Mucosal-associated invariant T cells modulate innate immune cells and inhibit colon cancer growth.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro-inflammatory functions and have potentials for use as adoptive cell therapy. However, studies into their anti-cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we showed that peritumoral injection of in vivo-expanded MAIT cells into RAG1-/- mice with MC38-derived tumours inhibits tumour growth compared to control. Multiplex cytokine analyses showed that tumours from the MAIT cell-treated group have higher expression of markers for eosinophil-activating cytokines, suggesting a potential association between eosinophil recruitment and tumour inhibition. In a human peripheral leukocyte co-culture model, we showed that leukocytes stimulated with MAIT ligand showed an increase in eotaxin-1 production and activation of eosinophils, associated with increased cancer cell killing. In conclusion, we showed that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil-associated mechanisms. Our results highlight the potential of MAIT cells for non-donor restricted colon cancer immunotherapy.

Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci.

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6, DALRD3, CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder.

The genetic landscape of substance use disorders.

Substance use disorders represent a significant public health concern with considerable socioeconomic implications worldwide. Twin and family-based studies have long established a heritable component underlying these disorders. In recent years, genome-wide association studies of large, broadly phenotyped samples have identified regions of the genome that harbour genetic risk variants associated with substance use disorders. These regions have enabled the discovery of putative causal genes and improved our understanding of genetic relationships among substance use disorders and other traits. Furthermore, the integration of these data with clinical information has yielded promising insights into how individuals respond to medications, allowing for the development of personalized treatment approaches based on an individual's genetic profile. This review article provides an overview of recent advances in the genetics of substance use disorders and demonstrates how genetic data may be used to reduce the burden of disease and improve public health outcomes.

Complex cutaneous leishmaniasis in a pediatric patient.

Cutaneous leishmaniasis (CL), a parasitic infection caused by Leishmania protozoa and transmitted by sandfly bites, can be classified into Old World and New World subtypes. We report a case of a 2-year-old female who developed complex CL after travel to Panama. Ultimately, successful treatment required two rounds of liposomal amphotericin B. We report this case for its challenging clinical course and management.

ß-arrestin-biased Allosteric Modulator of Neurotensin Receptor 1 Reduces Ethanol Drinking and Responses to Ethanol Administration in Rodents.

Alcohol use disorders (AUDs) impose an enormous societal and financial burden, and world-wide, alcohol misuse is the 7th leading cause of premature death1. Despite this, there are currently only 3 FDA approved pharmacological treatments for the treatment of AUDs in the United States. The neurotensin (Nts) system has long been implicated in modulating behaviors associated with alcohol misuse. Recently, a novel compound, SBI-553, that biases the action of Nts receptor 1 (NTSR1) activation, has shown promise in preclinical models of psychostimulant misuse. Here we investigate the efficacy of this compound to alter ethanol-mediated behaviors in a comprehensive battery of experiments assessing ethanol consumption, behavioral responses to ethanol, sensitivity to ethanol, and ethanol metabolism. Additionally, we investigated behavior in avoidance and cognitive assays to monitor potential side effects of SBI-553. We find that SBI-553 reduces binge-like ethanol consumption in mice without altering avoidance behavior or novel object recognition. We also observe sex-dependent differences in physiological responses to sequential ethanol injections in mice. In rats, we show that SBI-553 attenuates sensitivity to the interoceptive effects of ethanol (using a Pavlovian drug discrimination task). Our data suggest that targeting NTSR1 signaling may be promising to attenuate alcohol misuse, and adds to a body of literature that suggests NTSR1 may be a common downstream target involved in the psychoactive effects of multiple reinforcing substances.

Progression free survival of myeloma patients who become IFE-negative correlates with the detection of residual monoclonal free light chain (FLC) by mass spectrometry.

Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.

Analysis of the Snake Venom Peptidome.

Snake venom peptidomes are known to be a large source of molecules with different pharmacological properties. The complexity and variability of snake venoms, the presence of proteinases, and the lack of complete species-specific genome sequences make snake venom peptidome profiling a challenging task that requires especial technical strategies for sample processing and mass spectrometric analysis. Here, we describe a method for assessing the content of snake venom peptides and highlight the importance of sampling procedures, as they substantially influence the peptidomic complexity of snake venoms.

