Photothermal treatment-based heat stress regulates function of myeloid-derived suppressor cells.

Photothermal therapy is an alternative cancer therapy that uses a photothermal agent with light irradiation to induce fatal hyperthermia in cancer cells. In a previous study, we found that ex vivo photothermal (PT) treatment induced expression of heat shock proteins (HSPs), such as HSP70, HSP27, and HSP90, in cancer cells; moreover, immunization with lysates from PT-treated tumor cells resulted in significant tumor growth inhibition in tumor-bearing mice. In this study, we hypothesized that sublethal PT treatment of antigen-presenting cells regulates their immunogenicity. We observed the upregulation of expression of intracellular HSP70 and surface activation markers, such as CD40, CD80, CD86, and MHC class II, in sublethal PT-treated cells. The protumoral activity of myeloid-derived suppressor cells (MDSCs) was reduced by sublethal hyperthermia. Furthermore, poorly immunogenic MDSCs were converted into immunogenic antigen-presenting cells by PT treatment. The differences in immunogenicity between MDSCs untreated or treated with the PT technique were evaluated using the Student's t-test or Mann-Whitney rank sum test. Collectively, direct hyperthermic treatment resulted in phenotypic changes and the functional regulation of immune cells.

Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations.

BACKGROUND: Our study aims to evaluate the genetic and phenotypic spectrum of Frontotemporal dementia (FTD) gene variant carriers in Chinese populations, investigate mutation frequencies, and assess the functional properties of TBK1 and OPTN variants. METHODS: Clinically diagnosed FTD patients underwent genetic analysis through exome sequencing, repeat-primed polymerase chain reaction, and Sanger sequencing. TBK1 and OPTN variants were biologically characterized in vitro using immunofluorescence, immunoprecipitation, and immunoblotting analysis. The frequencies of genes implicated in FTD in China were analyzed through a literature review and meta-analysis. RESULTS: Of the 261 Chinese FTD patients, 61 (23.4%) carried potential causative variants in FTD-related genes, including MAPT (n = 17), TBK1 (n = 7), OPTN (n = 6), GRN (n = 6), ANXA11 (n = 4), CHMP2B (n = 3), C9orf72 GGGGCC repeats (n = 2), CYLD (n = 2), PRNP (n = 2), SQSTM1 (n = 2), TARDBP (n = 2), VCP (n = 1), CCNF (n = 1), CHCHD10 (n = 1), SIGMAR1 (n = 1), CHCHD2 (n = 1), FUS (n = 1), TMEM106B (n = 1), and UBQLN2 (n = 1). 29 variants can be considered novel, including the MAPT p.D54N, p.E342K, p.R221P, p.T263I, TBK1 p.E696G, p.I37T, p.E232Q, p.S398F, p.T78A, p.Q150P, p.W259fs, OPTN p.R144G, p.F475V, GRN p.V473fs, p.C307fs, p.R101fs, CHMP2B p.K6N, p.R186Q, ANXA11 p.Q155*, CYLD p.T157I, SQSTM1 p.S403A, UBQLN2 p.P509H, CCNF p.S160N, CHCHD10 p.A8T, SIGMAR1 p.S117L, CHCHD2 p.P53fs, FUS p.S235G & p.S236G, and TMEM106B p.L144V variants. Patients with TBK1 and OPTN variants presented with heterogeneous clinical phenotypes. Functional analysis demonstrated that TBK1 I37T and E232Q mutants showed decreased autophosphorylation, and the OPTN phosphorylation was reduced by the TBK1 I37T mutant. The OPTN-TBK1 complex formation was enhanced by the TBK1 E696G mutant, while OPTN R144G and F475V mutants exhibited reduced recruitment to autophagosomes compared to the wild-type. The overall frequency of TBK1 and OPTN in Chinese FTD patients was 2.0% and 0.3%, respectively. CONCLUSIONS: Our study demonstrates the extensive genetic and phenotypic heterogeneity of Chinese FTD patients. TBK1 mutations are the second most frequent cause of clinical FTD after MAPT in the Chinese.

A light-controlled phospholipase C for imaging of lipid dynamics and controlling neural plasticity.

