Miracle-dz/UniFAR-FTUs huggingface dataset:
Promoting Long-Term Survival of Insulin-Producing Cell Grafts That Differentiate from Adipose Tissue-Derived Stem Cells to Cure Type 1 Diabetes

Background Insulin-producing cell clusters (IPCCs) have recently been generated in vitro from adipose tissue-derived stem cells (ASCs) to circumvent islet shortage. However, it is unknown how long they can survive upon transplantation, whether they are eventually rejected by recipients, and how their long-term survival can be induced to permanently cure type 1 diabetes. IPCC graft survival is critical for their clinical application and this issue must be systematically addressed prior to their in-depth clinical trials. Methodology/Principal Findings Here we found that IPCC grafts that differentiated from murine ASCs in vitro, unlike their freshly isolated islet counterparts, did not survive long-term in syngeneic mice, suggesting that ASC-derived IPCCs have intrinsic survival disadvantage over freshly isolated islets. Indeed, β cells retrieved from IPCC syngrafts underwent faster apoptosis than their islet counterparts. However, blocking both Fas and TNF receptor death pathways inhibited their apoptosis and restored their long-term survival in syngeneic recipients. Furthermore, blocking CD40-CD154 costimulation and Fas/TNF signaling induced long-term IPCC allograft survival in overwhelming majority of recipients. Importantly, Fas-deficient IPCC allografts exhibited certain immune privilege and enjoyed long-term survival in diabetic NOD mice in the presence of CD28/CD40 joint blockade while their islet counterparts failed to do so. Conclusions/Significance Long-term survival of ASC-derived IPCC syngeneic grafts requires blocking Fas and TNF death pathways, whereas blocking both death pathways and CD28/CD40 costimulation is needed for long-term IPCC allograft survival in diabetic NOD mice. Our studies have important clinical implications for treating type 1 diabetes via ASC-derived IPCC transplantation.
Oncogenic Ki-Ras Inhibits the Expression of Interferon-responsive Genes through Inhibition of STAT1 and STAT2 Expression*

Endogenous interferon γ (IFNγ) promotes the host response to primary tumors, and IFNγ-insensitive tumors display increased tumorigenicity and can evade tumor surveillance mechanisms. Here we demonstrate that activating mutations of Ki-ras are sufficient to inhibit the expression of STAT1 and STAT2, transcription factors required for signaling by IFNs, providing a potential mechanism for the insensitivity of tumors to IFNs. We demonstrated that colon cancer cell lines with Ki-ras mutations display reduced expression of IFN-responsive genes compared with the cell lines that have retained wild type Ras and that inactivation of the mutant Ki-ras allele in the HCT116 colon cancer cell line is sufficient to restore the expression of STAT1, STAT2, and IRF-9. Accordingly, the expression of 27 interferon-inducible genes was reduced in HCT116 cells compared with the isogenic clones with targeted deletion of the mutant Ki-ras allele, Hkh2 and Hke-3. The expression of IFNγ receptors did not differ among the isogenic cell lines. IFNγ stimulated transcription of a STAT1-dependent reporter gene was impaired by RasV12, demonstrating a transmodulation of IFN/STAT signaling by activated Ras. Finally, we demonstrated that the expression of RasV12 in 293T cells is sufficient to inhibit the endogenous expression of STAT1 and STAT2, confirming the negative regulation of IFN signaling by oncogenic Ras. Our data demonstrate that the signaling initiated by activated Ki-ras interferes with the IFN/STAT signaling pathway and modulates the responsiveness of cancer cells to interferons. Furthermore, the data suggest that tumors harboring activating Ki-ras mutations may escape tumor surveillance mechanisms due to reduced responsiveness to IFNγ.
Regenerative Medicine for Periodontal and Peri-implant Diseases

