Sensitization of hepatocellular carcinoma cells to HDACi is regulated through hsa-miR-342-5p/CFL1.

BACKGROUND: Increased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance. METHODS: MicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro. RESULTS: Here we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner. CONCLUSION: Our findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation.

The functional logic of odor information processing in the Drosophila antennal lobe.

Recent advances in molecular transduction of odorants in the Olfactory Sensory Neurons (OSNs) of the Drosophila Antenna have shown that the odorant object identity is multiplicatively coupled with the odorant concentration waveform. The resulting combinatorial neural code is a confounding representation of odorant semantic information (identity) and syntactic information (concentration). To distill the functional logic of odor information processing in the Antennal Lobe (AL) a number of challenges need to be addressed including 1) how is the odorant semantic information decoupled from the syntactic information at the level of the AL, 2) how are these two information streams processed by the diverse AL Local Neurons (LNs) and 3) what is the end-to-end functional logic of the AL? By analyzing single-channel physiology recordings at the output of the AL, we found that the Projection Neuron responses can be decomposed into a concentration-invariant component, and two transient components boosting the positive/negative concentration contrast that indicate onset/offset timing information of the odorant object. We hypothesized that the concentration-invariant component, in the multi-channel context, is the recovered odorant identity vector presented between onset/offset timing events. We developed a model of LN pathways in the Antennal Lobe termed the differential Divisive Normalization Processors (DNPs), which robustly extract the semantics (the identity of the odorant object) and the ON/OFF semantic timing events indicating the presence/absence of an odorant object. For real-time processing with spiking PN models, we showed that the phase-space of the biological spike generator of the PN offers an intuit perspective for the representation of recovered odorant semantics and examined the dynamics induced by the odorant semantic timing events. Finally, we provided theoretical and computational evidence for the functional logic of the AL as a robust ON-OFF odorant object identity recovery processor across odorant identities, concentration amplitudes and waveform profiles.

Human Thg1 displays tRNA-inducible GTPase activity.

tRNAHis guanylyltransferase (Thg1) catalyzes the 3'-5' incorporation of guanosine into position -1 (G-1) of tRNAHis. G-1 is unique to tRNAHis and is crucial for recognition by histidyl-tRNA synthetase (HisRS). Yeast Thg1 requires ATP for G-1 addition to tRNAHis opposite A73, whereas archaeal Thg1 requires either ATP or GTP for G-1 addition to tRNAHis opposite C73. Paradoxically, human Thg1 (HsThg1) can add G-1 to tRNAsHis with A73 (cytoplasmic) and C73 (mitochondrial). As N73 is immediately followed by a CCA end (positions 74-76), how HsThg1 prevents successive 3'-5' incorporation of G-1/G-2/G-3 into mitochondrial tRNAHis (tRNAmHis) through a template-dependent mechanism remains a puzzle. We showed herein that mature native human tRNAmHis indeed contains only G-1. ATP was absolutely required for G-1 addition to tRNAmHis by HsThg1. Although HsThg1 could incorporate more than one GTP into tRNAmHisin vitro, a single-GTP incorporation prevailed when the relative GTP level was low. Surprisingly, HsThg1 possessed a tRNA-inducible GTPase activity, which could be inhibited by ATP. Similar activity was found in other high-eukaryotic dual-functional Thg1 enzymes, but not in yeast Thg1. This study suggests that HsThg1 may downregulate the level of GTP through its GTPase activity to prevent multiple-GTP incorporation into tRNAmHis.

MPK12 in stomatal CO2 signaling: function beyond its kinase activity.

Protein phosphorylation is a major molecular switch involved in the regulation of stomatal opening and closure. Previous research defined interaction between MAP kinase 12 and Raf-like kinase HT1 as a required step for stomatal movements caused by changes in CO2 concentration. However, whether MPK12 kinase activity is required for regulation of CO2 -induced stomatal responses warrants in-depth investigation. We apply genetic, biochemical, and structural modeling approaches to examining the noncatalytic role of MPK12 in guard cell CO2 signaling that relies on allosteric inhibition of HT1. We show that CO2 /HCO3 - -enhanced MPK12 interaction with HT1 is independent of its kinase activity. By analyzing gas exchange of plant lines expressing various kinase-dead and constitutively active versions of MPK12 in a plant line where MPK12 is deleted, we confirmed that CO2 -dependent stomatal responses rely on MPK12's ability to bind to HT1, but not its kinase activity. We also demonstrate that purified MPK12 and HT1 proteins form a heterodimer in the presence of CO2 /HCO3 - and present structural modeling that explains the MPK12:HT1 interaction interface. These data add to the model that MPK12 kinase-activity-independent interaction with HT1 functions as a molecular switch by which guard cells sense changes in atmospheric CO2 concentration.

