Gut microbial ß-glucuronidases influence endobiotic homeostasis and are modulated by diverse therapeutics.

Hormones and neurotransmitters are essential to homeostasis, and their disruptions are connected to diseases ranging from cancer to anxiety. The differential reactivation of endobiotic glucuronides by gut microbial ß-glucuronidase (GUS) enzymes may influence interindividual differences in the onset and treatment of disease. Using multi-omic, in vitro, and in vivo approaches, we show that germ-free mice have reduced levels of active endobiotics and that distinct gut microbial Loop 1 and FMN GUS enzymes drive hormone and neurotransmitter reactivation. We demonstrate that a range of FDA-approved drugs prevent this reactivation by intercepting the catalytic cycle of the enzymes in a conserved fashion. Finally, we find that inhibiting GUS in conventional mice reduces free serotonin and increases its inactive glucuronide in the serum and intestines. Our results illuminate the indispensability of gut microbial enzymes in sustaining endobiotic homeostasis and indicate that therapeutic disruptions of this metabolism promote interindividual response variabilities.

Factors associated with willingness to receive coronavirus disease vaccination during the pandemic: A nationwide survey in Taiwan.

BACKGROUND/PURPOSE: Vaccination is the most important preventive measure to protect people from coronavirus disease 2019 (COVID-19). Governments worldwide have prioritized their vaccination policy against COVID-19. However, there is a lack of relevant research on Taiwanese attitudes and considerations toward COVID-19 vaccination. This study aimed to investigate the cognition, preventive behaviors, and attitudes toward COVID-19 vaccines that influence people's willingness to get vaccinated in Taiwan. METHODS: From October 1 to 31, 2021, a computer-assisted telephone interview system was used to randomly select Taiwanese people to investigate their COVID-19 preventive behaviors, knowledge, and willingness to be vaccinated. RESULTS: We included 2000 participants of whom 96.45% showed vaccination willingness. The overall mean age and knowledge scores were 48.6 years and 5.78, respectively. All of the participants chose to wear masks, and 80% chose to be vaccinated to prevent COVID-19. Compared with the non-willing vaccination participants, those with younger ages, higher incomes, and higher knowledge scores regarding masks and vaccination were more likely to be vaccinated. Furthermore, apprehensions about vaccine side effects and negative news about COVID-19 vaccines were the major reasons for vaccination hesitancy. CONCLUSION: To improve people's willingness to get vaccinated, the government should strive to deliver correct knowledge and refute inappropriate negative information about COVID-19 vaccination. Moreover, recommendation by physicians was an important factor for older individuals to decide on receiving the COVID-19 vaccine, and policies could be implemented from this aspect.

Stable Interstrand Cross-Links Generated from the Repair of 1,N6-Ethenoadenine in DNA by α-Ketoglutarate/Fe(II)-Dependent Dioxygenase ALKBH2.

DNA cross-links severely challenge replication and transcription in cells, promoting senescence and cell death. In this paper, we report a novel type of DNA interstrand cross-link (ICL) produced as a side product during the attempted repair of 1,N6-ethenoadenine (εA) by human α-ketoglutarate/Fe(II)-dependent enzyme ALKBH2. This stable/nonreversible ICL was characterized by denaturing polyacrylamide gel electrophoresis analysis and quantified by high-resolution LC-MS in well-matched and mismatched DNA duplexes, yielding 5.7% as the highest level for cross-link formation. The binary lesion is proposed to be generated through covalent bond formation between the epoxide intermediate of εA repair and the exocyclic N6-amino group of adenine or the N4-amino group of cytosine residues in the complementary strand under physiological conditions. The cross-links occur in diverse sequence contexts, and molecular dynamics simulations rationalize the context specificity of cross-link formation. In addition, the cross-link generated from attempted εA repair was detected in cells by highly sensitive LC-MS techniques, giving biological relevance to the cross-link adducts. Overall, a combination of biochemical, computational, and mass spectrometric methods was used to discover and characterize this new type of stable cross-link both in vitro and in human cells, thereby uniquely demonstrating the existence of a potentially harmful ICL during DNA repair by human ALKBH2.