The balance between bone resorption and bone formation is vital for maintenance and regeneration of alveolar bone and supporting structures around teeth and dental implants. Tissue regeneration in the oral cavity is regulated by multiple cell types, signaling mechanisms, and matrix interactions. A goal for periodontal tissue engineering/regenerative medicine is to restore oral soft and hard tissues through cell, scaffold, and/or signaling approaches to functional and aesthetic oral tissues. Bony defects in the oral cavity can vary significantly, ranging from smaller intrabony lesions resulting from periodontal or peri-implant diseases to large osseous defects that extend through the jaws as a result of trauma, tumor resection, or congenital defects. The disparity in size and location of these alveolar defects is compounded further by patient-specific and environmental factors that contribute to the challenges in periodontal regeneration, peri-implant tissue regeneration, and alveolar ridge reconstruction. Efforts have been made over the last few decades to produce reliable and predictable methods to stimulate bone regeneration in alveolar bone defects. Tissue engineering/regenerative medicine provide new avenues to enhance tissue regeneration by introducing bioactive models or constructing patient-specific substitutes. This review presents an overview of therapies (e.g., protein, gene, and cell based) and biomaterials (e.g., resorbable, nonresorbable, and 3-dimensionally printed) used for alveolar bone engineering around teeth and implants and for implant site development, with emphasis on most recent findings and future directions.
CLINICAL AND MICROBIOLOGIC REVIEW OF CULTURE-PROVEN ENDOPHTHALMITIS CAUSED BY MULTIDRUG-RESISTANT BACTERIA IN PATIENTS SEEN AT A TERTIARY EYE CARE CENTER IN SOUTHERN INDIA

Purpose: To determine the type of bacteria and the visual outcome of culture-proven multidrug-resistant bacterial endophthalmitis in patients at a tertiary eye care center in southern India. Methods: This is a retrospective case series in which clinical and microbiologic records of culture-proven bacterial endophthalmitis between January 2000 and December 2007 were reviewed. Multidrug resistance was defined as resistance to two or more different groups of typically susceptible classes of antibiotics. Results: Of 807 patients, vitreous from 42 patients (5.2%) yielded multidrug-resistant bacteria in culture. Thirty-two (71%) of these patients had a poor visual outcome (31.6% in non–multidrug-resistant group). Multidrug resistance was more common in gram-negative bacteria (33; 78.6%) compared with gram-positive bacteria (9; 21.4%). Pseudomonas spp. (24 isolates) were the most common isolated bacteria. Fifteen (45%) of the 33 gram-negative isolates were resistant to ceftazidime, 18 (54.5%) were resistant to amikacin, and 11 (33.3%) were resistant to both amikacin and ceftazidime. Five (55.56%) of the 9 gram-positive isolates were resistant to vancomycin. Conclusion: Gram-negative bacteria, chiefly Pseudomonas, are the most common multidrug-resistant organisms, and the outcome is usually poor. Emergence of multidrug-resistant bacteria is a matter of concern. A new alternative group of drugs may be considered for the management of these isolated cases.
Nanoscale Focused Ion Beam Tomography of Single Bacterial Cells for Assessment of Antibiotic Effects

Abstract Antibiotic resistance is a major risk to human health, and to provide valuable insights into mechanisms of resistance, innovative methods are needed to examine the cellular responses to antibiotic treatment. Focused ion beam tomography is proposed to image and assess the detailed three-dimensional (3D) ultrastructure of single bacterial cells. By iteratively removing slices of thickness in the order of 10 nm, high magnification 2D images can be acquired by scanning electron microscopy at single-digit nanometer resolution. In this study, Klebsiella pneumoniae was treated with polymyxin B, and 3D models of both cell envelope and cytoplasm regions containing the nucleoid and ribosomes were reconstructed. The 3D volume containing the nucleoid and ribosomes was significantly smaller, and the cell length along the longitudinal axis was extended by 40% in the treated cells, implying stress responses to the drug treatment. More than a 200% increase in protrusions per unit surface area on the cell envelope was observed in the curvature analysis after treatment. Experiments by conventional transmission electron microscopy and atomic force microscopy were also performed, followed by comparison and discussions. In conclusion, the proposed 3D imaging method and associated analysis provide a unique tool for the assessment of antibiotic effects on multidrug-resistant bacteria at nanometer resolution.
THE EFFECT OF LABOR AND FINANCIAL FRICTIONS ON AGGREGATE FLUCTUATIONS