Prognostic and Clinical Implications of UNC13C expression in Hepatocellular Carcinoma Patients.

Aberrant expression of UNC13C (Unc-13 Homolog C) has been observed during the progression of oral squamous cell carcinoma. However, the expression pattern and clinical relevance of UNC13C in Hepatocellular carcinoma (HCC) remain to be elucidated. The purpose of this study is to examine UNC13C expression in HCC and explore its role in clinicopathological factor or prognosis in HCC. Two hundred and sixty-five patients diagnosed with HCC were included in the present study. The expression of UNC13C in HCC tissues was analyzed by immunohistochemistry analysis. The relationship between UNC13C protein and clinicopathological characteristics in HCC was investigated. Moreover, the high expression of UNC13C was significantly correlated with T stage, AJCC stage and overall survival rates. Cox regression analysis identified UNC13C as an independent prognostic indicator for HCC patients. UNC13C might be a prognostic biomarker and therapeutic target in HCC. Further studies with larger sample sets are needed to understand the clinical implications of UNC13C in hepatocellular carcinoma.

Multicenter Prospective Study of Biomarkers for Diagnosis of Invasive Candidiasis in Children and Adolescents.

BACKGROUND: Diagnosis of invasive candidiasis (IC) relies on insensitive cultures; the relative utility of fungal biomarkers in children is unclear. METHODS: This multinational observational cohort study enrolled patients aged >120 days and <18 years with concern for IC from 1 January 2015 to 26 September 2019 at 25 centers. Blood collected at onset of symptoms was tested using T2Candida, Fungitell (1→3)-ß-D-glucan, Platelia Candida Antigen (Ag) Plus, and Platelia Candida Antibody (Ab) Plus assays. Operating characteristics were determined for each biomarker, and assays meeting a defined threshold considered in combination. Sterile site cultures were the reference standard. RESULTS: Five hundred participants were enrolled at 22 centers in 3 countries, and IC was diagnosed in 13 (2.6%). Thirteen additional blood specimens were collected and successfully spiked with Candida species, to achieve a 5.0% event rate. Valid T2Candida, Fungitell, Platelia Candida Ag Plus, and Platelia Candida Ab Plus assay results were available for 438, 467, 473, and 473 specimens, respectively. Operating characteristics for T2Candida were most optimal for detecting IC due to any Candida species, with results as follows: sensitivity, 80.0% (95% confidence interval, 59.3%-93.2%), specificity 97.1% (95.0%-98.5%), positive predictive value, 62.5% (43.7%-78.9%), and negative predictive value, 98.8% (97.2%-99.6%). Only T2Candida and Platelia Candida Ag Plus assays met the threshold for combination testing. Positive result for either yielded the following results: sensitivity, 86.4% (95% confidence interval, 65.1%- 97.1%); specificity, 94.7% (92.0%-96.7%); positive predictive value, 47.5% (31.5%-63.9%); and negative predictive value, 99.2% (97.7%-99.8%). CONCLUSIONS: T2Candida alone or in combination with Platelia Candida Ag Plus may be beneficial for rapid detection of Candida species in children with concern for IC. CLINICAL TRIALS REGISTRATION: NCT02220790.

A novel synthetic-genetic-array-based yeast one-hybrid system for high discovery rate and short processing time.

