Depression and risk of arthritis: A Mendelian randomization study.

INTRODUCTION: Observational studies have found that most patients with arthritis have depression. We aimed to determine the causal relationship between various types of arthritis and depression. METHODS: We conducted a two-sample bidirectional Mendelian randomized (MR) analysis to determine whether there was a significant causal relationship between depression and multiple types of arthritis. The data of our study were derived from the publicly released genome-wide association studies (GWASs) and the largest GWAS meta-analysis. MR analysis mainly used inverse-variance weighted method; supplementary methods included weighted median, weighted mode, and MR-Egger using MR pleiotropy residual sum and outlier to detect and correct for the presence of pleiotropy. RESULTS: After adjusting for heterogeneity and horizontal pleiotropy, we found that depression was associated with an increased risk of osteoarthritis (OA) (OR = 1.02, 95%CI: 1.01-1.02, p = 2.96 × E - 5). In the reverse analysis, OA was also found to increase the risk of depression (OR = 1.10, 95%CI: 1.04-1.15, p = .0002). Depression only increased the risk of knee OA (KOA) (OR = 1.25, 95%CI: 1.10-1.42, p = 6.46 × E - 4). Depression could potentially increase the risk of spondyloarthritis (OR = 1.52, 95%CI: 1.19-1.94, p ≤ 8.94 × E - 4). CONCLUSION: There is a bidirectional causal relationship of depression with OA. However, depression only augments the risk of developing KOA. Depression may increase the risk of spondyloarthritis and gout.

Assessment of chemotherapy resistance changes in human colorectal cancer xenografts in rats based on MRI histogram features.

Purpose: We investigated the value of magnetic resonance imaging (MRI) histogram features, a non-invasive method, in assessing the changes in chemoresistance of colorectal cancer xenografts in rats. Methods: A total of 50 tumor-bearing mice with colorectal cancer were randomly divided into two groups: control group and 5-fluorouracil (5-FU) group. The MRI histogram characteristics and the expression levels of p53 protein and MRP1 were obtained at 24 h, 48 h, 72 h, 120 h, and 168 h after treatment. Results: Sixty highly repeatable MRI histogram features were obtained. There were 16 MRI histogram parameters and MRP1 resistance protein differences between groups. At 24 h after treatment, the MRI histogram texture parameters of T2-weighted imaging (T2WI) images (10%, 90%, median, energy, and RootMeanSquared) and D images (10% and Range) were positively correlated with MRP1 (r = 0.925, p = 0.005). At 48 h after treatment, histogram texture parameters of apparent diffusion coefficient (ADC) images (Energy) were positively correlated with the presence of MRP1 resistance protein (r = 0.900, p = 0.037). There was no statistically significant difference between MRI histogram features and p53 protein expression level. Conclusions: MRI histogram texture parameters based on T2WI, D, and ADC maps can help to predict the change of 5-FU resistance in colorectal cancer in the early stage and provide important reference significance for clinical treatment.

Mitochondrial Inner Membrane ABC Transporter Bcmdl1 Is Involved in Conidial Germination, Virulence, and Resistance to Anilinopyrimidine Fungicides in Botrytis cinerea.

Botrytis cinerea causes gray mold on thousands of plants, leading to huge losses in production. Anilinopyrimidine (AP) fungicides have been applied to control B. cinerea since the 1990s. Although resistance to AP fungicides was detected soon after their application, the mechanism of AP resistance remains to be elucidated. In this study, a sexual cross between resistant and sensitive isolates was performed, and the genomes of parental isolates and progenies were sequenced to identify resistance-related single nucleotide polymorphisms (SNPs). After screening and verification, mutation E407K in the Bcmdl1 gene was identified and confirmed to confer resistance to AP fungicides in B. cinerea. Bcmdl1 was predicted to encode a mitochondrial protein that belonged to a half-type ATP-binding cassette (ABC) transporter. Although Bcmdl1 was a transporter, it did not mediate resistance to multiple fungicides but mediated resistance specifically to AP fungicides. On the other hand, reductions in conidial germination and virulence were observed in Bcmdl1 knockout transformants compared to the parental isolate and complemented transformants, illustrating the biological functions of Bcmdl1. Subcellular localization analysis indicated that Bcmdl1 was localized in mitochondria. Interestingly, the production of ATP was reduced after cyprodinil treatment in Bcmdl1 knockout transformants, suggesting that Bcmdl1 was involved in ATP synthesis. Since Mdl1 could interact with ATP synthase in yeast, we hypothesize that Bcmdl1 forms a complex with ATP synthase, which AP fungicides might target, thereby interfering with the metabolism of energy. IMPORTANCE Gray mold, caused by B. cinerea, causes huge losses in the production of many fruits and vegetables. AP fungicides have been largely adopted to control this disease since the 1990s, and the development of resistance to AP fungicides initiates new problems for disease control. Due to the unknown mode of action, information on the mechanism of AP resistance is also limited. Recently, mutations in mitochondrial genes were reported to be related to AP resistance. However, the mitochondrial process of these genes remains to be elucidated. In this study, we identified several AP resistance-related mutations by quantitative trait locus sequencing (QTL-seq) and confirmed that mutation E407K in Bcmdl1 conferred AP resistance. We further characterized the expression patterns, biological functions, subcellular localization, and mitochondrial processes of the Bcmdl1 gene. This study deepens our understanding of the mechanism of resistance to and mode of action of AP fungicides.

