A serotonergic circuit regulates aversive associative learning under mitochondrial stress in C. elegans.

SignificancePhysiological stress triggers avoidance behavior, allowing the animals to stay away from potential threats and optimize their chance of survival. Mitochondrial disruption, a common physiological stress in diverse species, induces the nematode Caenorhabditis elegans to avoid non-pathogenic bacteria through a serotonergic neuronal circuit. We find that distinct neurons, communicated through serotonin and a specific serotonin receptor, are required for the formation and retrieval of this learned aversive behavior. This learned avoidance behavior is associated with increased serotonin synthesis, altered neuronal response property, and reprogramming of locomotion patterns. The circuit and neuromodulatory mechanisms described here offer important insights for stress-induced avoidance behavior.

Farnesoid X Receptor Protects Murine Lung against IL-6-promoted Ferroptosis Induced by Polyriboinosinic-Polyribocytidylic Acid.

Various infections trigger a storm of proinflammatory cytokines in which IL-6 acts as a major contributor and leads to diffuse alveolar damage in patients. However, the metabolic regulatory mechanisms of IL-6 in lung injury remain unclear. Polyriboinosinic-polyribocytidylic acid [poly(I:C)] activates pattern recognition receptors involved in viral sensing and is widely used in alternative animal models of RNA virus-infected lung injury. In this study, intratracheal instillation of poly(I:C) with or without an IL-6-neutralizing antibody model was combined with metabonomics, transcriptomics, and so forth to explore the underlying molecular mechanisms of IL-6-exacerbated lung injury. We found that poly(I:C) increased the IL-6 concentration, and the upregulated IL-6 further induced lung ferroptosis, especially in alveolar epithelial type II cells. Meanwhile, lung regeneration was impaired. Mechanistically, metabolomic analysis showed that poly(I:C) significantly decreased glycolytic metabolites and increased bile acid intermediate metabolites that inhibited the bile acid nuclear receptor farnesoid X receptor (FXR), which could be reversed by IL-6-neutralizing antibody. In the ferroptosis microenvironment, IL-6 receptor monoclonal antibody tocilizumab increased FXR expression and subsequently increased the Yes-associated protein (YAP) concentration by enhancing PKM2 in A549 cells. FXR agonist GW4064 and liquiritin, a potential natural herbal ingredient as an FXR regulator, significantly attenuated lung tissue inflammation and ferroptosis while promoting pulmonary regeneration. Together, the findings of the present study provide the evidence that IL-6 promotes ferroptosis and impairs regeneration of alveolar epithelial type II cells during poly(I:C)-induced murine lung injury by regulating the FXR-PKM2-YAP axis. Targeting FXR represents a promising therapeutic strategy for IL-6-associated inflammatory lung injury.

Association of Ultra-processed Food and Unprocessed or Minimally Processed Food Consumption With Bowel Habits Among U.S. Adults.

BACKGROUND & AIMS: Ultra-processed foods (UPFs) may have a negative impact on bowel habits. We aimed to assess the association between UPF and unprocessed or minimally processed food (MPF) intake and bowel habits among adults in the United States (U.S.). METHODS: We performed a cross-sectional study using data from the National Health and Nutrition Examination Survey (2005-2010). We used two 24-hour dietary recalls and, based on the Nova classification, calculated intakes of UPFs and MPFs. Constipation and diarrhea were defined using the Bristol Stool Form Scale and stool frequency. We performed survey-weighted logistic regression and substitution analysis to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 12,716 U.S. adults, there were 1290 cases of constipation and 1067 cases of diarrhea. Median UPF and MPF intakes were 26.5% and 66.2% of total grams per day, respectively. Greater UPF consumption (in % gram/d) was associated with higher odds of constipation (adjusted OR [aORQ4 vs Q1], 2.20; 95% CI, 1.76-2.74) (Ptrend < .001) but not diarrhea (aORQ4 vs Q1, 0.82; 95% CI, 0.62-1.09) (Ptrend = .12). Increased MPF consumption was associated with lower odds of constipation (aORQ4 vs Q1, 0.46; 95% CI, 0.370-0.57) (Ptrend < .001). Associations with constipation were attenuated after adjusting for diet quality (aORQ4 vs Q1, UPF, 1.53; MPF, 0.69). Substituting 10% of UPF intake with an equivalent proportion of MPFs was associated with lower odds of constipation (aOR, 0.90; 95% CI, 0.87-0.93). CONCLUSIONS: UPF intake was associated with higher odds of constipation, whereas the odds were lower with greater MPF consumption. The effect of food processing on bowel habits was independent of diet quality.

