Molecular determinants and signaling effects of PKA RIα phase separation.

Spatiotemporal regulation of intracellular signaling molecules, such as the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures proper cellular function. Liquid-liquid phase separation (LLPS) of the ubiquitous PKA regulatory subunit RIα promotes cAMP compartmentation and signaling specificity. However, the molecular determinants of RIα LLPS remain unclear. Here, we reveal that two separate dimerization interfaces, combined with the cAMP-induced unleashing of the PKA catalytic subunit (PKA-C) from the pseudosubstrate inhibitory sequence, drive RIα condensate formation in the cytosol of mammalian cells, which is antagonized by docking to A-kinase anchoring proteins. Strikingly, we find that the RIα pseudosubstrate region is critically involved in forming a non-canonical R:C complex, which recruits active PKA-C to RIα condensates to maintain low basal PKA activity in the cytosol. Our results suggest that RIα LLPS not only facilitates cAMP compartmentation but also spatially restrains active PKA-C, thus highlighting the functional versatility of biomolecular condensates in driving signaling specificity.

Non-canonical ß-adrenergic activation of ERK at endosomes.

G-protein-coupled receptors (GPCRs), the largest family of signalling receptors, as well as important drug targets, are known to activate extracellular-signal-regulated kinase (ERK)-a master regulator of cell proliferation and survival1. However, the precise mechanisms that underlie GPCR-mediated ERK activation are not clearly understood2-4. Here we investigated how spatially organized ß2-adrenergic receptor (ß2AR) signalling controls ERK. Using subcellularly targeted ERK activity biosensors5, we show that ß2AR signalling induces ERK activity at endosomes, but not at the plasma membrane. This pool of ERK activity depends on active, endosome-localized Gαs and requires ligand-stimulated ß2AR endocytosis. We further identify an endosomally localized non-canonical signalling axis comprising Gαs, RAF and mitogen-activated protein kinase kinase, resulting in endosomal ERK activity that propagates into the nucleus. Selective inhibition of endosomal ß2AR and Gαs signalling blunted nuclear ERK activity, MYC gene expression and cell proliferation. These results reveal a non-canonical mechanism for the spatial regulation of ERK through GPCR signalling and identify a functionally important endosomal signalling axis.

Mortality after cardiac arrest in children less than 2 years: relevant factors.

BACKGROUND: There are only scant studies of predicting outcomes of pediatric resuscitation due to lack of population-based data. This study aimed to determine variable factors that may impact the survival of resuscitated children aged under 24 months. METHODS: This is a retrospective study of 66 children under 24 months. Cardiopulmonary resuscitation (CPR) with pediatric advanced life support guideline was performed uniformly for all children. Linear regression analysis with variable factors was conducted to determine impacts on mortality. RESULT: Factors with statistically significant increases in mortality were the number of administered epinephrine (p value < 0.001), total CPR duration (p value < 0.001), in-hospital CPR duration of out-hospital cardiac arrest (p value < 0.001), and changes in cardiac rhythm (p value < 0.040). However, there is no statistically significant association between patient outcomes and remaining factors such as age, sex, underlying disease, etiology, time between last normal to CPR, initial CPR location, initial cardiac rhythm, venous access time, or inotropic usage. CONCLUSION: More than 10 times of epinephrine administration and CPR duration longer than 30 minutes were associated with a higher mortality rate, while each epinephrine administration and prolonged CPR time increased mortality. IMPACT STATEMENT: This study analyzed various factors influencing mortality after cardiac arrest in patients under 24 months. Increased number of administered epinephrine and prolonged cardiopulmonary resuscitation duration do not increase survival rate in patients under 24 months. In patients with electrocardiogram rhythm changes during CPR, mortality increased when the rhythm changed into asystole in comparison to no changes occurring in the rhythm.

The Link of COVID-19-Related Beliefs and Information Sources to Ageism: Myth or Reality?