Eukaryotic gene expression is often tightly regulated by interactions between transcription factors (TFs) and their DNA cis targets. Yeast one-hybrid (Y1H) is one of the most extensively used methods to discover these interactions. We developed a high-throughput meiosis-directed yeast one-hybrid system using the Magic Markers of the synthetic genetic array analysis. The system has a transcription factor-DNA interaction discovery rate twice as high as the conventional diploid-mating approach and a processing time nearly one-tenth of the haploid-transformation method. The system also offers the highest accuracy in identifying TF-DNA interactions that can be authenticated in vivo by chromatin immunoprecipitation. With these unique features, this meiosis-directed Y1H system is particularly suited for constructing novel and comprehensive genome-scale gene regulatory networks for various organisms.

High-fat diet attenuates morphine withdrawal effects on sensory-evoked locus coeruleus norepinephrine neural activity in male obese rats.

Objective: These experiments sought to characterize the effects of obesity propensity and obesogenic diet on locus coeruleus (LC) norepinephrine (NE) activity and determine the effects of obesity on LC neural responses to morphine withdrawal.Methods: In vivo single-unit LC electrophysiological activity was measured in obese prone (OP) and obese resistant (OR) male SD rats following high-fat (HFD: 45% fat) or low-fat (LFD; 10% fat) feeding. A separate cohort of LFD and HFD rats underwent in vivo LC recording on day 3 of spontaneous morphine withdrawal following an escalation dose paradigm (5-15 mg/kg; SQ twice daily).Results: OP (LFD: 34 cells/7 rats; HFD: 32 cells/6 rats) had higher spontaneous and tonic activity, and lower sensory-evoked activity compared with OR (LFD: 31 cells/6 rats; HFD: 41 cells/7 rats). Interacting effect of diet x strain status was observed on signal-to-noise ratio with OR-LFD having higher ratio than OP-LFD and OP-HFD. Morphine treatment decreased body weights. Withdrawal increased sensory-evoked rate in LFD (morphine; 20 cells/10 rats; saline 24 cells/6 rats) but not HFD (saline: 22 cells/7 rats; morphine: 21 cells/5 rats) rats. In a separate group of age-matched SD rats, a similar weight loss (5-7%) in response to the morphine did not alter sensory-evoked rate but decreased signal-to-noise ratio (Control: 22 cells/8 rats; Weight-matched: 23 cells/8 rats).Discussion: Taken together, our findings suggest that obesity and diet alter the sensory-evoked LC-NE neural responses, which could have implication for emotional stress and opioid-withdrawal behaviors.

Changes in self-harm- and violence-related urgent psychiatric consultation in the emergency department during the different stages of the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 pandemic significantly affected emergency department (ED) visits and urgent psychiatric consultation (UPC) seeking behavior in EDs. Our study explored the changes in UPCs during and after the pandemic peak. METHODS: This retrospective observational study evaluated UPCs in the ED of a referral medical center in Taiwan, where treated both physical and psychiatric complaints. We defined the COVID-19 pandemic peak period as calendar week 4-18, 2020. The corresponding baseline as calendar week 4-18, 2019, and the slack period as week 4-18, 2021. The total number of UPCs, patient demographic data such as sex and age of the patients seen, the referral system (whether police or emergency medical service [EMS] or other sources), and the chief complaint (self-harm or violence) were recorded. RESULTS: Compared with the baseline period, a significant decline in UPCs was observed in the pandemic peak period, and a rebound was observed in the slack period, with the median [IQR] Q1, Q3 values of 22 [18, 26], 12 [10, 17]), and 16 [15, 23], respectively. We observed significantly few men (34.9% vs 45.2%) and less violence (10.2% vs 17.6%) in the peak period compared with in the baseline period, but no significant difference was found compared with the slack period. Throughout the pandemic, younger patients (41.8 ± 17.4 in 2019, 39.2 ± 18.5 [p = 0.121] in 2020, and 35.6 ± 17.2 [p < 0.001] in 2021), higher proportions of police/EMS referral (38.7% in 2019, 41.9% [p = 0.473] in 2020, and 51.9% [p = 0.001] in 2021) and self-harm-related complaints (57% in 2019, 62.4% [p = 0.233] in 2020, and 64.9% [p = 0.049] in 2021) was noted among UPC seekers during the pandemic. However, the proportion of violence-related UPCs (17.6% in 2019, 10.2% [p = 0.023] in 2020, and 12.3% [p = 0.072] in 2021) declined. CONCLUSIONS: This study found that UPCs changed throughout the pandemic. This result raises the concern that mental health needs are masked during the pandemic.