Psychological well-being in Europe after the outbreak of war in Ukraine.

The Russian invasion of Ukraine on February 24, 2022, has had devastating effects on the Ukrainian population and the global economy, environment, and political order. However, little is known about the psychological states surrounding the outbreak of war, particularly the mental well-being of individuals outside Ukraine. Here, we present a longitudinal experience-sampling study of a convenience sample from 17 European countries (total participants = 1,341, total assessments = 44,894, countries with >100 participants = 5) that allows us to track well-being levels across countries during the weeks surrounding the outbreak of war. Our data show a significant decline in well-being on the day of the Russian invasion. Recovery over the following weeks was associated with an individual's personality but was not statistically significantly associated with their age, gender, subjective social status, and political orientation. In general, well-being was lower on days when the war was more salient on social media. Our results demonstrate the need to consider the psychological implications of the Russo-Ukrainian war next to its humanitarian, economic, and ecological consequences.

Survival and Success Rates of Endodontically Treated Teeth Restored with Full Veneer Crowns or Full Cuspal Coverage onlays: A Systematic Review.

INTRODUCTION: The aim of this paper is to compare the survival and success rates of endodontically treated posterior teeth restored with full veneer crowns or full cuspal coverage onlays in vivo. METHODS: A literature search using PubMed, Medline and Embase via Ovid, and The Cochrane Library retrieved English and non-English language articles from 1946 to April 2022. Electronic searches were supplemented with the use of forward citation chaining via Google Scholar. RESULTS: A total of eleven studies met all predetermined search criteria. Data were extracted and tabulated. Survival rates for onlays ranged from 95% to 100% at two years and 90.7% to 100% at three years with success rates ranging from 86.6% - 96.6% at two years and 86.6% to 96% at three years. Survival results for full veneer crowns were reported at 87.8% at over two years, 95.1% at three years, and 84% - 97.73% at five to ten years. Success rates have been reported at 91.11% - 92.64% at five years and 60% at six years. CONCLUSIONS: The data suggest that the use of onlays instead of full veneer crowns in the restoration of endodontically treated posterior teeth is favourable in the short to midterm.

A creativity stereotype perspective on the Bamboo Ceiling: Low perceived creativity explains the underrepresentation of East Asian leaders in the United States.

The "Bamboo Ceiling" refers to the perplexing phenomenon that, despite the educational and economic achievements of East Asians (e.g., ethnic Chinese, Koreans) in the United States, they are disproportionately underrepresented in leadership positions. To help elucidate this phenomenon, we propose a novel theoretical perspective: East Asians are underselected for leadership positions partially because they are stereotyped as lacking creativity, a prized leadership attribute in U.S. culture. We first tested our proposition in two field studies in a natural setting: Across 33 full class sections of 2,304 Master of Business Administration (MBA) students in a U.S. business program, East Asians were perceived by their classmates as less creative than other ethnicities (e.g., South Asian, White) at the beginning of the MBA program-when the students had limited interactions and thus were likely influenced by creativity stereotypes. Lower perceived creativity mediated why East Asians were less likely than other ethnicities to be nominated (Study 1) and elected (Study 2) as class-section leaders by their classmates. These patterns were robust after accounting for variables such as assertiveness (parallel mediator), leadership motivation, English proficiency, and demographics. These findings were conceptually replicated in two preregistered vignette experiments of non-Asian Americans with managerial experience (Studies 3 and 4, N = 1,775): Compared to candidates of other ethnicities, East Asian American candidates with a substantively identical profile were viewed as less leader-like as a function of lower perceived creativity. Overall, although East Asians are commonly stereotyped as competent, they are also stereotyped as lacking creativity, which can hinder their leadership emergence in U.S. organizations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Nuclear Pyruvate Dehydrogenase Complex Regulates Histone Acetylation and Transcriptional Regulation in the Ethylene Response.