This paper embeds labor market search frictions into a New Keynesian model with financial frictions. The econometric estimation establishes that labor market frictions substantially improve the empirical fit of the model. The effect of the interaction between labor and financial frictions on aggregate fluctuations depends on the nature of the shock. For monetary policy, technology, and entrepreneurial wealth shocks, labor market frictions amplify the effect of financial frictions, because robust changes in hiring lead to persistent movements in employment and return on capital that reinforce the original effect of financial frictions. For cost-push, labor supply, marginal efficiency of investment, and preference shocks, labor market frictions dampen the effect of financial frictions by reducing the real cost of repaying existing debt, which lowers the external finance premium.
CYTOCHROME P450 3A4 IS THE MAJOR ENZYME RESPONSIBLE FOR THE METABOLISM OF LAQUINIMOD, A NOVEL IMMUNOMODULATOR

In the present study, the involvement of cytochrome P450 enzyme(s) in the primary metabolism of laquinimod, a new orally active immunomodulator, has been investigated in human liver microsomes. Hydroxylated and dealkylated metabolites were formed. The metabolite formation exhibited single enzyme Michaelis-Menten kinetics with apparent KM in the range of 0.09 to 1.9 mM and Vmax from 22 to 120 pmol/mg/min. A strong correlation between the formation rate of metabolites and 6β-hydroxylation of testosterone was obtained within a panel of liver microsomes from 15 individuals (r2 = 0.6 to 0.94). Moreover, ketoconazole and troleandomycin, specific inhibitors of CYP3A4 metabolism, demonstrated a significant inhibition of laquinimod metabolism. Furthermore, in incubations with recombinant CYP3A4, all the primary metabolites were formed. In vitro interaction studies with CYP3A4 substrates and possible concomitant medication demonstrated that laquinimod inhibits the metabolism of ethinyl estradiol with an IC50 value of about 150 μM, which is high above the plasma level of laquinimod after clinically relevant doses. Ketoconazole, troleandomycin, erythromycin, prednisolone, and ethinyl estradiol inhibited the metabolism of laquinimod, and IC50 values of 0.2, 11, 24, 87, and 235 μM, respectively, were calculated. In conclusion, the present study demonstrates that laquinimod is a low affinity substrate for CYP3A4 in human liver microsomes. The likelihood for in vivo effects of laquinimod on the metabolism of other CYP3A4 substrates is minor. However, inhibitory effects on the metabolism of laquinimod by potent and specific inhibitors of CYP3A4, such as ketoconazole, are anticipated and should be considered in the continued clinical program for laquinimod.
Homelessness Predicts Attrition but Not Alcohol Abstinence in Outpatients Experiencing Co-Occurring Alcohol Dependence and Serious Mental Illness

