Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells.

Effective tumor immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute a specialized microenvironment that excludes T cells from the vicinity of cancer cells, and its underlying mechanisms are still poorly understood. DOCK2 is a Rac activator critical for migration and activation of lymphocytes. We herein show that cancer-derived cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tumor infiltration by effector T cells. Using clinical samples, we found that CS was abundantly produced in certain types of human cancers such as colon cancers. Functionally, CS-producing cancer cells exhibited resistance to cancer-specific T-cell transfer and immune checkpoint blockade. Although SULT2B1b is known to sulfate oxysterols and inactivate their tumor-promoting activity, the expression levels of cholesterol hydroxylases, which mediate oxysterol production, are low in SULT2B1b-expressing cancers. Therefore, SULT2B1b inhibition could be a therapeutic strategy to disrupt tumor immune evasion in oxysterol-non-producing cancers. Thus, our findings define a previously unknown mechanism for tumor immune evasion and provide a novel insight into the development of effective immunotherapies.

Rhythmic swaying induced by sound in chimpanzees (Pan troglodytes).

Music and dance are universal across human culture and have an ancient history. One characteristic of music is its strong influence on movement. For example, an auditory beat induces rhythmic movement with positive emotions in humans from early developmental stages. In this study, we investigated if sound induced spontaneous rhythmic movement in chimpanzees. Three experiments showed that: 1) an auditory beat induced rhythmic swaying and other rhythmic movements, with larger responses from male chimpanzees than female chimpanzees; 2) random beat as well as regular beat induced rhythmic swaying and beat tempo affected movement periodicity in a chimpanzee in a bipedal posture; and 3) a chimpanzee showed close proximity to the sound source while hearing auditory stimuli. The finding that male chimpanzees showed a larger response to sound than female chimpanzees was consistent with previous literature about "rain dances" in the wild, where male chimpanzees engage in rhythmic displays when hearing the sound of rain starting. The fact that rhythmic swaying was induced regardless of beat regularity may be a critical difference from humans, and a further study should reveal the physiological properties of sound that induce rhythmic movements in chimpanzees. These results suggest some biological foundation for dancing existed in the common ancestor of humans and chimpanzees ∼6 million years ago. As such, this study supports the evolutionary origins of musicality.

Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity.

Effective cancer immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute special microenvironments that exclude T cells and resist immunotherapy. Cholesterol sulfate (CS) is a product of sulfotransferase SULT2B1b and acts as an endogenous inhibitor of DOCK2, a Rac activator essential for migration and activation of lymphocytes. We have recently shown that cancer-derived CS prevents tumor infiltration by effector T cells. Therefore, SULT2B1b may be a therapeutic target to dampen CS-mediated immune evasion. Here, we identified 3ß-hydroxy-5-cholenoic acid (3ß-OH-5-Chln) as a cell-active inhibitor of SULT2B1b. 3ß-OH-5-Chln inhibited the cholesterol sulfotransferase activity of SULT2B1b in vitro and suppressed CS production from cancer cells expressing SULT2B1b. In vivo administration of 3ß-OH-5-Chln locally reduced CS level in murine CS-producing tumors and increased infiltration of CD8+ T cells. When combined with immune checkpoint blockade or antigen-specific T cell transfer, 3ß-OH-5-Chln suppressed the growth of CS-producing tumors. These results demonstrate that pharmacological inhibition of SULT2B1b can promote antitumor immunity through suppressing CS-mediated T cell exclusion.

Bonding system in nonhuman primates and biological roots of musicality.

Comparative studies of primates indicate that humans have evolved unique motivations and cognitive skills for sharing emotions, experiences, and collaborative actions. Given the characteristics of music, the music and social bonding (MSB) hypothesis by Savage et al. fits this view. Within a cross-species approach, predispositions not observed in current communication system may contribute to a better understanding of the biological roots of human musicality.

Perception of the motion trajectory of objects from moving cast shadows in infant Japanese macaques (Macaca fuscata).