APP in the Neuromuscular Junction for the Development of Sarcopenia and Alzheimer's Disease.

Sarcopenia, an illness condition usually characterized by a loss of skeletal muscle mass and muscle strength or function, is often associated with neurodegenerative diseases, such as Alzheimer's disease (AD), a common type of dementia, leading to memory loss and other cognitive impairment. However, the underlying mechanisms for their associations and relationships are less well understood. The App, a Mendelian gene for early-onset AD, encodes amyloid precursor protein (APP), a transmembrane protein enriched at both the neuromuscular junction (NMJ) and synapses in the central nervous system (CNS). Here, in this review, we highlight APP and its family members' physiological functions and Swedish mutant APP (APPswe)'s pathological roles in muscles and NMJ. Understanding APP's pathophysiological functions in muscles and NMJ is likely to uncover insights not only into neuromuscular diseases but also AD. We summarize key findings from the burgeoning literature, which may open new avenues to investigate the link between muscle cells and brain cells in the development and progression of AD and sarcopenia.

Cranial irradiation impairs intrinsic excitability and synaptic plasticity of hippocampal CA1 pyramidal neurons with implications for cognitive function.

Radiation therapy is a standard treatment for head and neck tumors. However, patients often exhibit cognitive impairments following radiation therapy. Previous studies have revealed that hippocampal dysfunction, specifically abnormal hippocampal neurogenesis or neuroinflammation, plays a key role in radiation-induced cognitive impairment. However, the long-term effects of radiation with respect to the electrophysiological adaptation of hippocampal neurons remain poorly characterized. We found that mice exhibited cognitive impairment 3 months after undergoing 10 minutes of cranial irradiation at a dose rate of 3 Gy/min. Furthermore, we observed a remarkable reduction in spike firing and excitatory synaptic input, as well as greatly enhanced inhibitory inputs, in hippocampal CA1 pyramidal neurons. Corresponding to the electrophysiological adaptation, we found reduced expression of synaptic plasticity marker VGLUT1 and increased expression of VGAT. Furthermore, in irradiated mice, long-term potentiation in the hippocampus was weakened and GluR1 expression was inhibited. These findings suggest that radiation can impair intrinsic excitability and synaptic plasticity in hippocampal CA1 pyramidal neurons.

Analysis of SARS-CoV-2 RNA Persistence across Indoor Surface Materials Reveals Best Practices for Environmental Monitoring Programs.

Environmental monitoring in public spaces can be used to identify surfaces contaminated by persons with coronavirus disease 2019 (COVID-19) and inform appropriate infection mitigation responses. Research groups have reported detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on surfaces days or weeks after the virus has been deposited, making it difficult to estimate when an infected individual may have shed virus onto a SARS-CoV-2-positive surface, which in turn complicates the process of establishing effective quarantine measures. In this study, we determined that reverse transcription-quantitative PCR (RT-qPCR) detection of viral RNA from heat-inactivated particles experiences minimal decay over 7 days of monitoring on eight out of nine surfaces tested. The properties of the studied surfaces result in RT-qPCR signatures that can be segregated into two material categories, rough and smooth, where smooth surfaces have a lower limit of detection. RT-qPCR signal intensity (average quantification cycle [Cq]) can be correlated with surface viral load using only one linear regression model per material category. The same experiment was performed with untreated viral particles on one surface from each category, with essentially identical results. The stability of RT-qPCR viral signal demonstrates the need to clean monitored surfaces after sampling to establish temporal resolution. Additionally, these findings can be used to minimize the number of materials and time points tested and allow for the use of heat-inactivated viral particles when optimizing environmental monitoring methods. IMPORTANCE Environmental monitoring is an important tool for public health surveillance, particularly in settings with low rates of diagnostic testing. Time between sampling public environments, such as hospitals or schools, and notifying stakeholders of the results should be minimal, allowing decisions to be made toward containing outbreaks of coronavirus disease 2019 (COVID-19). The Safer At School Early Alert program (SASEA) (https://saseasystem.org/), a large-scale environmental monitoring effort in elementary school and child care settings, has processed >13,000 surface samples for SARS-CoV-2, detecting viral signals from 574 samples. However, consecutive detection events necessitated the present study to establish appropriate response practices around persistent viral signals on classroom surfaces. Other research groups and clinical labs developing environmental monitoring methods may need to establish their own correlation between RT-qPCR results and viral load, but this work provides evidence justifying simplified experimental designs, like reduced testing materials and the use of heat-inactivated viral particles.