Breaking Osteoclast-Acid Vicious Cycle to Rescue Osteoporosis via an Acid Responsive Organic Framework-Based Neutralizing and Gene Editing Platform.

In the osteoporotic microenvironment, the acidic microenvironment generated by excessive osteoclasts not only causes irreversible bone mineral dissolution, but also promotes reactive oxygen species (ROS) production to induce osteoblast senescence and excessive receptor activator of nuclear factor kappa-B ligand (RANKL) production, which help to generate more osteoclasts. Hence, targeting the acidic microenvironment and RANKL production may break this vicious cycle to rescue osteoporosis. To achieve this, an acid-responsive and neutralizing system with high in vivo gene editing capacity is developed by loading sodium bicarbonate (NaHCO3) and RANKL-CRISPR/Cas9 (RC) plasmid in a metal-organic framework. This results showed ZIF8-NaHCO3@Cas9 (ZNC) effective neutralized acidic microenvironment and inhibited ROS production . Surprisingly, nanoparticles loaded with NaHCO3 and plasmids show higher transfection efficiency in the acidic environments as compared to the ones loaded with plasmid only. Finally, micro-CT proves complete reversal of bone volume in ovariectomized mice after ZNC injection into the bone remodeling site. Overall, the newly developed nanoparticles show strong effect in neutralizing the acidic microenvironment to achieve bone protection through promoting osteogenesis and inhibiting osteolysis in a bidirectional manner. This study provides new insights into the treatment of osteoporosis for biomedical and clinical therapies.

Genetic predisposition to porto-sinusoidal vascular disorder: A functional genomic-based, multigenerational family study.

BACKGROUND AND AIMS: Porto-sinusoidal vascular disorder (PSVD) is a group of liver vascular diseases featuring lesions encompassing the portal venules and sinusoids unaccompanied by cirrhosis, irrespective of the presence/absence of portal hypertension. It can occur secondary to coagulation disorders or insult by toxic agents. However, the cause of PSVD remains unknown in most cases. Hereditary cases of PSVD are exceptionally rare, but they are of particular interest and may unveil genetic alterations and molecular mechanisms associated with the disease. APPROACH AND RESULTS: We performed genome sequencing of four patients and two healthy individuals of a large multigenerational Lebanese family with PSVD and identified a heterozygous deleterious variant (c.547C>T, p.R183W) of FCH and double SH3 domains 1 ( FCHSD1 ), an uncharacterized gene, in patients. This variant segregated with the disease, and its pattern of inheritance was suggestive of autosomal dominant with variable expressivity. RNA structural modelling of human FCHSD1 suggests that the C-to-T substitution at position 547, corresponding to FCHSD1R183W , may increase both messenger RNA (mRNA) and protein stability and its interaction with MTOR-associated protein, LST8 homolog, a key protein of the mechanistic target of rapamycin (mTOR pathway). These predictions were substantiated by biochemical analyses, which showed that FCHSD1R183W induced high FCHSD1 mRNA stability, overexpression of FCHSD1 protein, and an increase in mTORC1 activation. This human FCHSD1 variant was introduced into mice through CRISPR/Cas9 genome editing. Nine out of the 15 mice carrying the human FCHSD1R183W variant mimicked the phenotype of human PSVD, including splenomegaly and enlarged portal vein. CONCLUSIONS: Aberrant FCHSD1 structure and function leads to mTOR pathway overactivation and may cause PSVD.

Lipid-modifying agents and risk of all-cause, natural and suicide mortality in schizophrenia: nationwide cohort study.

