A naturally occurring variant of SHLP2 is a protective factor in Parkinson's disease.

Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) have been associated with a reduced risk of developing Parkinson's disease (PD), yet the underlying mechanisms remain elusive. In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD.

Effects of genetics on odor perception: Can a quick smell test effectively screen everyone?

SCENTinel, a rapid smell test designed to screen for olfactory disorders, including anosmia (no ability to smell an odor) and parosmia (distorted sense of smell), measures 4 components of olfactory function: detection, intensity, identification, and pleasantness. Each test card contains one of 9 odorant mixtures. Some people born with genetic insensitivities to specific odorants (i.e. specific anosmia) may fail the test if they cannot smell an odorant but otherwise have a normal sense of smell. However, using odorant mixtures has largely been found to prevent this from happening. To better understand whether genetic differences affect SCENTinel test results, we asked genetically informative adult participants (twins or triplets, N = 630; singletons, N = 370) to complete the SCENTinel test. A subset of twins (n = 304) also provided a saliva sample for genotyping. We examined data for differences between the 9 possible SCENTinel odors; effects of age, sex, and race on SCENTinel performance, test-retest variability; and heritability using both structured equation modeling and SNP-based statistical methods. None of these strategies provided evidence for specific anosmia for any of the odors, but ratings of pleasantness were, in part, genetically determined (h2 = 0.40) and were nominally associated with alleles of odorant receptors (e.g. OR2T33 and OR1G1; P < 0.001). These results provide evidence that using odorant mixtures protected against effects of specific anosmia for ratings of intensity but that ratings of pleasantness showed effects of inheritance, possibly informed by olfactory receptor genotypes.

Thiazolidinediones are Partially Effective Bitter Blockers.

PURPOSE: The bad bitter taste of some medicines is a barrier to overcoming noncompliance with medication use, especially life-saving drugs given to children and the elderly. Here, we evaluated a new class of bitter blockers (thiazolidinediones, TZDs). METHODS: In this study, 2 TZDs were tested, rosiglitazone (ROSI) and a simpler form of TZD, using a high-potency sweetener as a positive control (neohesperidin dihydrochalcone, NHDC). We tested bitter-blocking effects using the bitter drugs tenofovir alafenamide fumarate (TAF), a treatment for HIV and hepatitis B infection, and praziquantel (PRAZ), a treatment for schistosomiasis, by conducting taste testing with 2 separate taste panels: a general panel (N = 97, 20-23 years, 82.5% female, all Eastern European) and a genetically informative panel (N = 158, including 68 twin pairs, 18-82 years, 76% female, 87% European ancestry). Participants rated the bitterness intensity of the solutions on a 100-point generalized visual analog scale. FINDINGS: Person-to-person differences in drug bitterness were striking; TAF and PRAZ were weakly or not bitter for some people but moderately to highly bitter for others. Participants in both taste panels rated the bitter drugs TAF and PRAZ as less bitter on average when mixed with NHDC than when sampled alone. ROSI partially suppressed the bitterness of TAF and PRAZ, but effectiveness differed between the 2 panels: bitterness was significantly reduced for PRAZ but not TAF in the general panel and for TAF but not PRAZ in the genetically informative panel. ROSI was a more effective blocker than the other TZD. IMPLICATIONS: These results suggest that TZDs are partially effective bitter blockers and the suppression efficacy differs from drug to drug, from person to person, and from panel to panel, suggesting other TZDs should be designed and tested with more drugs and on diverse populations to define which ones work best with which drugs and for whom. The discovery of bitter receptor blockers can improve compliance with medication use.

Correlation between omega-3 intake and the incidence of diabetic retinopathy based on NHANES from 2005 to 2008.