Comparison of heat-inactivated and infectious SARS-CoV-2 across indoor surface materials shows comparable RT-qPCR viral signal intensity and persistence.

Environmental monitoring in public spaces can be used to identify surfaces contaminated by persons with COVID-19 and inform appropriate infection mitigation responses. Research groups have reported detection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) on surfaces days or weeks after the virus has been deposited, making it difficult to estimate when an infected individual may have shed virus onto a SARS-CoV-2 positive surface, which in turn complicates the process of establishing effective quarantine measures. In this study, we determined that reverse transcription-quantitative polymerase chain reaction (RT-qPCR) detection of viral RNA from heat-inactivated particles experiences minimal decay over seven days of monitoring on eight out of nine surfaces tested. The properties of the studied surfaces result in RT-qPCR signatures that can be segregated into two material categories, rough and smooth, where smooth surfaces have a lower limit of detection. RT-qPCR signal intensity (average quantification cycle (Cq)) can be correlated to surface viral load using only one linear regression model per material category. The same experiment was performed with infectious viral particles on one surface from each category, with essentially identical results. The stability of RT-qPCR viral signal demonstrates the need to clean monitored surfaces after sampling to establish temporal resolution. Additionally, these findings can be used to minimize the number of materials and time points tested and allow for the use of heat-inactivated viral particles when optimizing environmental monitoring methods.

Evaluation of the Degree of Agreement of Four Methods for Diagnosing Diabetic Autonomic Neuropathy.

Background: There are many methods to diagnose diabetic autonomic neuropathy (DAN); however, often, the various methods do not provide consistent results. Even the two methods recommended by the American Diabetes Association (ADA) guidelines, Ewing's test and heart rate variability (HRV), sometimes give conflicting results. The purpose of this study was to evaluate the degree of agreement of the results of the Composite Autonomic Symptom Score 31 (COMPASS-31), skin sympathetic reaction (SSR) test, Ewing's test, and HRV in diagnosing DAN. Methods: Patients with type 2 diabetes were recruited and each received the COMPASS-31, SSR, Ewing's test, and HRV for the diagnosis of DAN. Patients were categorized as DAN(+) and DAN(-) by each of the tests. Kappa consistency tests were used to evaluate the agreement of diagnosing DAN between any two methods. Spearman's correlation test was used to evaluate the correlations of the severity of DAN between any two methods. Receiver operating characteristic (ROC) analyses were used to evaluate the diagnostic value and the cutoff value of each method. Results: A total of 126 type 2 diabetic patients were included in the study. The percentages of DAN(+) results by HRV, Ewing's test, COMPASS-31, and SSR were 61, 40, 35, and 33%, respectively. COMPASS-31 and Ewing's test had the best agreement for diagnosing DAN (κ = 0.512, p < 0.001). COMPASS-31 and Ewing's test also had the best correlation with respect to the severity of DAN (r = 0.587, p < 0.001). Ewing's test and COMPASS-31 had relatively good diagnostic values (AUC = 0.703 and 0.630, respectively) in the ROC analyses. Conclusions: COMPASS-31 and Ewing's test exhibit good diagnostic consistency and severity correlation for the diagnosis of DAN. Either test is suitable for the diagnosis of DAN and treatment follow-up.

A discrete serotonergic circuit regulates vulnerability to social stress.