This study aimed to understand ambivalent ageism among younger adults during the pandemic by examining whether younger adults' beliefs around COVID-19 and the sources from which they received COVID-19 information were associated with the intensity of their ageism. For this aim, survey data were collected from individuals ages 18 to 44 between July and September 2021. Multiple hierarchical regression analysis revealed that benevolent ageism was more intense than hostile ageism when two subscales of ambivalent ageism-benevolent and hostile-were compared. Hispanic or Latinx respondents showed less intense ambivalent ageism than non-Hispanic and non-Latinx respondents. The respondents' beliefs about safety measures and the prioritization of medical resources were significantly associated with the intensity of their ageism. Receiving COVID-19 information via traditional media and social media was also significantly associated with more intense ageism. These findings indicate that social work advocacy should continue to combat ageism in times of crisis.

Biochemical and biophysical characterization of the RAS family small GTPase protein DiRAS3.

DiRAS3, also called ARHI, is a RAS (sub)family small GTPase protein that shares 50-60% sequence identity with H-, K-, and N-RAS, with substitutions in key conserved G-box motifs and a unique 34 amino acid extension at its N-terminus. Unlike the RAS proto-oncogenes, DiRAS3 exhibits tumor suppressor properties. DiRAS3 function has been studied through genetics and cell biology, but there has been a lack of understanding of the biochemical and biophysical properties of the protein, likely due to its instability and poor solubility. To overcome this solubility issue, we engineered a DiRAS3 variant (C75S/C80S), which significantly improved soluble protein expression in E. coli. Recombinant DiRAS3 was purified by Ni-NTA and size exclusion chromatography (SEC). Concentration dependence of the SEC chromatogram indicated that DiRAS3 exists in monomer-dimer equilibrium. We then produced truncations of the N-terminal (ΔN) and both (ΔNC) extensions to the GTPase domain. Unlike full-length DiRAS3, the SEC profiles showed that ΔNC is monomeric while ΔN was monomeric with aggregation, suggesting that the N and/or C-terminal tail(s) contribute to dimerization and aggregation. The 1H-15N HSQC NMR spectrum of ΔNC construct displayed well-dispersed peaks similar to spectra of other GTPase domains, which enabled us to demonstrate that DiRAS3 has a GTPase domain that can bind GDP and GTP. Taken together, we conclude that, despite the substitutions in the G-box motifs, DiRAS3 can switch between nucleotide-bound states and that the N- and C-terminal extensions interact transiently with the GTPase domain in intra- and inter-molecular fashions, mediating weak multimerization of this unique small GTPase.

Synthesis and biological evaluation of xanthine derivatives with phenacyl group as tryptophan hydroxylase 1 (TPH1) inhibitors for obesity and fatty liver disease.

Tryptophan hydroxylase 1 (TPH1) has emerged as a target for the treatment of metabolic diseases including obesity and fatty liver disease. A series of xanthine derivatives were synthesized and evaluated for their TPH1 inhibition. Among the synthesized compounds, compound 40 showed good in vitro activity and liver microsomal stability. Docking studies revealed that compound 40 showed better binding to TPH1 via key intermolecular interactions involving the xanthine scaffold, imidazo-thiazolyl ring, and hydroxyl-containing phenacyl moiety. In addition, compound 40 effectively suppressed the adipocyte differentiation of 3 T3-L1 cells.

CT-based Hounsfield unit values reflect the degree of steatohepatitis in patients with low-grade fatty liver disease.