Phospholipase C (PLC) is a key enzyme that regulates physiological processes via lipid and calcium signaling. Despite advances in protein engineering, no tools are available for direct PLC control. Here, we developed a novel optogenetic tool, light-controlled PLCß (opto-PLCß). Opto-PLCß uses a light-induced dimer module, which directs an engineered PLC to the plasma membrane in a light-dependent manner. Our design includes an autoinhibitory capacity, ensuring stringent control over PLC activity. Opto-PLCß triggers reversible calcium responses and lipid dynamics in a restricted region, allowing precise spatiotemporal control of PLC signaling. Using our system, we discovered that phospholipase D-mediated phosphatidic acid contributes to diacylglycerol clearance on the plasma membrane. Moreover, we extended its applicability in vivo, demonstrating that opto-PLCß can enhance amygdala synaptic plasticity and associative fear learning in mice. Thus, opto-PLCß offers precise spatiotemporal control, enabling comprehensive investigation of PLC-mediated signaling pathways, lipid dynamics, and their physiological consequences in vivo.

Ex vivo photothermal treatment-induced immunogenic cell death for anticancer vaccine development.

Photothermal therapy is an anti-cancer strategy that induce cell death by converting light energy into heat energy. During photothermal therapy, cancer cells were treated with photothermal agents, such as indocyanine green, and irradiated with a laser. Heat stress in cancer cells results in cellular death and inflammatory responses. In the present study, we demonstrated how ex vivo photothermal (PT)-treated cells underwent immunogenic cell death. PT treatment caused significant expression of heat shock protein (HSP) 27, HSP70, and HSP90 in murine tumor cells. To evaluate the immunogenicity of heat-stressed cells, lysate from PT-treated tumor cells or water-based heated cells was pulsed to syngeneic bone-marrow-derived dendritic cells (DCs) to generate a DC-based vaccine. Administration with PT-treated tumor lysates-pulsed DC vaccine resulted in significant inhibition of tumor growth in BALB/c and C57BL/6 syngeneic tumor-bearing mice. The immunogenicity of PT-treated cancer cells was reduced in the presence of HSP inhibitors, J2, VER-155008 or 17-AAG. Our study elucidates how PT techniques have distinct mechanisms from water-based heating and might be a potentially robust and efficient solution to developing an anti-cancer vaccine.

Moral beacons: Understanding moral character and moral influence.

OBJECTIVE: We introduce the concept of moral beacons-individuals who are higher in moral character than their peers and prominent within their social environment-and examine the degree to which moral beacons increase the moral awareness of their peers. BACKGROUND: Using data from cohorts of students in graduate business education across two universities, we applied theory and methods from organizational behavior, personality psychology, and social networks analysis to test two research questions about moral beacons. METHOD: We used latent profile analysis of data from personality questionnaires and social network surveys completed by graduate business students at two universities (N = 502) to identify individuals classified as moral beacons. We used peer nominations and an in-class business case discussion exercise to assess moral influence. RESULTS: Latent profile analysis identified a latent class of moral beacons in our sample. These individuals received more nominations from their peers in end-of-class surveys as guides for moral thought and action and positively impacted the moral awareness of their peers in a discussion of a difficult business case about possible lead poisoning of employees, but did not significantly change their counterparts' moral awareness in a different case. CONCLUSIONS: These results provide promising initial evidence that moral beacons can be distinguished from their peers by both moral character and social prominence and can act as guides for others, at times encouraging greater consideration of the moral aspects of situations and decisions. As these results are the first of their kind, we encourage further replication and investigations of moral beacons and moral influence in other settings.

Synthesis of Au-Ag bimetallic nanoparticles using Korean red ginseng (Panax ginseng Meyer) root extract for chemo-photothermal anticancer therapy.