Ethylene plays its essential roles in plant development, growth, and defense responses by controlling the transcriptional reprograming, in which EIN2-C-directed regulation of histone acetylation is the first key-step for chromatin to perceive ethylene signaling. But how the nuclear acetyl coenzyme A (acetyl CoA) is produced to ensure the ethylene-mediated histone acetylation is unknown. Here we report that ethylene triggers the accumulation of the pyruvate dehydrogenase complex (PDC) in the nucleus to synthesize nuclear acetyl CoA to regulate ethylene response. PDC is identified as an EIN2-C nuclear partner, and ethylene triggers its nuclear accumulation. Mutations in PDC lead to an ethylene-hyposensitivity that results from the reduction of histone acetylation and transcription activation. Enzymatically active nuclear PDC synthesize nuclear acetyl CoA for EIN2-C-directed histone acetylation and transcription regulation. These findings uncover a mechanism by which PDC-EIN2 converges the mitochondrial enzyme mediated nuclear acetyl CoA synthesis with epigenetic and transcriptional regulation for plant hormone response.

Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies.

Conventional type 1 dendritic cells (cDC1s) are superior in antigen cross-presentation and priming CD8+ T cell anti-tumor immunity and thus, are a target of high interest for cancer immunotherapy. Type I interferon (IFN) is a potent inducer of antigen cross-presentation, but, unfortunately, shows only modest results in the clinic given the short half-life and high toxicity of current type I IFN therapies, which limit IFN exposure in the tumor. CD8+ T cell immunity is dependent on IFN signaling in cDC1s and preclinical studies suggest targeting IFN directly to cDC1s may be sufficient to drive anti-tumor immunity. Here, we engineered an anti-XCR1 antibody (Ab) and IFN mutein (IFNmut) fusion protein (XCR1Ab-IFNmut) to determine whether systemic delivery could drive selective and sustained type I IFN signaling in cDC1s leading to anti-tumor activity and, in parallel, reduced systemic toxicity. We found that the XCR1Ab-IFNmut fusion specifically enhanced cDC1 activation in the tumor and spleen compared to an untargeted control IFN. However, multiple treatments with the XCR1Ab-IFNmut fusion resulted in robust anti-drug antibodies (ADA) and loss of drug exposure. Using other cDC1-targeting Ab-IFNmut fusions, we found that localizing IFN directly to cDC1s activates their ability to promote ADA responses, regardless of the cDC1 targeting antigen. The development of ADA remains a major hurdle in immunotherapy drug development and the cellular and molecular mechanisms governing the development of ADA responses in humans is not well understood. Our results reveal a role of cDC1s in ADA generation and highlight the potential ADA challenges with targeting immunostimulatory agents to this cellular compartment.

Unveiling the peptidome diversity of Lachesismuta snake venom: Discovery of novel fragments of metalloproteinase, l-amino acid oxidase, and bradykinin potentiating peptides.

Snake venoms are known to be major sources of peptides with different pharmacological properties. In this study, we comprehensively explored the venom peptidomes of three specimens of Lachesismuta, the largest venomous snake in South America, using mass spectrometry techniques. The analysis revealed 19 main chromatographic peaks common to all specimens. A total of 151 peptides were identified, including 69 from a metalloproteinase, 58 from the BPP-CNP precursor, and 24 from a l-amino acid oxidase. To our knowledge, 126 of these peptides were reported for the first time in this work, including a new SVMP-derived peptide fragment, Lm-10a. Our findings highlight the dynamic nature of toxin maturation in snake venoms, driven by proteolytic processing, post-translational modifications, and cryptide formation.

Cultural differences in humor: A systematic review and critique.

Humor is universal but also culturally nuanced. This review (including 31 empirical articles in English) systematically examines cultural differences in humor perception and use. Most notably, North Americans tend to perceive humor more positively, rate themselves as more humorous, and use humor more than East Asians. Moreover, this review highlights complex cultural differences in the use of four humor styles (affiliative, self-enhancing, aggressive, and self-defeating). Finally, I discuss limitations of the cross-cultural literature on humor and propose future research directions. Theoretically, more studies should move beyond comparing East Asian and North American cultures, examine the consequences of cultural differences in humor, and track changes in humor perception and use over time. Methodologically, more studies should employ experiments to strengthen causality, recruit larger and more representative samples, and preregister theory-driven hypotheses.