Risk factors for 30-day mortality in patients with head and neck cancer bleeding in the emergency department.

BACKGROUND: Acute head and neck cancer (HNC) bleeding is a life-threatening situation that frequently presents to the emergency department (ED). The purpose of the present study was to analyze the risk factors for the 30-day mortality in patients with HNC bleeding. METHODS: We included patients who presented to the ED with HNC bleeding (n = 241). Patients were divided into the survivor and nonsurvivor groups. Variables were compared, and the associated factors were examined with Cox's proportional hazard model. RESULTS: Of the 241 patients enrolled, the most common bleeding site was the oral cavity (n = 101, 41.9%). More than half of the patients had advanced HNC stage while 41.5% had local recurrence. The proportion of active bleeding was significantly higher in the nonsurvivor group (70.5% vs. 53.3%, p = 0.038). 42.3% received blood transfusion and 5.0% required inotropic support. In total, 21.2% of the patients experienced rebleeding, and 18.3% died within 30 days. Multivariate analyses indicated that a heart rate > 100 (beats/min) (HR = 2.42; Cl 1.15-5.06; p = 0.019) and inotropic support (HR = 3.00; Cl 1.14-7.89; p = 0.026) were statistically significant independent risk factors for 30-day mortality. CONCLUSIONS: The results of this study may aid physicians in the evaluation of short-term survival in HNC bleeding patients and provide critical information for risk stratification and medical decisions.

Defining the Kv2.1-syntaxin molecular interaction identifies a first-in-class small molecule neuroprotectant.

The neuronal cell death-promoting loss of cytoplasmic K+ following injury is mediated by an increase in Kv2.1 potassium channels in the plasma membrane. This phenomenon relies on Kv2.1 binding to syntaxin 1A via 9 amino acids within the channel intrinsically disordered C terminus. Preventing this interaction with a cell and blood-brain barrier-permeant peptide is neuroprotective in an in vivo stroke model. Here a rational approach was applied to define the key molecular interactions between syntaxin and Kv2.1, some of which are shared with mammalian uncoordinated-18 (munc18). Armed with this information, we found a small molecule Kv2.1-syntaxin-binding inhibitor (cpd5) that improves cortical neuron survival by suppressing SNARE-dependent enhancement of Kv2.1-mediated currents following excitotoxic injury. We validated that cpd5 selectively displaces Kv2.1-syntaxin-binding peptides from syntaxin and, at higher concentrations, munc18, but without affecting either synaptic or neuronal intrinsic properties in brain tissue slices at neuroprotective concentrations. Collectively, our findings provide insight into the role of syntaxin in neuronal cell death and validate an important target for neuroprotection.

Large-scale data analysis for robotic yeast one-hybrid platforms and multi-disciplinary studies using GateMultiplex.

BACKGROUND: Yeast one-hybrid (Y1H) is a common technique for identifying DNA-protein interactions, and robotic platforms have been developed for high-throughput analyses to unravel the gene regulatory networks in many organisms. Use of these high-throughput techniques has led to the generation of increasingly large datasets, and several software packages have been developed to analyze such data. We previously established the currently most efficient Y1H system, meiosis-directed Y1H; however, the available software tools were not designed for processing the additional parameters suggested by meiosis-directed Y1H to avoid false positives and required programming skills for operation. RESULTS: We developed a new tool named GateMultiplex with high computing performance using C++. GateMultiplex incorporated a graphical user interface (GUI), which allows the operation without any programming skills. Flexible parameter options were designed for multiple experimental purposes to enable the application of GateMultiplex even beyond Y1H platforms. We further demonstrated the data analysis from other three fields using GateMultiplex, the identification of lead compounds in preclinical cancer drug discovery, the crop line selection in precision agriculture, and the ocean pollution detection from deep-sea fishery. CONCLUSIONS: The user-friendly GUI, fast C++ computing speed, flexible parameter setting, and applicability of GateMultiplex facilitate the feasibility of large-scale data analysis in life science fields.

Application of Three-Repetition Tests Scheme to Improve Integrated Circuits Test Quality to Near-Zero Defect.