Green synthesis strategies have been widely applied for the preparation of versatile nanomaterials. Gold nanospheres with an average size of 6.95 ± 2.25 nm were green synthesized by using a 70% ethanol extract of Korean red ginseng (Panax ginseng Meyer) root as a reducing agent. A seed-mediated synthesis was conducted to prepare Au-Ag bimetallic nanoparticles using gold nanospheres as seeds. Remarkably, Au-Ag bimetallic nanoparticles with an average size of 80.4 ± 11.9 nm were synthesized. Scanning transmission electron microscopy, energy dispersive X-ray spectroscopy and elemental mappings revealed bimetallic nanoparticles with Au-Ag alloy core and Au-rich shells. A face-centered cubic structure of Au-Ag bimetallic nanoparticles was confirmed by X-ray diffraction analysis. For Au-Ag bimetallic nanoparticles, the ratio of Ag/Au was 0.20 which was detected and analyzed by inductively coupled plasma-mass spectrometry. Gold nanospheres and Au-Ag bimetallic nanoparticles were functionalized by PEGylation, folic acid conjugation and grafting onto graphene oxide. Finally, docetaxel was loaded for evaluating the in vitro cell viability on cancer cells. Successful functionalization was confirmed by Fourier-transform infrared spectra. The anticancer activity of the docetaxel-loaded nanoparticles was higher than that of their non-docetaxel-loaded counterparts. The highest anticancer activity on human gastric adenocarcinoma cells (AGS) was observed in the docetaxel-loaded gold nanospheres that were functionalized by PEGylation, folic acid conjugation and grafting onto graphene oxide. Additionally, grafting onto graphene oxide and docetaxel loading induced high intracellular reactive oxygen species generation. For chemo-photothermal (PTT) anticancer therapy, cell viability was investigated using near-infrared laser irradiation at 808 nm. The highest chemo-PTT anticancer activity on AGS cells was observed in the docetaxel-loaded Au-Ag bimetallic nanoparticles. Therefore, the newly prepared docetaxel-loaded Au-Ag bimetallic nanoparticles in the current report have potential applications in chemo-PTT anticancer therapy.

Case report: Reversible brain atrophy with low titer anti-amphiphysin antibodies related to gastric adenocarcinoma.

Amphiphysin (AMPH) autoimmunity is associated with a variety of neurological complications, including encephalitis, peripheral neuropathy, myelopathy, and cerebellar syndrome. Its diagnosis is based on clinical neurological deficits and the presence of serum anti-AMPH antibodies. Active immunotherapy, such as intravenous immunoglobulins, steroids, and other immunosuppressive therapies, has been reported to be effective in most patients. However, the extent of recovery varies depending on the case. Herein, we report the case of a 75-year-old woman with semi-rapidly progressive systemic tremors, visual hallucinations, and irritability. Upon hospitalization, she developed a mild fever and cognitive impairment. Brain magnetic resonance imaging (MRI) showed semi-rapidly progressive diffuse cerebral atrophy (DCA) over 3 months, while no clear abnormal intensities were observed. The nerve conduction study revealed sensory and motor neuropathy in the limbs. The fixed tissue-based assay (TBA) failed to detect antineuronal antibodies; however, based on commercial immunoblots, the presence of anti-AMPH antibodies was suspected. Therefore, serum immunoprecipitation was performed, which confirmed the presence of anti-AMPH antibodies. The patient also had gastric adenocarcinoma. High-dose methylprednisolone, and intravenous immunoglobulin were administered and tumor resection was performed, resulting in resolution of the cognitive impairment and improvement in the DCA on the post-treatment MRI. After immunotherapy and tumor resection, the patient's serum was analyzed using immunoprecipitation, which showed a decrease in the level of anti-AMPH antibodies. This case is noteworthy because the DCA showed improvement after immunotherapy and tumor resection. Additionally, this case demonstrates that negative TBA with positive commercial immunoblots do not necessarily indicate false positive results.

Increased PDGFRB and NF-κB signaling caused by highly prevalent somatic mutations in intracranial aneurysms.

Intracranial aneurysms (IAs) are a high-risk factor for life-threatening subarachnoid hemorrhage. Their etiology, however, remains mostly unknown at present. We conducted screening for sporadic somatic mutations in 65 IA tissues (54 saccular and 11 fusiform aneurysms) and paired blood samples by whole-exome and targeted deep sequencing. We identified sporadic mutations in multiple signaling genes and examined their impact on downstream signaling pathways and gene expression in vitro and an arterial dilatation model in mice in vivo. We identified 16 genes that were mutated in at least one IA case and found that these mutations were highly prevalent (92%: 60 of 65 IAs) among all IA cases examined. In particular, mutations in six genes (PDGFRB, AHNAK, OBSCN, RBM10, CACNA1E, and OR5P3), many of which are linked to NF-κB signaling, were found in both fusiform and saccular IAs at a high prevalence (43% of all IA cases examined). We found that mutant PDGFRBs constitutively activated ERK and NF-κB signaling, enhanced cell motility, and induced inflammation-related gene expression in vitro. Spatial transcriptomics also detected similar changes in vessels from patients with IA. Furthermore, virus-mediated overexpression of a mutant PDGFRB induced a fusiform-like dilatation of the basilar artery in mice, which was blocked by systemic administration of the tyrosine kinase inhibitor sunitinib. Collectively, this study reveals a high prevalence of somatic mutations in NF-κB signaling pathway-related genes in both fusiform and saccular IAs and opens a new avenue of research for developing pharmacological interventions.