BACKGROUND: Individuals with schizophrenia face high mortality risks. The effects of lipid-modifying agents on this risk remain understudied. AIM: This study was conducted to investigate the effects of lipid-modifying agents on mortality risk in people with schizophrenia. METHOD: This nationwide cohort study collected the data of people with schizophrenia from Taiwan's National Health Insurance Research Database for the period between 1 January 2001 and 31 December 2019. Multivariable Cox proportional hazards regression with a time-dependent model was used to estimate the hazard ratio for mortality associated with each lipid-modifying agent. RESULTS: This study included 110 300 people with schizophrenia. Of them, 22 528 died (19 754 from natural causes and 1606 from suicide) during the study period, as confirmed using data from Taiwan's national mortality database. The use of lipid-modifying agents was associated with reduced risks of all-cause (adjusted hazard ratio [aHR]:0.37; P < 0.001) and natural (aHR:0.37; P < 0.001) mortality during a 5-year period. Among the lipid-modifying agents, statins and fibrates were associated with reduced risks of all-cause mortality (aHRs:0.37 and 0.39, respectively; P < 0.001 for both) and natural mortality (aHRs: 0.37 and 0.42, respectively; P < 0.001 for both). Notably, although our univariate analysis indicated an association between the use of lipid-modifying agents and a reduced risk of suicide mortality, the multivariate analysis revealed no significant association. CONCLUSIONS: Lipid-modifying agents, particularly statins and fibrates, reduce the risk of mortality in people with schizophrenia. Appropriate use of lipid-modifying agents may bridge the mortality gap between these individuals and the general population.

Lead-free Perovskite with Distorted [InX6]3- Octahedron Induced by Organic Cation and Enhanced PLQY by Sb Doping.

In-based halide perovskites have attracted a lot of attention because of their unique broadband emission properties. Herein, a series of In-based hybrid perovskites of (H2MP)2InCl7·H2O (1), (H2EP)2InCl7·H2O (2), (H2MP)2InBr7·H2O (3), and (H2EP)2InBr7·H2O (4) were synthesized under the control of halogen ions and organic cations. 1, 2, and 4 exhibit obvious photoluminescence properties with peaks at 392, 442, and 652 nm, respectively. The effects of the different components on the crystal structure and photoluminescence properties are discussed by calculating the structural distortion of the [InX6]3- octahedron. The photoluminescence properties of 1 and 4 were significantly improved after Sb3+ doping with PLQY values of 57.12 and 41.53%. Finally, a white LED was successfully fabricated with the two doped compounds coated onto the 365 nm blue LED chip.

Emerging perfluoroalkyl substances retard skeletal growth by accelerating osteoblasts senescence via ferroptosis.

Due to the persistent nature and significant negative impacts of perfluorooctanoic acid (PFOA) on human health and other organisms, the emergence of new PFOA alternatives, such as perfluoro (2-methyl-3-oxhexanoic) acid (GenX) and perfluoro-3,6,9-trioxyundecanoic acid (PFO3TDA), have drawn significant attention. However, the toxic effects of PFOA and its substitutes on bones remain limited. In this study, we administered different concentrations of PFOA, GenX, and PFO3TDA via gavage to 3-week-old male BALB/C mice for four weeks. X-ray and micro-CT scans revealed shortening of the femur and tibia and significant reduction in bone density. Additionally, PFOA, GenX, and PFO3TDA promoted osteoblast senescence and impaired osteogenic capabilities. This was characterized by a decrease in the expression of osteogenesis-related genes (OCN, ALP, Runx2, etc.) and an increase in the expression of aging and inflammation-related factors (p16INK4a, P21, MMP3, etc). Furthermore, RNA sequencing revealed activation of the ferroptosis pathway in PFOA-treated osteoblasts, characterized by notable lipid peroxidation and excessive iron accumulation. Finally, by inhibiting the ferroptosis pathway with ferrostatin-1 (Fer-1), we effectively alleviated the senescence of MC3T3-E1 cells treated with PFOA, GenX, and PFO3TDA, and improved their osteogenic capabilities. Therefore, our study provides a new therapeutic insight into the impact of PFOA and its substitutes on bone growth and development.

Racial Disparities in Alcoholic Hepatitis Hospitalizations in the United States: Trends, Outcomes, and Future Projections.

INTRODUCTION: Alcoholic hepatitis (AH) is a serious complication of alcohol consumption with high morbidity and mortality, particularly in the United States where alcohol-related liver diseases rank as one of the leading causes of preventable death. Our study aims to analyze the morbidity and mortality of AH across racial groups and project hospitalization trends up to 2028, thereby informing public health initiatives. METHODS: We conducted a cross-sectional study utilizing data from the Nationwide Inpatient Sample (NIS) spanning 2012 to 2021. The study population comprised hospitalizations identified using specific ICD-9-CM and ICD-10-CM codes for AH. We assessed hospitalizations, in-hospital mortality rates, length of stay (LOS), and morbidities related to alcoholic hepatitis adjusting for sociodemographic factors and hospital characteristics. Statistical analyses were performed using Stata and R software, employing logistic and linear regression analyses, and SARIMA models for forecasting. RESULTS: Our results indicated a predominantly White cohort (68%), with a notable increase in AH hospitalizations among Hispanics (129.1% from 2012 to 2021). Racial disparities were observed in inpatient mortality, liver transplant accessibility, and the occurrence of in-hospital complications. The study forecasts a continued rise in hospitalizations across all racial groups, with Hispanics experiencing the sharpest increase. CONCLUSION: Our study reveals a disproportionate rise in the AH burden among Hispanics with projections indicating a persistent upward trend through 2028. These findings highlight the need for targeted public health strategies and improved healthcare access to mitigate the increasing AH burden and address disparities in care and outcomes.