Different wavelengths of LED irradiation promote secondary metabolite production in Pycnoporus sanguineus for antioxidant and immunomodulatory applications.

Pycnoporus sanguineus is a fungus of the phylum Basidiomycota that has many applications in traditional medicine, modern pharmaceuticals, and agricultural industries. Light plays an essential role in the metabolism, growth, and development of fungi. This study evaluated the mycelial growth and antioxidant and anti-inflammatory activities in P. sanguineus fermentation broth (PFB) cultured under different wavelengths of LED irradiation or in the dark. Compared to the dark cultures, the dry weight of mycelia in red- and yellow-light cultures decreased by 37 and 35% and the yields of pigments increased by 30.92 ± 2.18 mg and 31.75 ± 3.06 mg, respectively. Compared with the dark culture, the DPPH free radical scavenging ability, ABTS+ free radical scavenging capacity, and reducing power of yellow-light cultures increased significantly, and their total phenolic content peaked at 180.0 ± 8.34 µg/mL. However, the reducing power in blue-light cultures was significantly reduced, though the total phenol content did not vary with that of dark cultures. In LPS- and IFN-γ-stimulated RAW 264.7 cells, nitrite release was significantly reduced in the red and yellow light-irradiated PFB compared with the dark culture. In the dark, yellow-, and green-light cultures, TNF-α production in the inflamed RAW 264.7 cells was inhibited by 62, 46, and 14%, respectively. With red-, blue-, and white-light irradiation, TNF-α production was significantly enhanced. Based on these results, we propose that by adjusting the wavelength of the light source during culture, one can effectively modulate the growth, development, and metabolism of P. sanguineus.

Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma.

Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides an aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.

Co-detection of azoxystrobin and thiabendazole fungicides in mold and mildew resistant wallboards and in children.

The study measured the levels of azoxystrobin (AZ) and thiabendazole (TBZ) in wallboards and metabolite levels of these fungicides in children. The paper covering of wallboard samples contained a higher concentration of AZ and TBZ than the gypsum core, and similar amounts (w/w) of these two fungicides were present in the samples. These data suggest that commercial products containing a 1:1 (w/w) amount of AZ and TBZ, such as Sporgard® WB or Azo Tech™, were applied to the wallboard paper. This is the first detection of TBZ in mold-and-mildew resistant wallboards. The TBZ metabolite, 5OH-TBZ, was detected in 48% of urine samples collected from children aged 40-84 months, and was co-detected with AZ-acid, a common AZ metabolite, in 37.5% of the urine samples. The detection frequency of 5OH-TBZ was positively associated with the detection frequency of AZ-acid. These findings suggest that certain types of wallboards used in homes and commercial buildings may be a potential source of co-exposure to AZ and TBZ in humans.

Preliminary evaluation of a commercial shampoo and fine bubble bathing in the treatment of canine atopic dermatitis: A single-blinded, randomised, controlled study.

BACKGROUND: Fine bubble (FB) bathing has shown benefits on a mouse model of atopic dermatitis (AD). However, its efficacy in dogs with AD remains to be evaluated. OBJECTIVE: This study aimed to assess the clinical effectiveness of FB bathing in dogs with AD. ANIMALS: Seventeen dogs with AD whose clinical presentation showed a Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) score of <40. MATERIALS AND METHODS: The dogs were randomly assigned to either the FB bathing group or the shampoo group. The treatments were administered once a week as per the instructions, in a trial totalling 4 weeks. Evaluations were conducted on Day (D)0 and D28 to assess the outcomes of the trial. The severity of AD was measured using the CADESI-04 and the pruritus Visual Analog Scale (PVAS). The skin barrier function parameters, transepidermal water loss (TEWL) and stratum corneum hydration were measured before and after the treatment. RESULTS: Both treatment groups demonstrated a decreasing trend in CADESI-04 scores, yet the FB group exhibited significant improvement in comparison to the shampoo group after 1 month of trial. There were no significant changes in PVAS scores in either group. No significant difference was found in skin barrier function parameters between the two treatments, although TEWL slightly decreased in the FB group and slightly increased in the shampoo group after treatment. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggested that FB treatment provides benefits for dogs with AD and offers an alternative topical treatment option with a lesser impact on skin barrier function compared to frequent shampooing.