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Ultrasound, the most used tool for diagnosing NAFLD, is operator-dependent and shows suboptimal performance in patients with mild steatosis. However, few studies have been conducted on whether alternative noninvasive methods are useful for diagnosing mild hepatic steatosis. Also, little is known about whether noninvasive tests are useful for grading the severity of hepatic steatosis or the degree of intrahepatic inflammation. Therefore, we aimed to evaluate whether the HSI, the FLI and HU values in CT could be used to discriminate mild hepatic steatosis and to evaluate the severity of hepatic steatosis or the degree of intrahepatic inflammation in patients with low-grade fatty liver disease using liver biopsy as a reference standard. METHODS: Demographic, laboratory, CT imaging, and histological data of patients who underwent liver resection or biopsy were analyzed. The performance of the HSI, HU values and the FLI for diagnosing mild hepatic steatosis was evaluated by calculating the area under the receiver operating characteristic curve. Whether the degree of hepatic steatosis and intrahepatic inflammation could be predicted using the HSI, HU values or the FLI was also analyzed. Moreover, we validate the results using magnetic resonance imaging proton density fat fraction as an another reference standard. RESULTS: The AUROC for diagnosing mild hepatic steatosis was 0.810 (p < 0.001) for the HSI, 0.732 (p < 0.001) for liver HU value, 0.802 (p < 0.001) for the difference between liver and spleen HU value (L-S HU value) and 0.813 (p < 0.001) for the FLI. Liver HU and L-S HU values were negatively correlated with the percentage of hepatic steatosis and NAFLD activity score (NAS) and significantly different between steatosis grades and between NAS grades. The L-S HU value was demonstrated the good performance for grading the severity of hepatic steatosis and the degree of intrahepatic inflammation. CONCLUSIONS: The HU values on CT are feasible for stratifying hepatic fat content and evaluating the degree of intrahepatic inflammation, and the HSI and the FLI demonstrated good performance with high sensitivity and specificity in diagnosing mild hepatic steatosis.

Clinical features of chronic fungal rhinosinusitis in Korean geriatric and non-geriatric patients.

PURPOSE: Worldwide, the incidence of chronic fungal rhinosinusitis (CFRS) has increased. Although ageing leads to weakening of the immune system, which increases susceptibility to CFRS, the CFRS characteristics in geriatric patients are unclear. Therefore, we comparatively analysed the clinical characteristics of CFRS in geriatric and non-geriatric patients. METHODS: This retrospective analysis compared the demographics, rhinologic symptoms, multiple allergen simultaneous tests, olfactory function tests, paranasal sinus computed tomography findings, and outcomes of 131 patients with CFRS who underwent functional endoscopic sinus surgery and 131 enrolled patients were divided in geriatric (> 65 years) and non-geriatric (≤ 65 years) groups. RESULTS: Among the geriatric and non-geriatric participants (n = 65, 49.6% and n = 66, 50.4%, respectively), hypertension and diabetes mellitus were more common in the geriatric group. Demographics, including symptoms, showed no significant intergroup differences. Normosmia and hyposmia were significantly less prevalent, whereas phantosmia and parosmia were more prevalent in the geriatric group than in the non-geriatric group (p = 0.03 and p = 0.01, respectively). Sphenoidal sinus involvement was significantly higher in geriatric patients than in non-geriatric patients (p = 0.02). CONCLUSION: Based on greater sphenoidal sinus involvement, a deeper anatomical area is more vulnerable to fungal infection in the geriatric group than in the non-geriatric group. Increasing clinicians' awareness of CFRS in geriatric patients with olfactory dysfunction, including phantosmia and parosmia, is important for early intervention.

CMOS Detector Staggered Array Module for Sub-Terahertz Imaging on Conveyor Belt System.

A complementary metal-oxide-semiconductor (CMOS) detector array is proposed to improve the sub-terahertz imaging resolution for objects in the conveyor belt system. The image resolution is limited to the implemented configuration, such as the wide spacing in the detector array, the high conveyor belt speed, and the slow response of the signal conditioning block. The proposed array can improve the image resolution in the direction perpendicular to the movement of the belt, which is determined by the size and interval of the detector pixel, by configuring the array into two replaceable columns located at the misaligned horizontal positions. Replaceable detector unit pixels are individually attached to the motherboard after measuring and evaluating the detection performance to construct the proposed array. The intensities of 32 detector pixels placed under the conveyor belt with a width of 160 mm were initially calibrated in every image, including the beam pattern of 0.2 THz signals generated from the gyrotron. The image resolution of the perpendicular direction obtained from the proposed array was measured to be approximately 5 mm at a conveyor belt speed of 16 mm/s, demonstrating a 200% improvement in resolution compared to the conventional linear array under the same conditions.

Concurrent-Mode CMOS Detector IC for Sub-Terahertz Imaging System.