In this research, the normal distribution is assumed to be the product characteristic, and the DITM (Digital Integrated Circuit Test Model) model is used to evaluate the integrated circuits (IC) test yield and test quality. Testing technology lags far behind manufacturing technology due to the different rates of development of the two technologies. As a result, quality control will pose significant challenges in pursuing high-quality near-zero defect products (automotive and biomedical electronics and avionics, etc.). In order to ensure product quality, we propose an effective repeated testing method (three-repetition tests scheme, TRTS), which utilizes the move test guardband (TGB) to improve the test yield and test quality. Based on the data in the International Roadmap for Devices and Systems table in 2021, the DITM model is used to estimate the future trend of semiconductor chip test yield, and the retest method (TRTS) is applied improve the test results. The method of repeated testing can increase the test yield and increase the shipment of semiconductor products. By estimating the test cost and profit, the method of repeated testing can obtain chips with near-zero defects with more corporate profits through increased product shipments.

Using mobility status as a frailty indicator to improve the accuracy of a computerised five-level triage system among older patients in the emergency department.

BACKGROUND: Owing to societal ageing, the number of older individuals visiting emergency departments (EDs) has increased in recent years. For this patient population, accurate triage systems are required. This retrospective cohort study assessed the accuracy of a computerised five-level triage system, the Taiwan Triage and Acuity System (TTAS), by determining its ability to predict in-hospital mortality in older adult patients and compare it with the corresponding rate in younger adult patients presenting to EDs. The association between frailty, which the current triage system does not consider, was also investigated. METHODS: The medical records of adult patients admitted to a single ED between 2016 and 2017 were reviewed. Data collected included information on demographics, triage level, frailty status, in-hospital mortality, and medical resource utilisation. The patients were divided into four age groups: two older adult groups (older: 65-84 years and very old: ≥85 years) and two younger adult groups (young: 18-39 and middle-aged: 40-64 years). RESULTS: Our study included 265,219 ED adult patients, of whom 64,104 and 16,009 were in the older and very old groups, respectively. The in-hospital mortality rate at each triage level increased with age. The ability of the TTAS to predict in-hospital mortality decreased with age (area under the receiver operating characteristic curve [AUROC]: young: 0.86; middle-aged, 0.84; and older and very old: 0.79). Frailty was associated with in-hospital mortality (odds ratio, 2.20; 95% confidence interval, 2.03-2.38). Adding mobility status as a frailty indicator to TTAS only slightly improved its ability to predict in-hospital mortality (AUROC: 0.74-0.77) in patients ≥65 years of age. CONCLUSIONS: The ability of the current triage system to predict in-hospital mortality decreases with age. Although frailty as mobility was associated with in-hospital mortality, its addition to the TTAS only slightly improved the accuracy with which in-hospital mortality in older patients presenting to EDs was predicted.

KLF10 Functions as an Independent Prognosis Factor for Gastric Cancer.

Background and Objectives: Kruppel-like factor 10 (KLF10) participates in the tumorigenesis of several human cancers by binding to the GC-rich region within the promoter regions of specific genes. KLF10 is downregulated in human cancers. However, the role of KLF10 in gastric cancer formation remains unclear. Materials and Methods: In this study, we performed immunohistochemical staining for KLF10 expression in 121 gastric cancer sections. Results: The loss of KLF10 expression was correlated with advanced stages and T status. Kaplan-Meier analysis revealed that patients with higher KLF10 levels had longer overall survival than those with lower KLF10 levels. Univariate analysis revealed that in patients with gastric cancer, advanced stages and low KLF10 levels were associated with survival. Multivariate analysis indicated that age, gender, advanced stages, and KLF10 expression were independent prognostic factors of the survival of patients with gastric cancer. After adjusting for age, gender, and stage, KLF10 expression was also found to be an independent prognostic factor in the survival of patients with gastric cancer. Conclusion: Our results collectively suggested that KLF10 may play a critical role in gastric cancer formation and is an independent prognosis factor of gastric cancer.

Clinical Characteristics and In-Hospital Outcomes in Dialysis Patients with Septic Arthritis.