Impact of household income on the risk of overweight and obesity over time among preschool-aged children: a population-based cohort study.

BACKGROUND: The temporality of household income level with overweight/obesity in children has not been extensively studied. Little research has been conducted to determine the impact of household income on the risk of childhood overweight/obesity over time. This population-based cohort study aimed to investigate the impact of household income on the risk of overweight/obesity over time among preschool-aged children in Taiwan. METHODS: From 2009 to 2018, we recruited 1,482 preschool-aged children ( ≦ 7 y of age) from low-income households and selected age- and sex-matched controls from non-low-income households for comparison; All participants were selected from those who consistently participated in the Taipei Child Development Screening Program and were monitored for overweight/obesity using body mass index (BMI) until December 31, 2018. Low-income households were defined as those with an average monthly disposable income < 60% of the minimum standard of living expense in Taiwan. The primary outcome was childhood overweight or obesity in study participants, defined as BMI (kg/m2) ≥ 85th percentile or ≥ 95th percentile, respectively. The generalized estimating equations (GEE) model was used to determine the impact of low-income households on the risk of overweight/obesity in study participants. RESULTS: Over 21,450 person-years of follow-up, 1,782 participants developed overweight /obesity, including 452 (30.5%) and 1,330 (22.4%) children from low- and non-low-income households, respectively. The GEE model showed that the first group had a significantly higher risk of becoming overweight/obese than the other during the follow-up period (adjusted odds ratio [aOR] = 1.44, 95% CI: 1.29-1.60). Moreover, children of foreign mothers had a higher risk of becoming overweight/obese than those of Taiwanese mothers during the follow-up period (aOR = 1.51, 95% CI: 1.24-1.8). The subgroup analysis revealed a significant association between low-income households and an increased risk of overweight/obesity in children aged 2-7 years (P =.01). However, this association was not observed in children aged 0-1 years (P >.999). CONCLUSIONS: During the follow-up period, there was a notable correlation between low-income households and an increased risk of preschool-aged children developing overweight or obesity. Implementing health promotion initiatives aimed at reducing overweight and obesity in this demographic is crucial.

Circulating myeloid-derived MMP8 in stress susceptibility and depression.

Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3, the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

Gene Expression Profile Analysis of the Molecular Mechanism of HOXD10 Regulation of Epithelial Ovarian Cancer Cells.

Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer. Although studies have reported that downregulation of HOXD10 expression may contribute to the migration and invasion abilities in EOC, much about its regulation remains to be fully elucidated. The present study aimed to identify different gene expression profiles associated with HOXD10 overexpression in EOC cells. The present study confirmed that HOXD10 overexpression effectively inhibited the proliferation and motility of the TOV21G and TOV112D cells. Further, we overexpress HOXD10 in TOV112D cells, the different gene expression (DEGs) profiles induce by HOXD10 was analyze by the Human OneArray microarray. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), ingenuity pathway analysis (IPA) was used to perform the pathway enrichment analysis for the DEGs. Integrated bioinformatics analysis showed that the DEGs were enriched for terms related to oxidative phosphorylation and mitochondrial function pathways. Dysfunction oxidative phosphorylation metabolic pathway occurs frequently in many tumors. We validated the expression of NDUFA7, UQCRB and CCL2 using qPCR, involving in metabolism-related pathway, were significantly changed by HOXD10 overexpression in EOC. The detailed regulatory mechanism that links HOXD10 and the oxidative phosphorylation genes is not yet fully understood, our findings provide novel insight into HOXD10-mediated pathways and their effects on cancer metabolism, carcinogenesis, and the progression of EOC. Thus, the data suggest that strategies to interfere with metabolism-related pathways associated with cancer drug resistance could be considered for the treatment of ovarian tumors.

Inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A2AR improves hepatic and cardiac dysfunction of NASH mice.

A2AR-disrupted mice is characterized by severe systemic and visceral adipose tissue (VAT) inflammation. Increasing adenosine cyclase (AC), cAMP, and protein kinase A (PKA) formation through A2AR activation suppress systemic/VAT inflammation in obese mice. This study explores the effects of 4 wk A2AR agonist PSB0777 treatment on the VAT-driven pathogenic signals in hepatic and cardiac dysfunction of nonalcoholic steatohepatitis (NASH) obese mice. Among NASH mice with cardiac dysfunction, simultaneous decrease in the A2AR, AC, cAMP, and PKA levels were observed in VAT, liver, and heart. PSB0777 treatment significantly restores AC, cAMP, PKA, and hormone-sensitive lipase (HSL) levels, decreased SREBP-1/FASN, MCP-1, and CD68 levels, reduces infiltrated CD11b+ F4/80+ cells and adipogenesis in VAT of NASH + PSB0777 mice. The changes in VAT were accompanied by the suppression of hepatic and cardiac lipogenic/inflammatory/injury/apoptotic/fibrotic markers, the normalization of cardiac contractile [sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2)] marker, and cardiac dysfunction. The in vitro approach revealed that conditioned media (CM) of VAT of NASH mice (CMnash) trigger palmitic acid (PA)-like lipotoxic (lipogenic/inflammatory/apoptotic/fibrotic) effects in AML-12 and H9c2 cell systems. Significantly, A2AR agonist pretreatment-related normalization of A2AR-AC-cAMP-PKA levels was associated with the attenuation of CMnash-related upregulation of lipotoxic markers and the normalization of lipolytic (AML-12 cells) or contractile (H9C2 cells) marker/contraction. The in vivo and in vitro experiments revealed that A2AR agonists are potential agent to inhibit the effects of VAT inflammation-driven pathogenic signals on the hepatic and cardiac lipogenesis, inflammation, injury, apoptosis, fibrosis, hypocontractility, and subsequently improve hepatic and cardiac dysfunction in NASH mice.NEW & NOTEWORTHY Protective role of adenosine A2AR receptor (A2AR) and AC-cAMP-PKA signaling against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) possibly via its actions on adipocytes is well known in the past decade. Thus, this study evaluates pharmacological activities of A2AR agonist PSB0777, which has already demonstrated to treat NASH. In this study, the inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A2AR with A2AR agonist PSB0777 improves the hepatic and cardiac dysfunction of high-fat diet (HFD)-induced NASH mice.

A machine learning-based ensemble model for estimating diurnal variations of nitrogen oxide concentrations in Taiwan.

Air pollution is inextricable from human activity patterns. This is especially true for nitrogen oxide (NOx), a pollutant that exists naturally and also as a result of anthropogenic factors. Assessing exposure by considering diurnal variation is a challenge that has not been widely studied. Incorporating 27 years of data, we attempted to estimate diurnal variations in NOx across Taiwan. We developed a machine learning-based ensemble model that integrated hybrid kriging-LUR, machine-learning, and an ensemble learning approach. Hybrid kriging-LUR was performed to select the most influential predictors, and machine-learning algorithms were applied to improve model performance. The three best machine-learning algorithms were suited and reassessed to develop ensemble learning that was designed to improve model performance. Our ensemble model resulted in estimates of daytime, nighttime, and daily NOx with high explanatory powers (Adj-R2) of 0.93, 0.98, and 0.94, respectively. These explanatory powers increased from the initial model that used only hybrid kriging-LUR. Additionally, the results depicted the temporal variation of NOx, with concentrations higher during the daytime than the nighttime. Regarding spatial variation, the highest NOx concentrations were identified in northern and western Taiwan. Model evaluations confirmed the reliability of the models. This study could serve as a reference for regional planning supporting emission control for environmental and human health.