Anisotropy and reproducibility of ultrasound shear wave elastography in patella tendons with and without tendinopathy.

PURPOSE: Ultrasound shear wave elastography (SWE) is a tool that can be utilized to assess biomechanical properties of tendons. Anisotropy, an ultrasound imaging artifact has been commonly cited as a potential source of error in the accuracy and reproducibility of SWE. The aim of the study was to assess reproducibility in performing SWE of patella tendons and differences in SWE and anisotropy between normal patella tendons and patellar tendinopathy. METHODS: After obtaining the Institutional Review Board approval and written informed consent, we prospectively measured the shear wave velocity (SWV) of patella tendons with and without tendinopathy in 25 volunteers. SWVs were measured in three anatomic planes: longitudinal, perpendicular transverse, and tilted transverse with the probe tilted 15-30° from the perpendicular transverse plane by three operators with varied levels of experience. Anisotropy coefficient (A) was calculated by formula of A = (SWVLongitudinal - SWVTransverse) / SWVTransverse. RESULTS: Differences in SWV and anisotropy coefficient between normal tendons and tendons with tendinopathy were significant (p < 0.05). The intra- and inter-observer reproducibility in performing SWE were moderate to good (intraclass correlation coefficient: 0.81-0.95). The mean difference of 95% Bland-Altman limits of agreement for measuring tendon SWV ranged -0.08 to 0.41 (upper 0.08 to 1.14, lower -1.22 to -0.22) between senior and junior operators. CONCLUSION: The results of this study suggest that SWE and anisotropy coefficient are feasible tools to differentiate patellar tendinopathy from normal patella tendons. The reproducibility of performing SWE of patella tendons is moderate to good.

Identification of drug repurposing candidates for the treatment of anxiety: A genetic approach.

Anxiety disorders are a group of prevalent and heritable neuropsychiatric diseases. We previously conducted a genome-wide association study (GWAS) which identified genomic loci associated with anxiety; however, the biological consequences underlying the genetic associations are largely unknown. Integrating GWAS and functional genomic data may improve our understanding of the genetic effects on intermediate molecular phenotypes such as gene expression. This can provide an opportunity for the discovery of drug targets for anxiety via drug repurposing. We used the GWAS summary statistics to determine putative causal genes for anxiety using MAGMA and colocalization analyses. A transcriptome-wide association study was conducted to identify genes with differential genetically regulated levels of gene expression in human brain tissue. The genes were integrated with a large drug-gene expression database (Connectivity Map), discovering compounds that are predicted to "normalise" anxiety-associated expression changes. The study identified 64 putative causal genes associated with anxiety (35 genes upregulated; 29 genes downregulated). Drug mechanisms adrenergic receptor agonists, sigma receptor agonists, and glutamate receptor agonists gene targets were enriched in anxiety-associated genetic signal and exhibited an opposing effect on the anxiety-associated gene expression signature. The significance of the project demonstrated genetic links for novel drug candidates to potentially advance anxiety therapeutics.

Genetic structure of major depression symptoms across clinical and community cohorts.

Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and aetiological subtypes. There are several challenges to integrating symptom data from genetically-informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data. We conducted genome-wide association studies of major depressive symptoms in three clinical cohorts that were enriched for affected participants (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors. The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for missing data patterns in the community cohorts (use of Depression and Anhedonia as gating symptoms). The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analysing genetic association data.

Mycobacterium tuberculosis PptT Inhibitors Based on Heterocyclic Replacements of Amidinoureas.

4'-Phosphopantetheinyl transferase (PptT) is an essential enzyme for Mycobacterium tuberculosis (Mtb) survival and virulence and therefore an attractive target for a tuberculosis therapeutic. In this work, two modeling-informed approaches toward the isosteric replacement of the amidinourea moiety present in the previously reported PptT inhibitor AU 8918 are reported. Although a designed 3,5-diamino imidazole unexpectedly adopted an undesired tautomeric form and was inactive, replacement of the amidinourea moiety afforded a series of active PptT inhibitors containing 2,6-diaminopyridine scaffolds.