Actively cross-linking hemostatic sealant enables rapid hemostasis and wound closure.

A rapid hemostatic sealant can save a patient's life from shock and death due to severe trauma or excessive bleeding from the wound site during surgery. However, an ideal hemostatic sealant needs to meet the standards of safety, efficacy, usability, cost, and approvability and overcome new challenges. Here, we devised a combinatorial hemostatic sealant of PEG succinimidyl glutarate-based cross-linking branched polymers (CBPs) and the active hemostatic peptide (AHP). After ex vivo optimization, the best hemostatic combination was called an active cross-linking hemostatic sealant (ACHS). Interestingly, ACHS formed cross-links with serum proteins, blood cells, and tissue and interconnected coating on blood cells, which might induce hemostasis and tissue adhesion based on SEM images. Moreover, ACHS showed the highest coagulation efficacy, formation, and agglomeration of thrombi within 12 s, and in vitro biocompatibility. Mouse model experiments represented rapid hemostasis within 1 min, wound closure of the liver incision, and less bleeding than the commercialized sealant with tissue biocompatibility. ACHS has the advantages of rapid hemostasis, mild sealant, and easy supply by chemical synthesis without inhibition by anticoagulants, which might minimize bacterial infection by immediate wound closure. Therefore, ACHS could become a new-type hemostatic sealant to match surgical needs for internal bleeding.

Antigen Delivery Systems: Past, Present, and Future.

The COVID-19 pandemic has increased demand for safe and effective vaccines. Research to develop vaccines against diseases including Middle East respiratory syndrome, Ebolavirus, human immunodeficiency virus, and various cancers would also contribute to global well-being. For successful vaccine development, the advancement of technologies such as antigen (Ag) screening, Ag delivery systems and adjuvants, and manufacturing processes is essential. Ag delivery systems are required not only to deliver a sufficient amount of Ag for vaccination, but also to enhance immune response. In addition, Ag types and their delivery systems determine the manufacturing processes of the vaccine product. Here, we analyze the characteristics of various Ag delivery systems: plasmids, viral vectors, bacterial vectors, nanoparticles, self-assembled particles, natural and artificial cells, and extracellular vesicles. This review provides insight into the current vaccine landscape and highlights promising avenues of research for the development and improvement of Ag delivery systems.

Ubap1 knock-in mice reproduced the phenotype of SPG80.

SPG80 is a neurodegenerative disorder characterized by a pure type of juvenile-onset hereditary spastic paraplegia and is caused by a heterozygous mutation of the UBAP1 (ubiquitin-associated protein 1) gene. UBAP1 is one of the subunits of the endosomal sorting complex required for transport I and plays a role in endosome sorting by binding to ubiquitin-tagged proteins. In this study, we generated novel Ubap1+/E176Efx23 knock-in mice, in which the SOUBA domain of Ubap1 was completely deleted with the UMA domain being intact, as an animal model of SPG80. The knock-in mice with this heterozygous Ubap1 truncated mutation appeared normal at birth, but they developed progressive hind limb dysfunction several months later. Molecular pathologically, loss of neurons in the spinal cord and accumulation of ubiquitinated proteins were observed in Ubap1+/E176Efx23 knock-in mice. In addition, changes in the distributions of Rab5 and Rab7 in the spinal cord suggest that this mutation in Ubap1 disturbs endosome-mediated vesicular trafficking. This is the first report of a mouse model that reproduces the phenotype of SPG80. Our knock-in mice may provide a clue for understanding the molecular pathogenesis underlying UBAP1-related HSP and screening of therapeutic agents.

Association of weekend catch-up sleep ratio and subjective sleep quality with depressive symptoms and suicidal ideation among Korean adolescents.