Evaluation of neurological behavior alterations and metabolic changes in mice under chronic glyphosate exposure.

Glyphosate is a widely used active ingredient in agricultural herbicides, inhibiting the biosynthesis of aromatic amino acids in plants by targeting their shikimate pathway. Our gut microbiota also facilitates the shikimate pathway, making it a vulnerable target when encountering glyphosate. Dysbiosis in the gut microbiota may impair the gut-brain axis, bringing neurological outcomes. To evaluate the neurotoxicity and biochemical changes attributed to glyphosate, we exposed mice with the reference dose (RfD) set by the U.S. EPA (1.75 mg/Kg-BW/day) and its hundred-time-equivalence (175 mg/Kg-BW/day) chronically via drinking water, then compared a series of neurobehaviors and their fecal/serum metabolomic profile against the non-exposed vehicles (n = 10/dosing group). There was little alteration in the neurobehavior, including motor activities, social approach, and conditioned fear, under glyphosate exposure. Metabolomic differences attributed to glyphosate were observed in the feces, corresponding to 68 and 29 identified metabolites with dysregulation in the higher and lower dose groups, respectively, compared to the vehicle-control. There were less alterations observed in the serum metabolome. Under 175 mg/Kg-BW/day of glyphosate exposure, the aromatic amino acids (phenylalanine, tryptophan, and tyrosine) were reduced in the feces but not in the serum of mice. We further focused on how tryptophan metabolism was dysregulated based on the pathway analysis, and identified the indole-derivatives were more altered compared to the serotonin and kynurenine derivatives. Together, we obtained a three-dimensional data set that records neurobehavioral, fecal metabolic, and serum biomolecular dynamics caused by glyphosate exposure at two different doses. Our data showed that even under the high dose of glyphosate irrelevant to human exposure, there were little evidence that supported the impairment of the gut-brain axis.

Engraftment and injury repair in regionally conditioned rat lung in vivo by lung progenitors derived from human pluripotent stem cells.

Although lung disease is a major cause of mortality, the mechanisms involved in human lung regeneration are unclear because of the lack of experimental models. Here we report a novel model where human pluripotent stem cell-derived expandable cell lines sharing features of airway secretory and basal cells engraft in the distal rat lung after conditioning by locoregional de-epithelialization followed by irradiation and immunosuppression. The engrafting cells, which we named distal lung epithelial progenitors (DLEPs), contributed to alveolar epithelial cells and generated 'KRT5-pods', structures involved in distal lung repair after severe injury, but only rarely to distal airways. Most strikingly, however, injury induced by the conditioning regimen was largely prevented by the engrafting DLEPs. The approach described here provides a model to study mechanisms involved in human lung regeneration, and potentially lays the foundation for the preclinical development of cell therapy to treat lung injury and disease.

A comparative analysis of complementary therapies use among patients attending diabetic clinics in Taiwan: 2007 vs. 2023.

BACKGROUND: We conducted a comparative study to examine the differences in the use of complementary therapies (CT) among patients who attended diabetic clinics for follow-up treatment between 2007 and 2023 in Taiwan. METHODS: This study employed a cross-sectional survey design to recruit individuals with diabetes from two regions (northern and southern) of Taiwan. A total of 183 and 307 participants were included in the surveys of 2007 and 2023, respectively. The data were analyzed using IBM SPSS Statistics version 28.0 to compare the survey results between the two time periods. RESULTS: Among the various CTs, nutritional supplements remained the most prevalent, with a significant increase in usage from 68.3% in 2007 to 89.9% in 2023. Conversely, other therapies, such as Chinese herbal medicines, manipulative-based therapies, supernatural healings, and bioelectromagnetic-based therapies, demonstrated a significant decrease in usage between the two time periods. Furthermore, the disclosure rate of CT use to healthcare professionals remained persistently low, with only 24.6% in 2007 and a slight increase to 30.3% in 2023. CONCLUSION: The significant rise in the use of nutritional supplements in conjunction with conventional medicine, without adequate monitoring and guidance from healthcare professionals, poses a substantial risk of unregulated blood sugar control, compromised diabetes management, and potential harm to health outcomes.