A CMOS detector with a concurrent mode for high-quality images in the sub-terahertz region has been proposed. The detector improves output-signal coupling characteristics at the output node. A cross-coupling capacitor is added to isolate the DC bias between the drain and gate. The detector is designed to combine a 180° phase shift based on common source operation and an in-phase output signal based on the drain input. The circuit layout and phase shift occurring in the cross-coupled capacitor during phase coupling are verified using an EM simulation. The detector is fabricated using the TSMC 0.25-µm mixed-signal 1-poly 5-metal layer CMOS process, where the size, including the pad, is 1.13 mm × 0.74 mm. The detector IC comprises a folded dipole antenna, the proposed detector, a preamplifier, and a voltage buffer. Measurement results using a 200-GHz gyrotron source demonstrate that the proposed detector voltage responsivity is 14.13 MV/W with a noise-equivalent power of 34.42 pW/√Hz. The high detection performance helps resolve the 2-mm line width. The proposed detector exhibits a signal-to-noise ratio of 49 dB with regard to the THz imaging performance, which is 9 dB higher than that of the previous CMOS detector core circuits with gate-drain capacitors.

Size-Dependent Effects of Polystyrene Nanoparticles (PS-NPs) on Behaviors and Endogenous Neurochemicals in Zebrafish Larvae.

Microplastics, small pieces of plastic derived from polystyrene, have recently become an ecological hazard due to their toxicity and widespread occurrence in aquatic ecosystems. In this study, we exposed zebrafish larvae to two types of fluorescent polystyrene nanoparticles (PS-NPs) to identify their size-dependent effects. PS-NPs of 50 nm, unlike 100 nm PS-NPs, were found to circulate in the blood vessels and accumulate in the brains of zebrafish larvae. Behavioral and electroencephalogram (EEG) analysis showed that 50 nm PS-NPs induce abnormal behavioral patterns and changes in EEG power spectral densities in zebrafish larvae. In addition, the quantification of endogenous neurochemicals in zebrafish larvae showed that 50 nm PS-NPs disturb dopaminergic metabolites, whereas 100 nm PS-NPs do not. Finally, we assessed the effect of PS-NPs on the permeability of the blood-brain barrier (BBB) using a microfluidic system. The results revealed that 50 nm PS-NPs have high BBB penetration compared with 100 nm PS-NPs. Taken together, we concluded that small nanoparticles disturb the nervous system, especially dopaminergic metabolites.

The spatial dynamics of commercial burglary during the COVID-19 lockdown in San Francisco.

Purpose: This paper investigated the impact of COVID-19 stay-at-home regulations on the spatial distribution of commercial burglary in San Francisco. Method: Geocoded commercial burglary data for 2003-2021 from San Francisco were analyzed using the Andresen Spatial Point Pattern Test to examine potential spatial movement in commercial burglary. Results: Concentrations of commercial burglary spatially shifted following the emergence of COVID-19 and the subsequent stay-at-home orders. Original hot spots experienced a relative decrease in commercial burglary, and crime spread out throughout the city. These spatial changes in commercial burglary appear to be related to variations in guardianship and criminal opportunity. Conclusion: These findings suggest that the dramatic shifts in routine activities resulting from the COVID-19 policies could disrupt spatial burglary patterns, especially burglary clustering. Law enforcement should consider the spatial dynamics of commercial burglary, as well as land use heterogeneity, to effectively respond to crime during periods of social distancing and business shutdowns.

RF Transceiver for the Multi-Mode Radar Applications.

In this work, a multi-mode radar transceiver supporting pulse, FMCW and CW modes was designed as an integrated circuit. The radars mainly detect the targets move by using the Doppler frequency which is significantly affected by flicker noise of the receiver from several Hz to several kHz. Due to this flicker noise, the long-range detection performance of the radars is greatly reduced, and the accuracy of range to the target and velocity is also deteriorated. Therefore, we propose a transmitter that suppresses LO leakage in consideration of long-range detection, target distance, velocity, and noise figure. We also propose a receiver structure that suppresses DC offset due to image signal and LO leakage. The design was conducted with TSMC 65 nm CMOS process, and the designed and fabricated circuit consumes a current of 265 mA at 1.2 V supply voltage. The proposed transmitter confirms the LO leakage suppression of 37 dB at 24 GHz. The proposed receiver improves the noise figure by about 20 dB at 100 Hz by applying a double conversion architecture and an image rejection, and it illustrates a DC rejection of 30 dB. Afterwards, the operation of the pulse, FMCW, and CW modes of the designed radar in integrated circuit was confirmed through experiment using a test PCB.