AIMS: To identify correlations between omega-3 intake and incidence of diabetic retinopathy (DR). METHODS: This was a cross-sectional study using data from participants over age 40 in the National Health and Nutrition Examination Survey (NHANES) 2005-2008. Metrics included participants' intake of omega-3 fatty acids, specifically three types of representative polyunsaturated fatty acids, DR prevalence, and demographic characteristics. Multiple logistic regression models were used to assess the relationship between omega-3 intake and DR. RESULTS: Of the 1243 participants included in this study, omega-3 intake was lower in patients with DR relative to those without DR. Of the three polyunsaturated fatty acids within the omega-3 fatty acid family that we focused on, participants without DR consumed more docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) than those with DR. In contrast, there was no significant difference in the intake of eicosapentaenoic acid (EPA). Higher omega-3 intake was associated with a decreased risk of DR. In a crude model, the odds ratio (OR) was 0.548 (95% CI 0.315, 0.951; p = 0.033). In the fully adjusted model of omega-3 (model II), the adjusted OR was 0.525 (95% CI 0.306, 0.901; p = 0.021). DPA and DHA were also associated with a decreased risk of DR. In the full adjustment model (model II) of DPA and DHA, the adjusted ORs were 0.0002 (95% CI 0.000, 0.166; p = 0.014) and 0.293 (95% CI 0.105, 0.819; p = 0.020). Subgroup analysis showed that the protective effect of omega-3 against DR was more significant in younger patients (p value = 0.015). CONCLUSIONS: In this cross-sectional study of the U.S. general population, we found that increased intake of omega-3 and its components, specifically DPA and DHA were negatively associated with DR incidence. This suggests that omega-3 may be a potential protective factor for DR and may help to prevent or delay the onset and progression of DR.

Blood-based liquid biopsy: A promising noninvasive test in diagnosis, surveillance, and prognosis of patients with upper tract urothelial carcinoma.

OBJECTIVES: To assess the efficacy of blood-based liquid biopsy in the diagnosis, surveillance, and prognosis of upper tract urothelial carcinoma (UTUC). METHODS AND MATERIALS: In this prospective study, peripheral blood samples were collected from patients with primary UTUC before surgery with curative intent and follow-up visits at University of Southern California between May 2021 and September 2022. The samples were analyzed using the third-generation comprehensive high-definition single-cell assay (HDSCA3.0) to detect rare events, including circulating tumor cells (CTCs) and oncosomes, based on the immunofluorescence signals of DAPI (D), cytokeratin (CK), CD45/CD31 (CD), and vimentin (V). The findings of pre-surgery liquid biopsies were compared with those of blood samples from normal donors (NDs) and matched follow-up liquid biopsies. The association between liquid biopsy findings and clinical data, including recurrence-free survival (RFS), was also assessed. RESULTS: Twenty-eight patients with UTUC were included, of whom 21 had follow-up samples. Significant differences in specific rare analytes were detected in the preoperative samples compared to the NDs. In the post- vs. presurgery matched analysis, a significant decrease was detected in total-, CK-, and CK|V oncosomes, as well as in D-, D|V-, and D|V|CD cells. With a median follow-up of 11 months, 8 patients had disease recurrence. Survival analysis demonstrated that patients with >1.95 preoperative CK|V oncosomes (p = 0.020) and those with >4.18 D|CK|V cells (p = 0.050) had worse RFS compared to other patients. CONCLUSIONS: This study demonstrated promising initial evidence for the biomarker role of CTCs and oncosomes in the diagnosis and surveillance of patients with UTUC.

Cross-domain information fusion for enhanced cell population delineation in single-cell spatial-omics data.