Background: Adults experiencing homelessness and serious mental illnesses (SMI) are at an increased risk of poor mental health and treatment outcomes compared with stably housed adults with SMI. The additional issue of alcohol misuse further complicates the difficulties of those living with homelessness and SMI. In this secondary data analysis, the authors investigated the impact of homelessness on attrition and alcohol use in a contingency management (CM) intervention that rewarded alcohol abstinence in outpatients with SMI. Methods: The associations between housing status and attrition and alcohol abstinence during treatment, as assessed by ethyl glucuronide (EtG) urine tests, were evaluated in 79 adults diagnosed with alcohol dependence and SMI. Results: Thirty-nine percent (n = 31) of participants reported being homeless at baseline. Individuals who were homeless were more likely to drop out of CM (n = 10, 62.5%) than those who were housed (n = 4, 16.7%), χ2(1) = 8.86, P < . 05. Homelessness was not associated with attrition in the noncontingent control group. Accounting for treatment group and prerandomization EtG levels, neither the effect of housing status nor the interaction of housing status and group were associated with EtG-assessed alcohol abstinence during treatment. Conclusions: Individuals experiencing homelessness and co-occurring alcohol dependence and SMI receiving CM had higher rates of attrition, relative to those who were housed. Homelessness was not associated with differences in biologically assessed alcohol abstinence.
Nardilysin Enhances Ectodomain Shedding of Heparin-binding Epidermal Growth Factor-like Growth Factor through Activation of Tumor Necrosis Factor-α-converting Enzyme*

Like other members of the epidermal growth factor family, heparin-binding epidermal growth factor-like growth factor (HB-EGF) is synthesized as a transmembrane protein that can be shed enzymatically to release a soluble growth factor. Ectodomain shedding is essential to the biological functions of HB-EGF and is strictly regulated. However, the mechanism that induces the shedding remains unclear. We have recently identified nardilysin (N-arginine dibasic convertase (NRDc)), a metalloendopeptidase of the M16 family, as a protein that specifically binds HB-EGF (Nishi, E., Prat, A., Hospital, V., Elenius, K., and Klagsbrun, M. (2001) EMBO J. 20, 3342-3350). Here, we show that NRDc enhances ectodomain shedding of HB-EGF. When expressed in cells, NRDc enhanced the shedding in cooperation with tumor necrosis factor-α-converting enzyme (TACE; ADAM17). NRDc formed a complex with TACE, a process promoted by phorbol esters, general activators of ectodomain shedding. NRDc enhanced TACE-induced HB-EGF cleavage in a peptide cleavage assay, indicating that the interaction with NRDc potentiates the catalytic activity of TACE. The metalloendopeptidase activity of NRDc was not required for the enhancement of HB-EGF shedding. Notably, a reduction in the expression of NRDc caused by RNA interference was accompanied by a decrease in ectodomain shedding of HB-EGF. These results indicate the essential role of NRDc in HB-EGF ectodomain shedding and reveal how the shedding is regulated by the modulation of sheddase activity.
Nephrolithiasis in elderly population; effect of demographic characteristics

Background Kidney stone (nephrolithiasis) is one of the most common diseases. During the past several decades, its prevalence and incidence have increased markedly in elderly population. Objectives This study was conducted to evaluate the risk factors for nephrolithiasis in elderly population. Patients and Methods This study was based on the Amirkola Health and Ageing Project (AHAP). Elderly people with kidney stones in every size, type and number were considered to be the case group and other subjects without a history of kidney stones served as control group. Demographic and anthropometric data, smoking, diabetes and metabolic syndrome (MetS), calcium (Ca), vitamin D, parathyroid hormone (PTH), uric acid and urine pH were compared in both groups. Results In this study, 1390 elderly people with the mean age of 69.37 ± 7.42 years were evaluated which 202 (14.53%) cases had renal stones. The patients with nephrolithiasis were younger (P = 0.010) and had higher uric acid and body mass index (BMI) levels (P = 0.041 and P = 0.006, respectively). Age <75 years, male gender and BMI ≥30 kg/m2 had a significant association with stone formation. The prevalence of diabetes, MetS and smoking in the patients with nephrolithiasis was lower than the subjects without it. Conclusions This study suggests that male gender, obesity and age <75 years might be independent risk factors for the development of nephrolithiasis. Hence, low animal protein intake and weight reduction should be included as part of the counseling of senior stone-formers.
Obstetric care, pregnancy risk factors and perinatal outcome in the province of Uusimaa, Finland, in 1980-1981.