The shadows cast by moving objects enable human adults and infants to infer the motion trajectories of objects. Nonhuman animals must also be able to discriminate between objects and their shadows and infer the spatial layout of objects from cast shadows. However, the evolutionary and comparative developmental origins of sensitivity to cast shadows have not been investigated. In this study, we used a familiarity/novelty preferential looking procedure to assess the ability of infant macaques, aged 7-24 weeks, to discriminate between a 'depth' display containing a ball and cast shadow moving diagonally and an 'up' display containing a ball with a diagonal trajectory and a shadow with a horizontal trajectory. The infant macaques could discriminate the trajectories of the balls based on the moving shadows. These findings suggest that the ability to perceive the motion trajectory of an object from the moving shadow is common to both humans and macaques.

Staring death in the face: chimpanzees' attention towards conspecific skulls and the implications of a face module guiding their behaviour.

Chimpanzees exhibit a variety of behaviours surrounding their dead, although much less is known about how they respond towards conspecific skeletons. We tested chimpanzees' visual attention to images of conspecific and non-conspecific stimuli (cat/chimp/dog/rat), shown simultaneously in four corners of a screen in distinct orientations (frontal/diagonal/lateral) of either one of three types (faces/skulls/skull-shaped stones). Additionally, we compared their visual attention towards chimpanzee-only stimuli (faces/skulls/skull-shaped stones). Lastly, we tested their attention towards specific regions of chimpanzee skulls. We theorized that chimpanzee skulls retaining face-like features would be perceived similarly to chimpanzee faces and thus be subjected to similar biases. Overall, supporting our hypotheses, the chimpanzees preferred conspecific-related stimuli. The results showed that chimpanzees attended: (i) significantly longer towards conspecific skulls than other species skulls (particularly in forward-facing and to a lesser extent diagonal orientations); (ii) significantly longer towards conspecific faces than other species faces at forward-facing and diagonal orientations; (iii) longer towards chimpanzee faces compared with chimpanzee skulls and skull-shaped stones, and (iv) attended significantly longer to the teeth, similar to findings for elephants. We suggest that chimpanzee skulls retain relevant, face-like features that arguably activate a domain-specific face module in chimpanzees' brains, guiding their attention.

The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1.

To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [123I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.

Tufted capuchin monkeys (Cebus apella) show understanding of human attentional states when requesting food held by a human.

Researchers have investigated to what extent non-human primates understand others' attentional states, as this ability is considered an important prerequisite for theory of mind. However, previous studies using food requesting tasks have failed to show that non-human primates attribute perception to others as a function of their attentional states. One possible reason is that food requesting tasks may require subjects not only to take into account an experimenter's attentional state but also to direct it toward the food. The present study tested tufted capuchin monkeys' (Cebus apella) understanding of others' attentional states in a food requesting task. In the first situation, monkeys were required only to attract an experimenter's attention. In the second situation, the monkeys were required to both attract the experimenter's attention and direct it toward food on a table. The results revealed that capuchin monkeys showed evidence of understanding the experimenter's attentional variations only in the former condition. This suggests that previous tasks, requiring referential gestures, lacking in most non-human primates, failed to reveal sensitivity to human attentional states because the subjects might not have understood the requesting situation. In conclusion, capuchin monkeys can understand variations in others' attentional states, although this ability appears limited compared to what is seen in humans.

Differential sensitivity to conspecific and allospecific cues in chimpanzees and humans: a comparative eye-tracking study.

Previous studies have shown that a variety of animals including humans are sensitive to social cues from others and shift their attention to the same objects attended to by others. However, little is known about how animals process conspecifics' and another species' actions, although primates recognize conspecific faces better than those of another species. In this study, using unrestrained eye-tracking techniques, we first demonstrated that conspecific social cues modulated looking behaviours of chimpanzees more than human cues, whereas human observers were equally sensitive to both species. Additionally, first pass gaze duration at the face indicates that chimpanzees looked at the chimpanzees' face longer than the human face, suggesting that chimpanzees might extract more referential information from a conspecific face. These results also imply that a unique ability for extracting referential information from a variety of social objects has emerged during human evolution.

Asymmetric perception of radial expansion/contraction in Japanese macaque (Macaca fuscata) infants.

Visual radial expansion/contraction motion provides important visual information that is used to control several adaptive actions. We investigated radial motion perception in infant Japanese macaque monkeys using an experimental procedure previously developed for human infants. We found that the infant monkeys' visual preference for the radial expansion pattern was greater than that for the radial contraction pattern. This trend towards an "expansion bias" is similar to that observed in human infants. These results suggest that asymmetrical radial motion processing is a basic visual function common to primates, and that it emerges early in life.