Circadian misalignment caused by differences in sleep duration between weekends and weekdays may be associated with adolescent mental health and sleep quality may be able to compensate for this problem. This study aimed to investigate the association between weekend catch-up sleep (CUS) ratio and sleep quality with depressive symptoms and suicidal ideation among South Korean adolescents. We used data from the Korea Youth Risk Behavior Web-based Survey 2015-2019 involving 270,619 adolescents. The weekend CUS ratio was calculated by dividing the average weekend sleep duration by the average weekday sleep duration (< 1.00, 1.00 ≤ CUS < 1.50, or ≥ 1.50). Subjective sleep quality was categorized as poor, moderate, or good. Multiple logistic regression analyses were performed. A weekend CUS ratio of < 1.00 and poor sleep quality was significantly associated with mental health. Absolutely short sleep duration (CUS < 1.00 and weekday sleep duration < 5 h) was most associated with depressive symptoms and suicidal ideation. Furthermore, adolescents with a CUS ratio of ≥ 1.50 showed increased odds of depressive symptoms despite having good sleep quality. Appropriate weekend CUS may benefit adolescents' mental health. When investigating the relationship between adolescents' sleep and mental health, a weekend CUS ratio should be considered in addition to sleep quality and duration.

Folic Acid and Chitosan-Functionalized Gold Nanorods and Triangular Silver Nanoplates for the Delivery of Anticancer Agents.

Background: Advances in the field of nanotechnology have shed light on the applications of nanoparticles for cancer treatment. Methods: Folic acid and chitosan-functionalized gold nanorods (FACS-R) and triangular silver nanoplates (FACS-T) were synthesized and their properties were elucidated by UV-visible spectrophotometry, Fourier-transform infrared spectroscopy, field emission transmission electron microscopy and high-resolution X-ray diffraction. Results: The average size of the FACS-R was determined to be a transverse length of 13.1 ± 1.8 nm and a longitudinal length of 47.2 ± 8.9 nm with an aspect ratio of 3.6. The average size of FACS-T was measured to be 31.8 ± 7.7 nm. Colloidal solutions of FACS-R and FACS-T were stable on the shelf at ambient temperature for 14 days in the dark. Anticancer agents were encapsulated in FACS-R and FACS-T. FACS-T showed a higher encapsulation efficiency with docetaxel, paclitaxel and diallyl disulfide than FACS-R. The cell viability on human gastric adenocarcinoma cells (AGS), human epithelial cervix adenocarcinoma cells (HeLa) and human colorectal adenocarcinoma cells (HT-29) after treatment with anticancer agent-encapsulated FACS-R and FACS-T was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Interestingly, paclitaxel-encapsulated FACS-R and FACS-T showed the highest percentages of early and late apoptosis on HeLa cells. A cell cycle analysis demonstrated increased G2/M arrest on HeLa cells with docetaxel and paclitaxel-encapsulated FACS-R and FACS-T. The FACS-T induced more G2/M arrest on HeLa cells than the FACS-R. To assess applications in near-infrared photothermal therapy (PTT), the cell viability on HeLa cells with the anticancer agent-encapsulated FACS-R and FACS-T was assessed in the presence or absence of 808 nm laser irradiation. The results showed that 808 nm laser irradiation significantly decreased cell viability. Conclusion: Collectively, the triangular silver nanoplates were more effective than the gold nanorods for PTT. We believe that as-prepared nanoparticles have remarkable features and will become promising future nanomedicine.

Novel SLC9A6 Variation in Female Carriers With Intellectual Disability and Atypical Parkinsonism.

BACKGROUND AND OBJECTIVES: Variations in SLC9A6 cause the X-linked neurologic disorder Christianson syndrome in males. Meanwhile, female carriers with SLC9A6 variations may remain asymptomatic or develop intellectual disability, behavioral problems, and psychiatric illnesses. Only a few female carriers have been reported to have associated atypical parkinsonism in late life. METHODS: We present a Japanese family with a novel SLC9A6 variation identified by quad whole-exome sequencing analysis and a reverse phenotyping strategy. The molecular and cellular impacts of the W89R variation in vitro were examined. RESULTS: The missense variation (c.265T>C, p.Trp89Arg) in SLC9A6 cosegregated with atypical parkinsonism and intellectual disability in female carriers of this family. The female carriers in this family presented with bradykinesia, rigidity, and tremor, predominately on the right side. We found that the W89R variation changed membrane traffic of NHE6-harboring vesicles, indicating potential involvement in the disease pathogenesis. DISCUSSION: This study might have revealed an example of a monogenic origin of atypical parkinsonism in females with SLC9A6 variations and draw attention to this understudied female-specific phenotype in clinical practice.

A Novel Heterozygous Missense Variant in the CIAO1 Gene in a Family with Alzheimer's Disease: The Val67Ile Variant Promotes the Interaction of CIAO1 and Amyloid-ß Protein Precursor.