Adsorption and Desorption Properties of Polyethylenimine/Polyvinyl Chloride Cross-Linked Fiber for the Treatment of Azo Dye Reactive Yellow 2.

In this study, the optimal conditions for the fabrication of polyethylenimine/polyvinyl chloride cross-linked fiber (PEI/PVC-CF) were determined by comparing the adsorption capacity of synthesized PEI/PVC-CFs for Reactive Yellow 2 (RY2). The PEI/PVC-CF prepared through the optimal conditions was characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and Brunauer-Emmett-Teller (BET) analyses. Several batch adsorption and desorption experiments were carried out to evaluate the sorption performance and reusability of PEI/PVC-CF for RY2. As a result, the adsorption of RY2 by PEI/PVC-CF was most effective at pH 2.0. A pseudo-second-order model fit better with the kinetics adsorption data. The adsorption isotherm process was described well by the Langmuir model, and the maximum dye uptake was predicted to be 820.6 mg/g at pH 2.0 and 25 °C. Thermodynamic analysis showed that the adsorption process was spontaneous and endothermic. In addition, 1.0 M NaHCO3 was an efficient eluent for the regeneration of RY2-loaded PEI/PVC-CF. Finally, the repeated adsorption-desorption experiments showed that the PEI/PVC-CF remained at high adsorption and desorption efficiencies for RY2, even in 17 cycles.

Development of a novel denture care agent with highly active enzyme, arazyme.

BACKGROUND: The importance of efficient denture deposit removal and oral hygiene has been further underscored by the continuous increase of denture wearers. Denture hygiene management has also become an important aspect associated with denture-induced stomatitis. This study aims to evaluate the denture cleaning effect of arazyme, the metalloprotease produced from the Serratia proteamaculans HY-3. We performed growth inhibition tests against oral opportunistic pathogens to be used as a potential oral health care agent. METHODS: The proteolytic activities of arazyme was evaluated over broad ranges of temperature, pH, and denture components compared to those of subtilisin in commercially available denture cleansers. The washing effects of arazyme were also measured by using homogeneously soiled EMPA 105 cottons. To investigate the denture cleaning capability of arazyme, artificially contaminated dentures were treated with arazyme, subtilisin (Everlase 6.0T), and Polident®, respectively. The growth kinetics of Candida albicans, Enterococcus faecalis, Staphylococcus epidermis, and Streptococcus mutans were evaluated in the presence of different concentrations of arazyme to estimate the prevention effects of arazyme against major oral opportunistic pathogens. RESULTS: Arazyme showed strong proteolytic activities over wide temperature and pH ranges compared with the serine protease of the subtilisin family. Arazyme demonstrated efficient removal and decomposition of artificially contaminated dentures and showed explicit washing effects against soiled cottons. Moreover arazyme inhibited the growth of oral opportunistic pathogens, including C. albicans, E. faecalis, S. epidermis, and S. mutans, with more than 80% inhibition against C. albicans, the major cause of denture stomatitis, with 250 mg/mL arazyme. CONCLUSIONS: Arazyme shows promise as a biological oral health care agent with effective cleaning and antimicrobial activities and is a potential source for developing novel denture care agents.

Similarities in Clinical and Psychosocial Characteristics of Functional Diarrhea and Irritable Bowel Syndrome With Diarrhea.