The Identification of Subsequent Events Following Out-of-Hospital Cardiac Arrests with Targeted Temperature Management.

Background: Out-of-hospital cardiac arrest (OHCA) is a critical issue due to poor neurological outcomes and high mortality rate. Severe ischemia and reperfusion injury often occur after cardiopulmonary resuscitation (CPR) and return of spontaneous circulation (ROSC). Targeted temperature management (TTM) has been shown to reduce neurological complications among OHCA survivors. However, it is unclear how "time-to-cool" influences clinical outcomes. In this study, we investigated the optimal timing to reach target temperature after cardiac arrest and ROSC. Methods: A total of 568 adults with OHCA and ROSC were admitted for targeted hypothermia assessment. Several events were predicted, including pneumonia, septic shock, gastrointestinal (GI) bleeding, and death. Results: One hundred and eighteen patients [70 men (59.32%); 48 women (40.68%)] were analyzed for clinical outcomes. The duration of CPR after ROSC was significantly associated with pneumonia, septic shock, GI bleeding, and mortality after TTM (all p < 0.001). The duration of CPR was also positively correlated with poor outcomes on the Elixhauser score (p = 0.001), APACHE II score (p = 0.008), Cerebral Performance Categories (CPC) scale (p < 0.001), and Glasgow Coma Scale (GCS) score (p < 0.001). There was a significant association between the duration of CPR and time-to-cool of TTM after ROSC (Pearson value = 0.447, p = 0.001). Pneumonia, septic shock, GI bleeding, and death were significantly higher in the patients who underwent TTM with a time-to-cool exceeding 360 minutes (all p < 0.001). Conclusions: For cardiac arrest patients, early cooling has clear benefits in reducing clinical sequelae. Clinical outcomes could be improved by improving the time to reach target temperature and feasibility for critically ill patients.

Inactivation Kinetics of Foodborne Pathogens in Carrot Juice by High-Pressure Processing.

In this study, Salmonella Typhimurium, Escherichia coli, and Listeria monocytogenes were separately inoculated in sterilized carrot juice and subjected to various types of high-pressure processing (HPP) at 200-600 MPa for 0.1-15 min to observe the effects of HPP on the inactivation kinetics of foodborne pathogens in carrot juice. The first-order model fits the destruction kinetics of high pressure on foodborne pathogens during the pressure hold period. An increase in pressure from 200 to 600 MPa decreased the decimal reduction time (D values) of S. Typhimurium, E. coli, and L. monocytogenes. Under pressure ≥ 400 MPa, the D values of E. coli were significantly higher than those of S. Typhimurium and L. monocytogenes, indicating that E. coli had greater resistance to high pressures than the others. The Zp values (the pressure range that causes the D values to change by 90%) of E. coli, S. Typhimurium, and L. monocytogenes were 195, 175, and 170 MPa, respectively. These results indicated that L. monocytogenes and E. coli were the most and least sensitive, respectively, to pressure changes. Additionally, the three bacteria were separately inoculated into thermal-sterilized carrot juice and subjected to 200-600 MPa HPP for 3 min. The treated carrot juices were stored at 4 °C for 27 d. Following S. Typhimurium and E. coli inoculation, the bacterial counts of the control and 200 MPa treatments remained the same during the storage duration. However, they decreased for the 300 and 400 MPa treatment groups with increasing storage duration. During the storage period, no bacterial growth was observed in the 500 and 600 MPa treatments. However, the bacterial number for the control and pressure treatment groups increased with prolonged storage duration following inoculation with L. monocytogenes. Therefore, following HPP, residual L. monocytogenes continued growing stably at low temperatures. Overall, HPP could inhibit and delay the growth of S. Typhimurium and E. coli in carrot juice during cold storage, but it was ineffective at inhibiting the growth of L. monocytogenes. There was a risk of foodborne illness despite the low-temperature storage of juice. The innovation of this preliminary study is to find the impact of high pressure on the inactivate kinetics of three food pathogens in carrot juice and its practical application in simulated contaminated juice.