Antipsychotic medications and severe sepsis in schizophrenia: A nested case-control study.

BACKGROUND: Sepsis constitutes a condition that involves life-threatening organ dysfunction induced by severe infection. This nested case-control study investigated risk factors for severe sepsis and whether antipsychotic use is associated with severe sepsis risk in patients with schizophrenia, a topic that has not been comprehensively explored in previous studies. METHODS: We selected 39,432 patients with schizophrenia aged between 15 and 65 years from Taiwan's Psychiatric Inpatient Medical Claims database for the period 2000-2012. The case group comprised patients with severe sepsis after their first psychiatric admission (n = 1382). The case and control groups were randomly matched (1:4) by age, sex and first psychiatric admission (year) and finally comprised 1382 and 5528 individuals, respectively. We employed multivariable conditional logistic regression to identify (1) risk factors (physical illnesses and nonpsychiatric medications) and (2) antipsychotic-severe sepsis associations. RESULTS: Higher numbers of psychiatric admissions and physical illnesses such as delirium, cerebrovascular disease and cancer were significantly associated with a higher risk of severe sepsis. Furthermore, severe sepsis was associated with the use of antithrombotic agents, systemic corticosteroids and agents targeting the renin-angiotensin system. Clozapine (adjusted risk ratio = 1.65) and quetiapine (adjusted risk ratio = 1.59) use were associated with an increased risk of severe sepsis. The use of more than one antipsychotic drug could further increase this risk. CONCLUSION: Several physical illnesses and nonpsychiatric medications increase the risk of severe sepsis in patients with schizophrenia. Specifically, clozapine or quetiapine use significantly increased the risk of severe sepsis in these patients.

Chanling Gao suppresses colorectal cancer via PI3K/Akt/mTOR pathway modulation and enhances quality of survival.

The Chinese medicine formula Chanling Gao (CLG) exhibits significant tumor inhibitory effects in colorectal cancer (CRC) nude mice. However, the detailed mechanisms remain elusive. CRC in situ nude mouse models were treated with CLG. Small animal magnetic resonance imaging (MRI) tracked tumor progression, and overall health metrics such as food and water intake, body weight, and survival were monitored. Posttreatment, tissues and blood were analyzed for indicators of tumor inhibition and systemic effects. Changes in vital organs were observed via stereoscope and hematoxylin-eosin staining. Immunohistochemistry quantified HIF-1α and P70S6K1 protein expression in xenografts. Double labeling was used to statistically analyze vascular endothelial growth factor (VEGF) and CD31 neovascularization. Enzyme-linked immunosorbent assay was used to determine the levels of VEGF, MMP-2, MMP-9, IL-6, and IL-10 in serum, tumors, and liver. Western blotting was used to assess the expression of the PI3K/Akt/mTOR signaling pathway-related factors TGF-ß1 and smad4 in liver tissues. CLG inhibited tumor growth, improved overall health metrics, and ameliorated abnormal blood cell counts in CRC nude mice. CLG significantly reduced tumor neovascularization and VEGF expression in tumors and blood. It also suppressed HIF-1α, EGFR, p-PI3K, Akt, p-Akt, and p-mTOR expression in tumors while enhancing PTEN oncogene expression. Systemic improvements were noted, with CLG limiting liver metastasis, reducing pro-inflammatory cytokines IL-6 and IL-10 in liver tissues, decreasing MMP-2 in blood and MMP-2 and MMP-9 in tumors, and inhibiting TGF-ß1 expression in liver tissues. CLG can enhance survival quality and inhibit tumor growth in CRC nude mice, likely through the regulation of the PI3K/Akt/mTOR signaling pathway.

A Bayesian proportional hazards mixture cure model for interval-censored data.