Exposure to social stress and dysregulated serotonergic neurotransmission have both been implicated in the etiology of psychiatric disorders. However, the serotonergic circuit involved in stress vulnerability is still unknown. Here, we explored whether a serotonergic input from the dorsal raphe (DR) to ventral tegmental area (VTA) influences vulnerability to social stress. We identified a distinct, anatomically and functionally defined serotonergic subpopulation in the DR that projects to the VTA (5-HTDR→VTA neurons). Moreover, we found that susceptibility to social stress decreased the firing activity of 5-HTDR→VTA neurons. Importantly, the bidirectional manipulation of 5-HTDR→VTA neurons could modulate susceptibility to social stress. Our findings reveal that the activity of 5-HTDR→VTA neurons may be an essential factor in determining individual levels of susceptibility to social stress and suggest that targeting specific serotonergic circuits may aid the development of therapies for the treatment of stress-related disorders.

Synergistic anticancer effect of exogenous wild-type p53 gene combined with 5-FU in human colon cancer resistant to 5-FU in vivo.

AIM: To investigate the anticancer effect of a recombinant adenovirus-mediated p53 (rAd-p53) combined with 5-fluorouracil (5-FU) in human colon cancer resistant to 5-FU in vivo and the mechanism of rAd-p53 in reversal of 5-FU resistance. METHODS: Nude mice bearing human colon cancer SW480/5-FU (5-FU resistant) were randomly assigned to four groups (n = 25 each): control group, 5-FU group, rAd-p53 group, and rAd-p53 + 5-FU group. At 24 h, 48 h, 72 h, 120 h and 168 h after treatment, 5 mice were randomly selected from each group and sacrificed using an overdose of anesthetics. The tumors were removed and the protein expressions of p53, protein kinase C (PKC), permeability-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) (Western blot) and apoptosis (TUNEL) were determined. RESULTS: The area ratios of tumor cell apoptosis were larger in the rAd/p53 + 5-FU group than that in the control, 5-FU and rAd/p53 groups (P < 0.05), and were larger in the rAd/p53 group than that of the control group (P < 0.05) and the 5-FU group at more than 48 h (P < 0.05). The p53 expression was higher in the rAd/p53 and the rAd/p53 + 5-FU groups than that of the control and 5-FU groups (P < 0.05), and were higher in the rAd/p53 + 5-FU group than that of the rAd/p53 group (P < 0.05). Overexpression of PKC, P-gp and MRP1 was observed in the 5-FU and control groups. In the rAd/p53 + 5-FU group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups (P < 0.05), and the expression of PKC was lower than that of the control, 5-FU and rAd/p53 groups at more than 48 h (P < 0.05). In the rAd/p53 group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups at more than 48 h (P < 0.05), and the expression of PKC was lower than that of the control and 5-FU groups at more than 120 h (P < 0.05). CONCLUSION: 5-FU combined with rAd-p53 has a synergistic anticancer effect in SW480/5-FU (5-FU resistance), which contributes to reversal of 5-FU resistance.

[Knowledge and practice on schistosomiasis control of boatmen along Yangtze River].

OBJECTIVE: To understand the knowledge and practice on schistosomiasis control of boatmen along the Yangtze River, so as to provide the evidence for making up schistosomiasis control measures for them. METHODS: In the anchor spots along the Yangtze River in Xinbei District, Changzhou City, a questionnaire survey was carried out for boatmen's knowledge and practice on schistosomiasis control. Among the boatmen of different genders, ages and education levels, the awareness rates of schistosomiasis control knowledge and the formation rates of correct behavior were compared. RESULTS: A total of 702 boatmen of 231 boats were surveyed. The total awareness rate of schistosomiasis control knowledge was 84.19%. Among the groups with different education levels, the awareness rates were significantly different (chi2 =14.42, P < 0.05). The total formation rate of correct behavior on schistosomiasis control was 43.16%. Between men and women groups, and among groups with different ages, the formation rates were significantly different (chi2 = 21.95, 15.00, P < 0.05 for all). Totally 94.81% of the boats discharged the excrement into water directly. CONCLUSION: The formation rate of correct behavior on schistosomiasis control of boatmen was low, thus the health promotion should be enhanced for them.

Formononetin, an isoflavone, relaxes rat isolated aorta through endothelium-dependent and endothelium-independent pathways.