BACKGROUND & AIMS: There have been few published studies of clinical and psychological characteristics of patients with functional diarrhea (FDr). We studied the clinical and psychological characteristics of patients with FDr presenting to a tertiary care clinic, and compared symptom profiles of FDr with those of IBS-diarrhea (IBS-D). METHODS: Consecutive patients with a diagnosis of FDr (n = 48) or IBS-D (n = 49), per Rome IV criteria, completed a detailed symptom survey from October 2017 through July 2018. Abdominal pain and diarrhea severity were assessed using patient-reported outcomes measurement information system (PROMIS) questionnaires. Patients with anxiety, depression, or sleep disturbances were identified based on PROMIS T-score of 60 or more. Mean and proportions were compared using the Student t test and chi-square analyses, respectively. RESULTS: A significantly lower proportion of patients with FDr reported abdominal pain (77.1%) than patients with IBS-D (100%, P < .001). The proportion of patients reporting abdominal bloating and level of severity did not differ significantly between groups. Proportions of bowel movements with diarrhea did not differ significantly between groups (P = .54), but the mean diarrhea PROMIS T-score was significantly higher among patients with IBS-D (P = .03). This difference resulted from the significantly higher levels of fecal urgency-related distress reported by patients with IBS-D (P = .007). Proportions of patients with anxiety, depression, or sleep disturbance, and their severities, did not differ significantly between groups. CONCLUSIONS: In an analysis of about 100 patients with FDr or IBS-D, we found overlap in gastrointestinal and psychosomatic symptoms. These 2 entities appear to be a continuum.

The study of transcarotid artery revascularization under local versus general anesthesia with results from the Society for Vascular Surgery Vascular Quality Initiative.

OBJECTIVE: The primary purpose of this study was to examine any potential difference in clinical outcomes between transcarotid artery revascularization performed under local anesthesia compared with general anesthesia by utilizing a large national database. METHODS: The primary outcome of the study was a composite endpoint of postoperative in-hospital stroke, myocardial infarction and mortality following transcarotid artery revascularization for the index procedure. Secondary outcomes included a composite outcome of postoperative in-hospital stroke, transient ischemic attack, myocardial infarction and mortality along with several subsets of its components and each individual component, flow reversal time (min), radiation dose (GY/cm2), contrast volume utilized (mL), total procedure time (min), extended total length of stay (>1 day) and extended postoperative length of stay (>1 day). Statistical analyses employed both descriptive measures to characterize the study population and analytic measures such as multivariable mixed-effect linear and logistic regressions using both unmatched and propensity-score matched cohorts. RESULTS: A total of 2609 patients undergoing transcarotid artery revascularization between the years 2016 and 2018 in the US were identified, with 82.3% performed under general anesthesia and 17.7% under local anesthesia. The primary composite outcome was observed in 2.3% of general anesthesia patients versus 2.6% of local anesthesia patients (p = 0.808). The rate of postoperative transient ischemic attack and/or myocardial infarction was 1.6% with general anesthesia versus 1.1% with local anesthesia (p = 0.511). For adjusted regression analysis, general anesthesia and local anesthesia were comparable in terms of primary outcome (OR: 0.72; 95% CI: 0.27-1.93, p = 0.515). As for the secondary outcomes, no significant differences were found except for contrast, where the results demonstrated significantly less need for contrast with procedures performed under general anesthesia (coefficient: 4.94; 95% CI: 1.34-8.54, p = 0.007). A trend towards significance was observed for lower rate of postoperative transient ischemic attack and/or myocardial infarction (OR: 0.33; 95% CI: 0.09-1.18, p = 0.088) and lower flow reversal time under local anesthesia (coefficient: -0.94: 95% CI: -2.1-0.22, p = 0.111). CONCLUSIONS: Excellent outcomes from transcarotid artery revascularization for carotid stenosis were observed in the VQI database between the years 2016 and 2018, under both local anesthesia and general anesthesia. The data demonstrate the choice of anesthesia for transcarotid artery revascularization does not appear to have any effect on clinical outcomes. Surgical teams should perform transcarotid artery revascularization under the anesthesia type they are most comfortable with.

Chronic Diarrhea and Constipation Are More Common in Depressed Individuals.