The proportional hazards mixture cure model is a popular analysis method for survival data where a subgroup of patients are cured. When the data are interval-censored, the estimation of this model is challenging due to its complex data structure. In this article, we propose a computationally efficient semiparametric Bayesian approach, facilitated by spline approximation and Poisson data augmentation, for model estimation and inference with interval-censored data and a cure rate. The spline approximation and Poisson data augmentation greatly simplify the MCMC algorithm and enhance the convergence of the MCMC chains. The empirical properties of the proposed method are examined through extensive simulation studies and also compared with the R package "GORCure". The use of the proposed method is illustrated through analyzing a data set from the Aerobics Center Longitudinal Study.

Cell polarity control by Wnt morphogens.

Cell polarity is regulated by both intrinsic properties of the cell and extrinsic factors in the environment. Wnts are secreted glycoproteins in graded distribution, and they function as morphogens to instruct cell fate and as guidance cues to steer axon growth cone, respectively. Recent studies suggest that Wnts also instruct cell polarization in diverse contexts, by engaging cytoskeletal machineries or transcriptional mechanisms. Here we review the literature of cell polarity control by Wnt glycoproteins, with an emphasis on the nematode Caenorhabditis elegans, a multi-cellular organism in which the importance of polarity-inducing factors can be verified in vivo. In both embryonic and postembryonic cell lineages that undergo asymmetric division, Wnts act as directional signals to instruct the asymmetry of mitosis. In C. elegans, Wnts polarize neuroblasts to control their directional migration, and they also specify axon-dendrite polarity by providing spatial instruction for postmitotic neurons. Together this review summarizes recent advances and unsolved issues in cell polarity control by Wnt glycoproteins.

Caenorhabditis elegans Flamingo FMI-1 controls dendrite self-avoidance through F-actin assembly.

Self-avoidance is a conserved mechanism that prevents crossover between sister dendrites from the same neuron, ensuring proper functioning of the neuronal circuits. Several adhesion molecules are known to be important for dendrite self-avoidance, but the underlying molecular mechanisms are incompletely defined. Here, we show that FMI-1/Flamingo, an atypical cadherin, is required autonomously for self-avoidance in the multidendritic PVD neuron of Caenorhabditis elegans The fmi-1 mutant shows increased crossover between sister PVD dendrites. Our genetic analysis suggests that FMI-1 promotes transient F-actin assembly at the tips of contacting sister dendrites to facilitate their efficient retraction during self-avoidance events, probably by interacting with WSP-1/N-WASP. Mutations of vang-1, which encodes the planar cell polarity protein Vangl2 previously shown to inhibit F-actin assembly, suppress self-avoidance defects of the fmi-1 mutant. FMI-1 downregulates VANG-1 levels probably through forming protein complexes. Our study identifies molecular links between Flamingo and the F-actin cytoskeleton that facilitate efficient dendrite self-avoidance.

Identification of FCN1 as a novel macrophage infiltration-associated biomarker for diagnosis of pediatric inflammatory bowel diseases.

BACKGROUND: The incidence of pediatric inflammatory bowel disease (PIBD) has been steadily increasing globally. Delayed diagnosis of PIBD increases the risk of complications and contributes to growth retardation. To improve long-term outcomes, there is a pressing need to identify novel markers for early diagnosis of PIBD. METHODS: The candidate biomarkers for PIBD were identified from the GSE117993 dataset by two machine learning algorithms, namely LASSO and mSVM-RFE, and externally validated in the GSE126124 dataset and our PIBD cohort. The role of ficolin-1 (FCN1) in PIBD and its association with macrophage infiltration was investigated using the CIBERSORT method and enrichment analysis of the single-cell dataset GSE121380, and further validated using immunoblotting, qRT-PCR, and immunostaining in colon biopsies from PIBD patients, a juvenile murine DSS-induced colitis model, and THP-1-derived macrophages. RESULTS: FCN1 showed great diagnostic performance for PIBD in an independent clinical cohort with the AUC of 0.986. FCN1 expression was upregulated in both colorectal biopsies and blood samples from PIBD patients. Functionally, FCN1 was associated with immune-related processes in the colonic mucosa of PIBD patients, and correlated with increased proinflammatory M1 macrophage infiltration. Furthermore, single-cell transcriptome analysis and immunostaining revealed that FCN1 was almost exclusively expressed in macrophages infiltrating the colonic mucosa of PIBD patients, and these FCN1+ macrophages were related to hyper-inflammation. Notably, proinflammatory M1 macrophages derived from THP-1 expressed high levels of FCN1 and IL-1ß, and FCN1 overexpression in THP-1-derived macrophages strongly promoted LPS-induced activation of the proinflammatory cytokine IL-1ß via the NLRP3-caspase-1 axis. CONCLUSIONS: FCN1 is a novel and promising diagnostic biomarker for PIBD. FCN1+ macrophages enriched in the colonic mucosa of PIBD exhibit proinflammatory phenotypes, and FCN1 promotes IL-1ß maturation in macrophages via the NLRP3-caspase-1 axis.