We evaluated the vasorelaxation effects of formononetin, an isoflavone/phytoestrogen found abundantly in Astragalus mongholicus Bunge, on rat isolated aorta and the underlying mechanisms involved. Cumulative administration of formononetin, genistein, daidzein and biochanin A relaxed phenylephrine-preconstricted aorta. Formononetin and biochanin A caused a similar magnitude of relaxation whereas daidzein was least potent. Mechanical removal of endothelium, L-NAME (100 microM) and methylene blue (10 microM) suppressed formononetin-induced relaxation. Formononetin increased endothelial nitric oxide (NO) synthase (eNOS), but not inducible NO synthase, activity with an up-regulation of eNOS mRNA and p-eNOS(Ser1177) protein expression. In endothelium-denuded preparations, formononetin-induced vasorelaxation was significantly reduced by glibenclamide (3 microM) and iberiotoxin (100 nM), and a combination of glibenclamide (3 microM) plus iberiotoxin (100 nM) abolished the relaxation. In contrast, formononetin-elicited endothelium-independent relaxation was not altered by ICI 182,780 (10 microM, an estrogen receptor (ER alpha/ER beta) antagonist) or mifepristone (10 microM, a progesterone receptor antagonist). In single aortic smooth muscle cells, formononetin caused opening of iberiotoxin-sensitive Ca(2+)-activated K(+) (BK(Ca)) channels and glibenclamide-sensitive adenosine triphosphate (ATP)-dependent K(+) (K(ATP)) channels. Thus, our results suggest that formononetin caused vascular relaxation via endothelium/NO-dependent mechanism and endothelium-independent mechanism which involves the activation of BK(Ca) and K(ATP) channels.

Reporter gene assay for detection of shellfish toxins.

OBJECTIVE: To explore the potential reporter gene assay for the detection of sodium channel-specific toxins in shellfish as an alternative for screening harmful algal bloom (HAB) toxins, considering the fact that the existing methods including HPLC and bioassay are inappropriate for identifying HAB toxins which poses a serious problem on human health and shellfish industry. METHODS: A reporter plasmid pEGFP-c-fos containing c-fos promoter and EGFP was constructed and transfected into T24 cells using LipofectAMINE 2000. Positive transfectants were screened by G418 to produce a pEGFP-c-fos-T24 cell line. After addition of increasing neurotoxic shellfish poison (NSP) or GTX2,3, primary components of paralytic shellfish poison (PSP), changes in expression of EGFP in the cell line were observed under a laser scanning confocal microscope and quantified with Image-pro Plus software. RESULTS: Dose-dependent changes in the intensity of green fluorescence were observed for NSP in a range from 0 to 10 ng/mL and for GTX2,3 from 0 to 16 ng/mL. CONCLUSION: pEGFP-c-fos-T24 can be applied in detecting HAB toxins, and cell-based assay can be used as an alternative for screening sodium channel-specific HAB toxins.

[Impact evaluation of universal salt iodization on spectrum of thyroid diseases in Changzhou area, Jiangsu, China].

OBJECTIVE: To evaluate the impact of universal salt iodization using monitoring data on correctional status of iodine deficiency and hospitalized thyroid diseases. METHODS: Retrospective survey was conducted to collect medical records of hospitalized thyroid disease cases. Routine monitoring data on population iodine nutrition status and goiter prevalence were analyzed. RESULTS: The coverage of adequately iodized salt was consistently above 95%. Hospitalization rate of thyroid diseases rose steadily, and peaked at 54.5 per 100,000. The proportion of hospitalized thyroid disease among hospitalized diseases also rose with female and those aged above 40 years old mostly affected. The proportion of hospitalized hyperthyroidism among total hospitalized thyroid disease rose from 13.6% to 34.7%. CONCLUSIONS: Universal salt iodization might eliminate iodine deficiency while other impact still exists. However, the benefits of universal salt iodization should be far overweight the adverse effects.

[Effect of long-term intake of Y3+ in drinking water on learning-memeory functions and growth-development of rats].

OBJECTIVE: The aim of this paper was to learn the effect of long-term intake of Y3+ in drinking water on learning-memory function and growth-development of rats. METHODS: The rats were fed with water dissolved different level Y3+ (0, 0.534, 53.4, 5340 mg/L) for 6 months, pregnant rate, survive rate, bear rate, variety in weight were calculated, the learning-memory function was observed by step-down test. RESULTS: The results showed that a significantly decrease in electric shock period and an increase in incubation period were observed for the low dose group, in contrast, a significantly increase in electric shock period and error times, and an decreases in weight and survive rate were observed for the high dose group. CONCLUSION: Y3+ in 0.534 mg/L might improve the function of learning and memory in rats, and that Y3+ in 5340mg/L could restrain both the function of learning-memory functions and growth-development in rats.