Familial dementia is a rare inherited disease involving progressive impairment of memory, thinking, and behavior. We report a novel heterozygous pathogenic variant (c.199G > A, p.Val67Ile) in the CIAO1 gene that appears to be co-segregated with Alzheimer's disease in a Japanese family. Biochemical analysis of CIAO1 protein revealed that the variant increases the interaction of CIAO1 with immature amyloid-ß protein precursor (AßPP), but not mature or soluble AßPP, indicating plausible CIAO1 involvement in AßPP processing. Our study indicates that a heterozygous variant in the CIAO1 gene may be closely related to autosomal dominant familial dementia.

RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia.

Recently, the expansion of an intronic AAGGG repeat in the replication factor C subunit 1 (RFC1) gene was reported to cause cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). In Europeans, the expansion accounted for 22% of sporadic patients with late-onset ataxia. We genotyped 37 Japanese patients comprising 25 familial (autosomal recessive or undecided transmission) and 12 sporadic ones with late-onset ataxia. We found intronic repeat expansions in RFC1 in three (12%) of the familial patients and one (8.5%) of the sporadic ones. Although our cohort study was small, the disease frequency in Japanese patients with CANVAS might be lower than that in European ones. In addition, we found biallelic ACAGG repeat expansion in one patient, indicating ACAGG repeat expansion might cause CANVAS. Clinically, we found one patient with sleep apnea syndrome, which has not been reported previously. Thus, this study might expand the clinical and genetic spectrum of CANVAS.

Astaxanthin Treatment Induces Maturation and Functional Change of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells which accumulate in stress conditions such as infection and tumor. Astaxanthin (ATX) is a well-known antioxidant agent and has a little toxicity. It has been reported that ATX treatment induces antitumor effects via regulation of cell signaling pathways, including nuclear factor erythroid-derived 2-related factor 2 (Nrf2) signaling. In the present study, we hypothesized that treatment with ATX might induce maturation of MDSCs and modulate their immunosuppressive activity. Both in vivo and in vitro treatment with ATX resulted in up-regulation of surface markers such as CD80, MHC class II, and CD11c on both polymorphonuclear (PMN)-MDSCs and mononuclear (Mo)-MDSCs. Expression levels of functional mediators involved in immune suppression were significantly reduced, whereas mRNA levels of Nrf2 target genes were increased in ATX-treated MDSCs. In addition, ATX was found to have antioxidant activity reducing reactive oxygen species level in MDSCs. Finally, ATX-treated MDSCs were immunogenic enough to induce cytotoxic T lymphocyte response and contributed to the inhibition of tumor growth. This demonstrates the role of ATX as a regulator of the immunosuppressive tumor environment through induction of differentiation and functional conversion of MDSCs.

Roles of GPRC5 family proteins: focusing on GPRC5B and lipid-mediated signalling.

In the past decade, physiological roles and molecular functions of GPRC5 family receptors, originally identified as retinoic acid-induced gene products, have been uncovered, even though their intrinsic agonists are still a mystery. They are differentially distributed in certain tissues and cells in the body suggesting that cell-type-specific regulations and functions are significant. Molecular biological approaches and knockout mouse studies reveal that GPRC5 family proteins have pivotal roles in cancer progression and control of metabolic homeostasis pathways. Remarkably, GPRC5B-mediated tyrosine-phosphorylation signalling cascades play a critical role in development of obesity and insulin resistance through dynamic sphingolipid metabolism.

For Whom Does Determinism Undermine Moral Responsibility? Surveying the Conditions for Free Will Across Cultures.

Philosophers have long debated whether, if determinism is true, we should hold people morally responsible for their actions since in a deterministic universe, people are arguably not the ultimate source of their actions nor could they have done otherwise if initial conditions and the laws of nature are held fixed. To reveal how non-philosophers ordinarily reason about the conditions for free will, we conducted a cross-cultural and cross-linguistic survey (N = 5,268) spanning twenty countries and sixteen languages. Overall, participants tended to ascribe moral responsibility whether the perpetrator lacked sourcehood or alternate possibilities. However, for American, European, and Middle Eastern participants, being the ultimate source of one's actions promoted perceptions of free will and control as well as ascriptions of blame and punishment. By contrast, being the source of one's actions was not particularly salient to Asian participants. Finally, across cultures, participants exhibiting greater cognitive reflection were more likely to view free will as incompatible with causal determinism. We discuss these findings in light of documented cultural differences in the tendency toward dispositional versus situational attributions.