Sex-specific risk profiles for suicide mortality in bipolar disorder: incidence, healthcare utilization and comorbidity.

BACKGROUND: Evidence on sex-specific incidence and comorbidity risk factors of suicide among patients with bipolar disorder is scarce. This study investigated the sex-specific risk profiles for suicide among the bipolar disorder population in terms of incidence, healthcare utilization and comorbidity. METHODS: Using data from the Taiwan National Health Insurance Research Database between 1 January 2000 and 31 December 2016, this nationwide cohort study included patients with bipolar disorder (N = 46 490) and individuals representative of the general population (N = 185 960) matched by age and sex at a 1:4 ratio. Mortality rate ratios (MRRs) of suicide were calculated between suicide rates of bipolar disorder cohort and general population. In addition, a nested case-control study (1428 cases died by suicide and 5710 living controls) was conducted in the bipolar disorder cohort to examine the sex-specific risk of healthcare utilization and comorbidities. RESULTS: Suicide risk was considerably higher in the cohort (MRR = 21.9) than in the general population, especially among women (MRR = 35.6). Sex-stratified analyses revealed distinct healthcare utilization patterns and physical comorbidity risk profiles between the sexes. Although female patients who died by suicide had higher risks of nonhypertensive cardiovascular disease, pneumonia, chronic kidney disease, peptic ulcer, irritable bowel syndrome, and sepsis compared to their living counterparts, male patients who died by suicide had higher risks of chronic kidney disease and sepsis compared to the living controls. CONCLUSIONS: Patients with bipolar disorder who died by suicide had sex-specific risk profiles in incidence and physical comorbidities. Identifying these modifiable risk factors may guide interventions for suicide risk reduction.

Healthcare utilization, psychiatric disorders, and physical illnesses shortly before suicide mortality in adolescents in Taiwan.

BACKGROUND: This study examined the pattern of medical utilization and the distribution of comorbidities shortly before death among adolescents who died from suicide and compared these data with those of living controls. METHODS: From Taiwan's National Health Insurance Research Database, this study identified adolescents aged 10-19 years who died from suicide (n = 935) between 1 January 2000, and 31 December 2016, by linking each patient with the national mortality database. The researchers conducted a nested case-control study through risk set sampling, and for each case, 20 age- and sex-matched controls (n = 18 700) were selected from the general population. The researchers applied conditional logistic regression to investigate differences in medical utilization and physical and psychiatric comorbidities between cases and controls. RESULTS: Cases had a higher proportion of contact with the psychiatric department but a similar proportion of contact with any non-psychiatric medical department within 1 year before suicide compared with controls. There were 18.6% of adolescent suicide victims who only had contacted with a psychiatric department 3 months before suicide. Moreover, cases had a higher proportion of contact with non-psychiatric services within 3 months before suicide, particularly with emergency, surgery, and internal medicine departments. Cases had higher risks of several psychiatric disorders and physical illnesses, including heart diseases, pneumonia, and ulcer disease, than did controls. CONCLUSIONS: The findings of increased medical utilization and higher risks of physical and psychiatric comorbidities in adolescent suicide victims are crucial for developing specific interventions to prevent suicide in this population.

Dihydroceramide desaturase 1 (DES1) promotes anchorage-independent survival downstream of HER2-driven glucose uptake and metabolism.

Oncogenic reprogramming of cellular metabolism is a hallmark of many cancers, but our mechanistic understanding of how such dysregulation is linked to tumor behavior remains poor. In this study, we have identified dihydroceramide desaturase (DES1)-which catalyzes the last step in de novo sphingolipid synthesis-as necessary for the acquisition of anchorage-independent survival (AIS), a key cancer enabling biology, and establish DES1 as a downstream effector of HER2-driven glucose uptake and metabolism. We further show that DES1 is sufficient to drive AIS and in vitro tumorigenicity and that increased DES1 levels-found in a third of HER2+ breast cancers-are associated with worse survival outcomes. Taken together, our findings reveal a novel pro-tumor role for DES1 as a transducer of HER2-driven glucose metabolic signals and provide evidence that targeting DES1 is an effective approach for overcoming AIS. Results further suggest that DES1 may have utility as a biomarker of aggressive and metastasis-prone HER2+ breast cancer.

