofilm formation was performed on bovine enamel slabs, carried by 10 subjects intraorally. The subjects rinsed with tannic acid, SnCl2, SnF2, a combination (50:50) of tannic acid and SnCl2, or a combination of tannic acid and SnF2, with no rinsing in the negative control. Bacterial adherence, glucan formation (8 h, 48 h oral exposition,) and calcium release kinetics were measured (pH 2; 2.3; 3). Statistics were performed with the Kruskal–Wallis test (p < 0.05), Mann–Whitney U test (p < 0.05), and Bonferroni–Holm correction. Results: All rinsing solutions reduced bacterial adherence by more than 50%. Initial bacterial colonization and glucan formation was significantly reduced by SnF2 and SnCl2 as well as their combinations with tannic acid. The most significant reductions in calcium release at pH 2; 2.3; and 3 were obtained by SnF2 and the combination of SnF2 and tannic acid. At the acidic pH 2.0, SnF2, SnCl2, and tannic acid and SnF2 showed significant protection compared to the control (p ≤ 0.01). TEM micrographs indicated that rinsing with SnF2 and tannic acid leads to pronounced electron dense, thick pellicle layers. Conclusions: SnCl2 and SnF2, as well as their combinations with tannic acid, led to a reduction in initial bacterial colonization and glucan formation, showing an erosion-protective effect. These findings confirm the clinical applicability hitherto suspected by in vitro findings.

High salt diet (HSD) is known to reduce cancer growth in some tumor models, which has been attributed to tissue accumulation of sodium that enhances local anti-tumor immunity. Here, we show that a HSD inhibits melanoma growth independent of sodium accumulation and immune cells in skin and lung. Melanoma cells from mice on a HSD upregulated the metabolic inhibitor Tuberous sclerosis complex 2 (TSC2), causing metabolic shutdown despite nutrient availability. Furthermore, Microphthalmia-associated transcription factor (MITF), a crucial regulator of melanoma metabolism and differentiation, was upregulated, resulting in enhanced melanogenesis and cell cycle arrest. Thus, a HSD reversed the de-differentiation of melanoma cells and promoted their re-differentiation into a “normal” melanocytic state. These findings suggest that the anti-tumor effect of HSD may be tumor-specific and in some cases immune cell-independent.

Methodological variations in experimental conditions can strongly influence animals' performances in cognitive tests. Specifically, the procedure of the so-called object-choice task has been controversially discussed; here, a human experimenter indicates the location of hidden food by pointing or gazing at one of two or more containers. Whereas dogs usually succeed, results for nonhuman primates are ambiguous. In the standard version of the task the majority of subjects do not respond appropriately to human pointing. However, modifying the task setup, such as placing the containers further apart, seems to improve subjects' performances, suggesting that cue salience may be an important variable. Here we investigated whether the visibility of the experimenter inhibits long-tailed macaques' (Macaca fascicularis) usage of the pointing cue. In our baseline condition, with the experimenter fully visible, the monkeys chose the correct container in 61% of the trials. The performance increased significantly, however, when the experimenter was hidden behind a curtain and only the arm of the experimenter, a doll's arm, or a stick was visible. Furthermore, the monkeys performed significantly better when the tip of the pointing finger or device was close to the target compared to the more distant condition. Intriguingly, after these experiments the monkeys' performance was also significantly improved in the baseline condition (70%). Apparently, the monkeys were first distracted by the presence of the experimenter, but then learned to use the cue. These findings highlight the importance of the test conditions, and question some of the assumptions about species-specific differences in the object-choice task.

A range of animal species possess an evolutionarily ancient system for representing number, which provides the foundation for simple arithmetical operations such as addition and numerical comparisons. Surprisingly, non-human primates tested in ecologically, highly valid quantity discrimination tasks using edible items often show a relatively low performance, suggesting that stimulus salience interferes with rational decision making. Here we show that quantity discrimination was indeed significantly enhanced when monkeys were tested with inedible items compared with food items (84 versus 69% correct). More importantly, when monkeys were tested with food, but rewarded with other food items, the accuracy was equally high (86%). The results indicate that the internal representation of the stimuli, not their physical quality, determined performance. Reward replacement apparently facilitated representation of the food items as signifiers for other foods, which in turn supported a higher acuity in decision making. Many animals can do simple quantity discrimination, but they often perform poorly when food is used. Here, the authors show that monkeys are good at food quantity discrimination when they are not allowed to eat it, suggesting that the mental representation of the stimuli is more important than the physical quality.

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.