Background and Objectives: Septic arthritis is a medical emergency associated with high morbidity and mortality. The incidence rate of septic arthritis among dialysis patients is higher than the general population, and dialysis patients with bacteremia frequently experience adverse outcomes. The aim of this study was to identify the clinical features and risk factors for longer hospital length of stay (LOS), positive blood culture, and in-hospital mortality in dialysis patients with septic arthritis. Materials and Methods: The medical records of 52 septic arthritis dialysis patients admitted to our hospital from 1 January 2009 to 31 December 2020 were analyzed. The primary outcomes were bacteremia and in-hospital mortality. Variables were compared, and risk factors were evaluated using linear and logistic regression models. Results: Twelve (23.1%) patients had positive blood cultures. A tunneled cuffed catheter for dialysis access was used in eight (15.4%) patients, and its usage rate was significantly higher in patients with positive blood culture than in those with negative blood culture (41.7 vs. 7.5%, p = 0.011). Fever was present in 15 (28.8%) patients, and was significantly more frequent in patients with positive blood culture (58.3 vs. 20%, p = 0.025). The most frequently involved site was the hip (n = 21, 40.4%). The most common causative pathogen was Gram-positive cocci, with MRSA (n = 7, 58.3%) being dominant. The mean LOS was 29.9 ± 25.1 days. The tunneled cuffed catheter was a significant predictor of longer LOS (Coef = 0.49; Cl 0.25−0.74; p < 0.001). The predictors of positive blood culture were fever (OR = 4.91; Cl 1.10−21.83; p = 0.037) and tunneled cuffed catheter (OR = 7.60; Cl 1.31−44.02; p = 0.024). The predictor of mortality was tunneled cuffed catheter (OR = 14.33; Cl 1.12−183.18; p = 0.041). Conclusions: In the dialysis population, patients with tunneled cuffed catheter for dialysis access had a significantly longer hospital LOS. Tunneled cuffed catheter and fever were independent predictors of positive blood culture, and tunneled cuffed catheter was the predictor of in-hospital mortality. The recognition of the associated factors allows for risk stratification and determination of the optimal treatment plan in dialysis patients with septic arthritis.

A molecular odorant transduction model and the complexity of spatio-temporal encoding in the Drosophila antenna.

Over the past two decades, substantial amount of work has been conducted to characterize different odorant receptors, neuroanatomy and odorant response properties of the early olfactory system of Drosophila melanogaster. Yet many odorant receptors remain only partially characterized, and the odorant transduction process and the axon hillock spiking mechanism of the olfactory sensory neurons (OSNs) have yet to be fully determined. Identity and concentration, two key characteristics of the space of odorants, are encoded by the odorant transduction process. Detailed molecular models of the odorant transduction process are, however, scarce for fruit flies. To address these challenges we advance a comprehensive model of fruit fly OSNs as a cascade consisting of an odorant transduction process (OTP) and a biophysical spike generator (BSG). We model odorant identity and concentration using an odorant-receptor binding rate tensor, modulated by the odorant concentration profile, and an odorant-receptor dissociation rate tensor, and quantitatively describe the mechanics of the molecular ligand binding/dissociation of the OTP. We model the BSG as a Connor-Stevens point neuron. The resulting spatio-temporal encoding model of the Drosophila antenna provides a theoretical foundation for understanding the neural code of both odorant identity and odorant concentration and advances the state-of-the-art in a number of ways. First, it quantifies on the molecular level the spatio-temporal level of complexity of the transformation taking place in the antennae. The concentration-dependent spatio-temporal code at the output of the antenna circuits determines the level of complexity of olfactory processing in the downstream neuropils, such as odorant recognition and olfactory associative learning. Second, the model is biologically validated using multiple electrophysiological recordings. Third, the model demonstrates that the currently available data for odorant-receptor responses only enable the estimation of the affinity of the odorant-receptor pairs. The odorant-dissociation rate is only available for a few odorant-receptor pairs. Finally, our model calls for new experiments for massively identifying the odorant-receptor dissociation rates of relevance to flies.

Women With Osteoarthritis Are at Increased Risk of Ischemic Stroke: A Population-Based Cohort Study.