Cell population delineation and identification is an essential step in single-cell and spatial-omics studies. Spatial-omics technologies can simultaneously measure information from three complementary domains related to this task: expression levels of a panel of molecular biomarkers at single-cell resolution, relative positions of cells, and images of tissue sections, but existing computational methods for performing this task on single-cell spatial-omics datasets often relinquish information from one or more domains. The additional reliance on the availability of "atlas" training or reference datasets limits cell type discovery to well-defined but limited cell population labels, thus posing major challenges for using these methods in practice. Successful integration of all three domains presents an opportunity for uncovering cell populations that are functionally stratified by their spatial contexts at cellular and tissue levels: the key motivation for employing spatial-omics technologies in the first place. In this work, we introduce Cell Spatio- and Neighborhood-informed Annotation and Patterning (CellSNAP), a self-supervised computational method that learns a representation vector for each cell in tissue samples measured by spatial-omics technologies at the single-cell or finer resolution. The learned representation vector fuses information about the corresponding cell across all three aforementioned domains. By applying CellSNAP to datasets spanning both spatial proteomic and spatial transcriptomic modalities, and across different tissue types and disease settings, we show that CellSNAP markedly enhances de novo discovery of biologically relevant cell populations at fine granularity, beyond current approaches, by fully integrating cells' molecular profiles with cellular neighborhood and tissue image information.

Worldwide study of the taste of bitter medicines and their modifiers.

The bitter taste of medicines hinders patient compliance, but not everyone experiences these difficulties because people worldwide differ in their bitterness perception. To better understand how people from diverse ancestries perceive medicines and taste modifiers, 338 adults, European and recent US and Canada immigrants from Asia, South Asia, and Africa, rated the bitterness intensity of taste solutions on a 100-point generalized visual analog scale and provided a saliva sample for genotyping. The taste solutions were five medicines, tenofovir alafenamide (TAF), moxifloxacin, praziquantel, amodiaquine, and propylthiouracil (PROP), and four other solutions, TAF mixed with sucralose (sweet, reduces bitterness) or 6-methylflavone (tasteless, reduces bitterness), sucralose alone, and sodium chloride alone. Bitterness ratings differed by ancestry for two of the five drugs (amodiaquine and PROP) and for TAF mixed with sucralose. Genetic analysis showed that people with variants in one bitter receptor variant gene (TAS2R38) reported PROP was more bitter than did those with a different variant (p= 7.6e-19) and that people with either an RIMS2 or a THSD4 genotype found sucralose more bitter than did others (p=2.6e-8, p=7.9e-11, resp.). Our findings may help guide the formulation of bad-tasting medicines to meet the needs of those most sensitive to them.

Transcription of HIV-1 at sites of intact latent provirus integration.

HIV-1 antiretroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses, leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here, we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 100-10,000× less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir, thereby influencing cytopathic effects and proviral immune evasion.

Transcription of HIV-1 at sites of intact latent provirus integration.

HIV-1 anti-retroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 10010,000X less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir thereby influencing cytopathic effects and proviral immune evasion.

Trends in diabetic ketoacidosis- and hyperosmolar hyperglycemic state-related mortality during the COVID-19 pandemic in the United States: A population-based study.

BACKGROUND: During the pandemic, a notable increase in diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS), conditions that warrant emergent management, was reported. We aimed to investigate the trend of DKA- and HHS-related mortality and excess deaths during the pandemic. METHODS: Annual age-standardized mortality rates related to DKA and HHS between 2006 and 2021 were estimated using a nationwide database. Forecast analyses based on prepandemic data were conducted to predict the mortality rates during the pandemic. Excess mortality rates were calculated by comparing the observed versus predicted mortality rates. Subgroup analyses of demographic factors were performed. RESULTS: There were 71 575 DKA-related deaths and 8618 HHS-related deaths documented during 2006-2021. DKA, which showed a steady increase before the pandemic, demonstrated a pronounced excess mortality during the pandemic (36.91% in 2020 and 46.58% in 2021) with an annual percentage change (APC) of 29.4% (95% CI: 16.0%-44.0%). Although HHS incurred a downward trend during 2006-2019, the excess deaths in 2020 (40.60%) and 2021 (56.64%) were profound. Pediatric decedents exhibited the highest excess mortality. More than half of the excess deaths due to DKA were coronavirus disease 2019 (COVID-19) related (51.3% in 2020 and 63.4% in 2021), whereas only less than a quarter of excess deaths due to HHS were COVID-19 related. A widened racial/ethnic disparity was observed, and females exhibited higher excess mortality than males. CONCLUSIONS: The DKA- and HHS-related excess mortality during the pandemic and relevant disparities emphasize the urgent need for targeted strategies to mitigate the escalated risk in these populations during public health crises.