A novel mucosal bivalent vaccine of EV-A71/EV-D68 adjuvanted with polysaccharides from Ganoderma lucidum protects mice against EV-A71 and EV-D68 lethal challenge.

BACKGROUND: Human enteroviruses A71 (EV-A71) and D68 (EV-D68) are the suspected causative agents of hand-foot-and-mouth disease, aseptic meningitis, encephalitis, acute flaccid myelitis, and acute flaccid paralysis in children. Until now, no cure nor mucosal vaccine existed for EV-A71 and EV-D68. Novel mucosal bivalent vaccines are highly important for preventing EV-A71 and EV-D68 infections. METHODS: In this study, formalin-inactivated EV-A71 and EV-D68 were used as antigens, while PS-G, a polysaccharide from Ganoderma lucidum, was used as an adjuvant. Natural polysaccharides have the characteristics of intrinsic immunomodulation, biocompatibility, low toxicity, and safety. Mice were immunized intranasally with PBS, EV-A71, EV-D68, or EV-A71 + EV-D68, with or without PS-G as an adjuvant. RESULTS: The EV-A71 + EV-D68 bivalent vaccine generated considerable EV-A71- and EV-D68-specific IgG and IgA titres in the sera, nasal washes, saliva, bronchoalveolar lavage fluid, and feces. These antibodies neutralized EV-D68 and EV-A71 infectivity. They also cross-neutralized infections by different EV-D68 and EV-A71 sub-genotypes. Furthermore, compared with the PBS group, EV-A71 + EV-D68 + PS-G-vaccinated mice exhibited an increased number of EV-D68- and EV-A71-specific IgA- and IgG-producing cells. In addition, T-cell proliferative responses, and IFN-γ and IL-17 secretion in the spleen were substantially induced when PS-G was used as an adjuvant with EV-A71 + EV-D68. Finally, in vivo challenge experiments demonstrated that the immune sera induced by EV-A71 + EV-D68 + PS-G conferred protection in neonate mice against lethal EV-A71 and EV-D68 challenges as indicated by the increased survival rate and decreased clinical score and viral RNA tissue expression. Taken together, all EV-A71/EV-D68 + PS-G-immunized mice developed potent specific humoral, mucosal, and cellular immune responses to EV-D68 and EV-A71 and were protected against them. CONCLUSIONS: These findings demonstrated that PS-G can be used as a potential adjuvant for EV-A71 and EV-D68 bivalent mucosal vaccines. Our results provide useful information for the further preclinical and clinical development of a mucosal bivalent enterovirus vaccine against both EV-A71 and EV-D68 infections.

Age-dependent winner-loser effects in a mangrove rivulus fish, Kryptolebias marmoratus.

The outcomes of recent fights can provide individuals information about their relative fighting ability and affect their contest decisions (winner-loser effects). Most studies investigate the presence/absence of the effects in populations/species, but here we examine how they vary between individuals of a species in response to age-dependent growth rate. Many animals' fighting ability is highly dependent on body size, so rapid growth makes information from previous fights unreliable. Furthermore, fast-growing individuals are often at earlier developmental stages and are relatively smaller and weaker than most other individuals but are growing larger and stronger quickly. We therefore predicted winner-loser effects to be less detectable in individuals with high than low growth rates and to decay more quickly. Fast-growing individuals should also display stronger winner than loser effects, because a victory when small indicates a strength which will grow, whereas a loss might soon become irrelevant. We tested these predictions using naïve individuals of a mangrove killifish, Kryptolebias marmoratus, in different growth stages. Measures of contest intensity revealed winner/loser effects only for slow-growth individuals. Both fast- and slow-growth fish with a winning experience won more of the subsequent non-escalated contests than those with a losing experience; in fast-growth individuals this effect disappeared in 3 days, but in slow-growth fish it did not. Fast-growth individuals also displayed winner effects but not loser effects. The fish therefore responded to their contest experiences in a way which reflected value of the information from these experiences to them, consistent with our predictions.