Flexibility in the use of requesting gestures in squirrel monkeys (Saimiri sciureus).

Three squirrel monkeys, trained to make a requesting gesture, were tested in the presence of a human assistant whose visual attention varied across trials. When food was available in one dish and an empty dish was nearby, the monkeys pointed overwhelmingly toward the former, regardless of where the assistant was looking. Looking at the assistant while pointing ("monitoring") peaked when she looked at them and when she attempted to engage them in joint attention. When only one dish was present, the monkeys refrained from gesturing if it was empty and if no assistant was present. They gestured more when the assistant made eye contact with them. Furthermore, when the assistant's focus of attention switched from the dish or the ceiling to the monkeys, the latter resumed pointing and increased their monitoring of the assistant. This is the first demonstration of such flexible use of an intentionally communicative requesting gesture in New World monkeys.

Pathological findings in a patient with alpha-synuclein p.A53T and familial Parkinson's disease.

The present report documents a patient harboring an alpha-synuclein p.A53T variant from a family presenting with autosomal dominant inheritance, including four patients clinically diagnosed with Parkinson's disease (PD) and two with dementia. The alpha-synuclein p.A53T variant is linked to young- or middle-aged onset parkinsonism and cognitive decline. Our patient had a different haplotype from that of a patient with a p.A53T variant from an Italian family. The proband presented at 42 years of age with progressive parkinsonism and good response to levodopa in the early stages of the disease. At 46 years of age, he developed delusions and cognitive decline. Brain magnetic resonance imaging showed bilateral atrophic changes in the hippocampus and temporal lobes. He died of pneumonia at the age of 52 years. Neuropathological examination revealed severe neuronal loss in the substantia nigra, locus coeruleus, and dorsal nucleus of the vagus nerve, as well as widespread Lewy pathology including Lewy bodies and neurites, corresponding to Braak stage 6, and diffuse neocortical-type PD. There was mild appearance of tau pathology and glial cytoplasmic inclusion, in the absence of TDP-43 pathology. Alpha-synuclein p.A53T characteristically cause the Lewy body pathology and the symptoms, that resembled those of the reported patients with p.A53T.

Detection of a High-Turnover Serotonin Circuit in the Mouse Brain Using Mass Spectrometry Imaging.

Monoamine neurotransmitters are released by specialized neurons regulating behavioral, motor, and cognitive functions. Although the localization of monoaminergic neurons in the brain is well known, the distribution and kinetics of monoamines remain unclear. Here, we generated a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels using mass spectrometry imaging (MSI). We found several nuclei rich in both 5-HT and a catecholamine (DA or NE) and identified the paraventricular nucleus of the thalamus (PVT), where 5-HT and NE are co-localized. The analysis of 5-HT fluctuations in response to acute tryptophan depletion and infusion of isotope-labeled tryptophan in vivo revealed a close kinetic association between the raphe nuclei, PVT, and amygdala but not the other nuclei. Our findings imply the existence of a highly dynamic 5-HT-mediated raphe to PVT pathway that likely plays a role in the brain monoamine system.

Quality before quantity: rapid learning of reverse-reward contingency by capuchin monkeys (Cebus apella).

Capuchin monkeys (Cebus apella) were tested on a reverse-reward task involving different quantities of the same food, or an identical quantity of different foods. All monkeys tested first on the qualitative version spontaneously mastered the task, whereas only one of four spontaneously mastered the quantitative version. No monkey reached criterion when the tasks were switched, although almost all did so following remedial procedures after the study. The results suggest that (a) qualitative reverse-reward is easier than quantitative versions of the problem, (b) quality and quantity dimensions are processed differently in food-related tasks, and (c) capuchin monkeys can show rapid and spontaneous learning of reverse-reward contingencies.

Pentalogy of Cantrell with a double-outlet right ventricle: 3.5-year follow-up in a prenatally diagnosed patient.

Pentalogy of Cantrell is a rare congenital defect associated with five ventral midline anomalies and high mortality. An obstetric sonogram revealed a fetus with a body wall defect suggesting a diagnosis of this condition. Soon after birth, the infant underwent a closure of the upper abdominal wall defect followed by the successful repair of double-outlet right ventricle and pulmonary valve stenosis at the age of 5 months. The patient is currently alive and well 3.5 years after surgery. It is concluded that a deliberate therapeutic strategy based on the intrauterine diagnosis may alter the natural history of this devastating disorder.

Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye.

Although immune responses are essential to protect the body from infection, they can also harm tissues. Certain tissues and organs, including the eye, constitute specialized microenvironments that locally inhibit immune reactivity. Dedicator of cytokinesis protein 2 (DOCK2) is a Rac-specific guanine nucleotide exchange factor (GEF) that is predominantly found in hematopoietic cells. DOCK2 plays a key role in immune surveillance because it is essential for the activation and migration of leukocytes. DOCK2 mutations cause severe immunodeficiency in humans. We found that DOCK2-mediated Rac activation and leukocyte migration were effectively inhibited by cholesterol sulfate (CS), but not by cholesterol or other sulfated steroids. CS bound to the catalytic domain of DOCK2 and suppressed its GEF activity. Mass spectrometric quantification revealed that CS was most abundantly produced in the Harderian gland, which provides the lipids that form the oily layer of the tear film. Sulfation of cholesterol is mediated by the sulfotransferases SULT2B1b and, to a lesser extent, SULT2B1a, which are produced from the same gene through alternative splicing. By genetically inactivating Sult2b1, we showed that the lack of CS in mice augmented ultraviolet- and antigen-induced ocular surface inflammation, which was suppressed by administration of eye drops containing CS. Thus, CS is a naturally occurring DOCK2 inhibitor and contributes to the generation of the immunosuppressive microenvironment in the eye.

Cooperative problem solving by tufted capuchin monkeys (Cebus apella): spontaneous division of labor, communication, and reciprocal altruism.

Using an experimentally induced cooperation task, the authors investigated whether tufted capuchin monkeys (Cebus apella) share the following 3 characteristics of cooperation with humans: division of labor, communication, and reciprocal altruism. In Experiment 1, the authors trained individual monkeys to perform the necessary sequence of actions for rewards and tested them in pairs to assess whether they could solve the task by spontaneously dividing the sequence of actions. All pairs solved this task. In Experiment 2, monkeys worked in the cooperation task and a task requiring no partner help. They looked at the partner significantly longer in the former task than in the latter, but communicative intent could not be determined. In Experiment 3, only 1 of 2 participants obtained a reward on each trial. Monkeys maintained cooperation when their roles were reversed on alternate trials. Their cooperative performances demonstrated division of labor; results suggest task-related communication and reciprocal altruism.

Attention to combined attention in new world monkeys (Cebus apella, Saimiri sciureus).

Co-orientation by capuchin (Cebus apella) and squirrel (Saimiri sciureus) monkeys in response to familiar humans abruptly switching the direction of their visual attention was recorded. Co-orientation occurred more frequently overall in capuchins than squirrel monkeys. Capuchins showed a tendency to habituate within trials involving consecutive attention switches performed by 2 different people, whereas squirrel monkeys co-oriented more when the 2nd attention switch was by a 2nd actor. These results suggest variable attention-processing abilities in New World monkeys, including differences in summation of attention by others.

Distractor Effect of Auditory Rhythms on Self-Paced Tapping in Chimpanzees and Humans.

Humans tend to spontaneously align their movements in response to visual (e.g., swinging pendulum) and auditory rhythms (e.g., hearing music while walking). Particularly in the case of the response to auditory rhythms, neuroscientific research has indicated that motor resources are also recruited while perceiving an auditory rhythm (or regular pulse), suggesting a tight link between the auditory and motor systems in the human brain. However, the evolutionary origin of spontaneous responses to auditory rhythms is unclear. Here, we report that chimpanzees and humans show a similar distractor effect in perceiving isochronous rhythms during rhythmic movement. We used isochronous auditory rhythms as distractor stimuli during self-paced alternate tapping of two keys of an electronic keyboard by humans and chimpanzees. When the tempo was similar to their spontaneous motor tempo, tapping onset was influenced by intermittent entrainment to auditory rhythms. Although this effect itself is not an advanced rhythmic ability such as dancing or singing, our results suggest that, to some extent, the biological foundation for spontaneous responses to auditory rhythms was already deeply rooted in the common ancestor of chimpanzees and humans, 6 million years ago. This also suggests the possibility of a common attentional mechanism, as proposed by the dynamic attending theory, underlying the effect of perceiving external rhythms on motor movement.