Stress-activated brain-gut circuits disrupt intestinal barrier integrity and social behaviour.

Chronic stress underlies the etiology of both major depressive disorder (MDD) and irritable bowel syndrome (IBS), two highly prevalent and debilitating conditions with high rates of co-morbidity. However, it is not fully understood how the brain and gut bi-directionally communicate during stress to impact intestinal homeostasis and stress-relevant behaviours. Using the chronic social defeat stress (CSDS) model, we find that stressed mice display greater intestinal permeability and circulating levels of the endotoxin lipopolysaccharide (LPS) compared to unstressed control (CON) mice. Interestingly, the microbiota in the colon also exhibit elevated LPS biosynthesis gene expression following CSDS. Additionally, CSDS triggers an increase in pro-inflammatory colonic IFNγ+ Th1 cells and a decrease in IL4+ Th2 cells compared to CON mice, and this gut inflammation contributes to stress-induced intestinal barrier permeability and social avoidance behaviour. We next investigated the role of enteric neurons and identified that noradrenergic dopamine beta-hydroxylase (DBH)+ neurons in the colon are activated by CSDS, and that their ablation protects against gut pathophysiology and disturbances in social behaviour. Retrograde tracing from the colon identified a population of corticotropin-releasing hormone-expressing (CRH+) neurons in the paraventricular nucleus of the hypothalamus (PVH) that innervate the colon and are activated by stress. Chemogenetically activating these PVH CRH+ neurons is sufficient to induce gut inflammation, barrier permeability, and social avoidance behaviour, while inhibiting these cells prevents these effects following exposure to CSDS. Thus, we define a stress-activated brain-to-gut circuit that confers colonic inflammation, leading to impaired intestinal barrier function, and consequent behavioural deficits.

Social stress induces autoimmune responses against the brain.

Clinical studies have revealed a high comorbidity between autoimmune diseases and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes by which stress impacts the adaptive immune system and the implications of such responses to depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. We also confirm that social stress leads to the expansion of specific T and B cell populations within the cervical lymph nodes, where brain-derived antigens are preferentially delivered. Sera from stress-susceptible (SUS) mice exhibited high reactivity against brain tissue, and brain-reactive immunoglobulin G (IgG) antibody levels positively correlated with social avoidance behavior. IgG antibody concentrations in the brain were significantly higher in SUS mice than in unstressed mice, and positively correlated with social avoidance. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. In vivo assessment of IgG antibodies showed they largely accumulate around blood vessels in the brain only in SUS mice. B cell-depleted mice exhibited stress resilience following CSDS, confirming the contribution of antibody-producing cells to social avoidance behavior. This study provides mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses might aid in the treatment of patients with MDD featuring immune abnormalities.

Museomics unveil systematics, diversity and evolution of Australian cycad-pollinating weevils.

Weevils have been shown to play significant roles in the obligate pollination of Australian cycads. In this study, we apply museomics to produce a first molecular phylogeny estimate of the Australian cycad weevils, allowing an assessment of their monophyly, placement and relationships. Divergence dating suggests that the Australian cycad weevils originated from the Late Oligocene to the Middle Miocene and that the main radiation of the cycad-pollinating groups occurred from the Middle to the Late Miocene, which is congruent with the diversification of the Australian cycads, thus refuting any notion of an ancient ciophilous system in Australia. Taxonomic studies reveal the existence of 19 Australian cycad weevil species and that their associations with their hosts are mostly non-species-specific. Co-speciation analysis shows no extensive co-speciation events having occurred in the ciophilous system of Australian cycads. The distribution pattern suggests that geographical factors, rather than diversifying coevolution, constitute the overriding process shaping the Australian cycad weevil diversity. The synchronous radiation of cycads and weevil pollinators is suggested to be a result of the post-Oligocene diversification common in Australian organisms.