BACKGROUND: Osteoarthritis (OA) is more prevalent in women with age. Comorbidities are prevalent in OA patients. In this study, we conducted a follow-up study to evaluate whether women with OA are at an increased risk of ischemic stroke using insurance claims data of Taiwan. METHODS: We identified 13,520 women with OA aged 20-99 newly diagnosed in 2000-2006 and 27,033 women without OA for comparison, frequency matched by age and diagnosis date. Women with baseline history of hypertension and other disorders associated with stroke were excluded for this study. Incident ischemic stroke was assessed by the end of 2013. A nested case-control analysis was used to identify factors associated with the stroke in the OA cohort. RESULTS: The incidence rate of ischemic stroke in the OA cohort was 1.5-fold greater than that in comparisons (1.93 versus 1.26 per 1,000 person-years), with an adjusted hazard ratio of 1.34 (95% confidence interval [CI], 1.09-1.66). The nested case-control analysis showed that stroke cases were twice as likely to develop hypertension during the follow-up period than controls without stroke. The ischemic stroke risk was significantly associated with hypertension (odds ratio [OR] 1.84; 95% CI, 1.37-2.46) and atrial fibrillation (OR 2.25; 95% CI, 1.24-4.09). Ischemic stroke was not associated with the use of non-steroidal anti-inflammatory drugs or aspirin. CONCLUSION: Women with OA are at an elevated risk of ischemic stroke. A close monitoring of hypertension, atrial fibrillation, and other stroke related comorbidities is required for stroke prevention for OA patients.

Prognostic Significance of Cytoplasmic SPNS2 Expression in Patients with Oral Squamous Cell Carcinoma.

Background and Objectives: Oral squamous cell carcinoma (OSCC) is a malignant disease with a particularly high incidence in Taiwan. Our objective in this study was to elucidate the involvement of sphingolipid transporter 2 (SPNS2) expression and SPNS2 protein expression in the clinicopathological indexes and the clinical outcomes of OSCC patients. Materials and Methods: Immunohistochemistry analysis was performed for SPNS2 protein expression in samples from 264 cases of OSCC. Correlations of SPNS2 expression with clinicopathological variables and patient survival were analyzed. Results: Our results revealed that the cytoplasmic protein expression of SPNS2 in OSCC tissue specimens was lower than in normal tissue specimens. Negative cytoplasmic protein expression of SPNS2 was significantly correlated with T status and stage. Kaplan-Meier survival curve analysis revealed that negative cytoplasmic SPNS2 expression was predictive of poorer overall survival of OSCC patients in stage III/IV. We also determined that low SPNS2 expression was an independent prognostic factor related to overall survival among OSCC patients in stage III/IV from univariate Cox proportional hazard models. Multivariate Cox proportional hazard models revealed that cytoplasmic SPNS2 expression, T status, lymph node metastasis, and histological grade were independent prognostic factors for survival. Conclusions: Overall, this study determined that SPNS2 protein may be a useful prognostic marker for OSCC patients and potential therapeutic target for OSCC treatment.

Synthetic switch-based baculovirus for transgene expression control and selective killing of hepatocellular carcinoma cells.

Baculovirus (BV) holds promise as a vector for anticancer gene delivery to combat the most common liver cancer-hepatocellular carcinoma (HCC). However, in vivo BV administration inevitably results in BV entry into non-HCC normal cells, leaky anticancer gene expression and possible toxicity. To improve the safety, we employed synthetic biology to engineer BV for transgene expression regulation. We first uncovered that miR-196a and miR-126 are exclusively expressed in HCC and normal cells, respectively, which allowed us to engineer a sensor based on distinct miRNA expression signature. We next assembled a synthetic switch by coupling the miRNA sensor and RNA binding protein L7Ae for translational repression, and incorporated the entire device into a single BV. The recombinant BV efficiently entered HCC and normal cells and enabled cis-acting transgene expression control, by turning OFF transgene expression in normal cells while switching ON transgene expression in HCC cells. Using pro-apoptotic hBax as the transgene, the switch-based BV selectively killed HCC cells in separate culture and mixed culture of HCC and normal cells. These data demonstrate the potential of synthetic switch-based BV to distinguish HCC and non-HCC normal cells for selective transgene expression control and killing of HCC cells.