BACKGROUND AND AIMS: Depression is a major health issue in the United States and is highly comorbid with gastrointestinal conditions. We collected data from the National Health and Nutrition Examination Survey (NHANES), a representative sample of the US population, to study the relationship between depression and bowel habits. METHODS: Using data from the NHANES (2009-2010), we identified 495 depressed and 4709 non-depressed adults who filled out the Bowel Health Questionnaire. Depression was defined according to a validated questionnaire. We used multivariable analysis, controlling for clinical and demographic variables, to evaluate the relationship between mood and bowel habits. RESULTS: In our weighed sample, 24.6% of depressed individuals and 12.6% of non-depressed individuals reported disordered bowel habits. Chronic diarrhea was significantly more prevalent in depressed individuals (15.53%; 95% CI, 11.34%-20.90%) than non-depressed individuals (6.05%; 95% CI, 5.24%-6.98%; P = .0001). Chronic constipation was also more common in depressed individuals (9.10%; 95% CI, 7.02%-11.69%) than non-depressed individuals (6.55%; 95% CI, 5.55%-7.70% CI; P = .003). Mean depression scores in patients with chronic diarrhea (4.9 ± 5.8) and with chronic constipation (4.4 ± 4.93) were significantly higher than mean depression scores for individuals with normal bowel habits (3.2 ± 4.6) (P < .001). Moderate and severe depression were significantly associated with chronic diarrhea but not chronic constipation. Only mild depression was significantly associated with chronic constipation. CONCLUSIONS: In an analysis of the NHANES database, we found a higher proportion of depressed individuals to have chronic diarrhea and constipation than non-depressed individuals; chronic diarrhea was more strongly associated with depression. Our findings provide support for the relationship between mood and specific bowel habits, accounting for multiple co-variables in a large sample of the general US population.

Effects of Irritable Bowel Syndrome on Daily Activities Vary Among Subtypes Based on Results From the IBS in America Survey.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is associated with significant disease burden and decreased quality of life (QOL). We investigated the effects of IBS on different areas of daily function and compared these among disease subtypes. METHODS: The Life with IBS survey was conducted by Gfk Public Affairs & Corporate Communications from September through October 2015. Respondents met Rome III criteria for constipation-predominant or diarrhea-predominant IBS (IBS-C and IBS-D, respectively). Data were collected from 3254 individuals (mean age, 47 years; 81% female; and 90% Caucasian) who met IBS criteria. RESULTS: Respondents who were employed or in school (n = 1885) reported that IBS symptoms affected their productivity an average of 8.0 days out of the month and they missed approximately 1.5 days of work/school per month because of IBS. More than half the individuals reported that their symptoms were very bothersome. Individuals with IBS-C were more likely than with IBS-D to report avoiding sex, difficulty concentrating, and feeling self-conscious. Individuals with IBS-D reported more avoidance of places without bathrooms, difficulty making plans, avoiding leaving the house, and reluctance to travel. These differences remained when controlling for symptom bothersomeness, age, sex, and employment status. In exchange for 1 month of relief from IBS, more than half of the sample reported they would be willing to give up caffeine or alcohol, 40% would give up sex, 24.5% would give up cell phones, and 21.5% would give up the internet for 1 month. CONCLUSIONS: Although the perceived effects of IBS symptoms on productivity are similar among its subtypes, patients with IBS-C and IBS-D report differences in specific areas of daily function.

RECK isoforms differentially regulate fibroblast migration by modulating tubulin post-translational modifications.

Cell migration is essential for proper development and the defense against pathogens. Our previous work detailed a pathway of REversion-inducing-Cysteine-rich protein with Kazal motifs (RECK) isoform-mediated invasion in which a shorter RECK protein competes with MMP9 for interaction with the canonical RECK protein on the cell surface. Here we demonstrate that the mechanism through which RECK isoforms affect cell migration is mediated through changes in the levels of post-translational modifications (PTM) of α-tubulin. We show that both the canonical and short RECK isoforms modulate levels of tubulin acetylation and detyrosination. We demonstrate that these changes are sufficient to modulate the rate of fibroblast migration. If these tubulin PTMs are not altered, the effects of the canonical RECK isoform on cell migration are reversed. In defining the molecular pathway linking RECK and tubulin PTMs, we found that MMP9 and integrin activity both act as upstream regulators of tubulin acetylation and detyrosination. Overall, we propose a mechanism in which RECK isoforms on the cell surface have opposing effects on cell migration through MMP9-modulated changes to integrin-extracellular matrix (ECM) interactions that, in turn, affect microtubule PTMs.