Epstein-Barr Virus Orchestrates Spatial Reorganization and Immunomodulation within the Classic Hodgkin Lymphoma Tumor Microenvironment.

Classic Hodgkin Lymphoma (cHL) is a tumor composed of rare malignant Hodgkin and Reed-Sternberg (HRS) cells nested within a T-cell rich inflammatory immune infiltrate. cHL is associated with Epstein-Barr Virus (EBV) in 25% of cases. The specific contributions of EBV to the pathogenesis of cHL remain largely unknown, in part due to technical barriers in dissecting the tumor microenvironment (TME) in high detail. Herein, we applied multiplexed ion beam imaging (MIBI) spatial pro-teomics on 6 EBV-positive and 14 EBV-negative cHL samples. We identify key TME features that distinguish between EBV-positive and EBV-negative cHL, including the relative predominance of memory CD8 T cells and increased T-cell dysfunction as a function of spatial proximity to HRS cells. Building upon a larger multi-institutional cohort of 22 EBV-positive and 24 EBV-negative cHL samples, we orthogonally validated our findings through a spatial multi-omics approach, coupling whole transcriptome capture with antibody-defined cell types for tu-mor and T-cell populations within the cHL TME. We delineate contrasting transcriptomic immunological signatures between EBV-positive and EBV-negative cases that differently impact HRS cell proliferation, tumor-immune interactions, and mecha-nisms of T-cell dysregulation and dysfunction. Our multi-modal framework enabled a comprehensive dissection of EBV-linked reorganization and immune evasion within the cHL TME, and highlighted the need to elucidate the cellular and molecular fac-tors of virus-associated tumors, with potential for targeted therapeutic strategies.

Combination of Proton Pump Inhibitors and Food Elimination Diet for Eosinophilic Esophagitis Refractory to Monotherapy.

Background and Aims: Eosinophilic esophagitis (EoE) is an antigen-mediated inflammatory esophageal disease that is commonly treated with high-dose proton-pump inhibitors (PPIs), topical corticosteroids, or food elimination diet (FED) monotherapy. Combination treatment has not been well studied in the management of EoE. We aimed to determine if PPI and FED combination therapy was able to induce histologic remission in patients with EoE refractory to monotherapy. Methods: We conducted a retrospective cohort study identifying patients with EoE that was refractory to PPI monotherapy and FED monotherapy but histologically responsive to PPI and FED combination therapy. We also identified symptom changes through chart review. Results: Out of 405 EoE patients, 12 patients were identified with EoE that was refractory to PPI monotherapy and FED monotherapy but histologically responsive to PPI and FED combination therapy. Out of 12 patients, 11 (91.67%) noted resolution of symptoms while on combination therapy. Comparative analysis of peak eosinophil counts showed that patients achieved a median of 4.5 eos/hpf (interquartile range [IQR], 2-6.5), which was significantly decreased compared to baseline (median, 45; IQR, 35.5-50; Wilcoxon signed-rank test, P < .001), PPI monotherapy (median, 41; IQR, 26-50; Wilcoxon signed-rank test, P < .001), and FED monotherapy (median, 45; IQR, 17-67.5; Wilcoxon signed-rank test, P < .001). Conclusion: Our work shows that patients with EoE refractory to PPI monotherapy and FED monotherapy can successfully achieve histologic remission and symptom benefit with PPI and FED combination therapy. Therefore, combination therapy should be considered a viable option for patients with EoE who fail treatment with first-line monotherapies.