The study was carried out in order to learn about the present state of obstetric care and perinatal outcome in the province of Uusimaa, Finland. The material consisted of 29,061 pregnant women, including 313 multiple pregnancies and 29,374 newborn infants born in the years 1980 and 1981. The information gathered was mostly retrospective. The overall frequency of LBW children was 3.9 percent, of very LBW children 0.8, of preterm children 5.8, of very preterm children 0.7, and of post-term children 4.7 percent. The overall frequency of neonatal transfers to a pediatric ward was 8.6 percent. Centralization of high risk deliveries has increased in Uusimaa since 1975, as judged by the frequencies of LBW children born at the two largest delivery units and four district hospitals. Almost 95 percent of mothers-to-be began their antenatal classes before 16 weeks of gestation. Late admission to antenatal care after week 15 was an independent risk factor for unfavorable pregnancy outcome. The cesarean section rate was 16.5 percent. The frequencies were highest at the State Maternity Hospital (19.7%) and Helsinki University Central Hospital (18.2%). The frequency varied largely in district hospitals (5.9-16.3%). This resulted partly from different indications for cesarean sections in these hospitals. The mean age of the parturients was 28.5 years. The best pregnancy outcome was observed in women aged 25-29 years. Almost half of the parturients were primiparous, and only 4.0 percent were quadri- or grand multiparous. Secundiparous women had the best pregnancy outcome. Terti-parity or more was not a risk factor per se; the difference in the frequency of unfavorable outcome between secundiparas and terti-paras or more disappeared after those with unsuccessful histories were excluded, while the difference still remained significant between primi- and secundiparas. Of all pregnant women, 23 percent had experienced one and 6.4 percent several spontaneous or legally induced abortions. The effect of the number of abortions on the frequency of preterm and very preterm deliveries was linear both in singleton and multiple pregnancies. Almost 70 percent of the parturients belonged to the two highest social classes and 86 percent were married. Children of married women from higher social classes had the best perinatal outcome. Unmarried women from lower social classes more often had 'behavioral' risk factors--they were more often heavy smokers, were uncertain about the dates, had had two or more abortions and neglected maternity care. (ABSTRACT TRUNCATED AT 400 WORDS)
Do Speeding Tickets Reduce the Likelihood of Receiving Subsequent Speeding Tickets? A Longitudinal Study of Speeding Violators in Maryland

Objective. Speeding tickets are the most commonly used tool to deter speeders, yet little is known about how speeding citations affect individual drivers' behavior over time. This study examined the effects of being cited for speeding and types of legal consequences on drivers' subsequent speeding citations, which are an indicator of speeding behavior. Methods. A cohort of 3,739,951 Maryland licensed drivers were identified and followed for one year. Drivers were categorized by whether or not they received a speeding citation in May 2002. Among those cited for speeding in May 2002, drivers were grouped by type of penalty (fines and points; probation before judgment [PBJ, which results in fines but no points]; or no legal consequences). The relative risks (RR) and 95 percent confidence intervals (CI) of receiving a speeding citation during follow-up were compared between drivers ticketed and not ticketed in May 2002, as well as among different penalty groups. Cox proportional hazards regression modeling was used to adjust for potential confounders, including age, gender, alcohol-impaired driving, and residence. Kaplan-Meier survival functions were used to examine timing of violations. Results. Young drivers and male drivers were more likely to receive a speeding citation. Drivers who received a speeding citation in May 2002 had almost twice the risk of receiving a speeding citation during follow-up, compared with those not cited for speeding that month (RR 1.6, 95% CI 1.52–1.68). Overall legal consequences had no significant effect on the risk of receiving a repeat speeding citation relative to ticketed drivers who escaped those consequences (RR 0.98, 95% CI 0.84–1.15); however, stratified analyses showed a significant decrease in repeat citations among females (RR 0.75, 95% CI 0.63–0.90) and drivers who received PBJ (RR 0.81, 95% CI 0.67–0.96). Kaplan-Meier curves showed that the study group of speeders had a significantly shorter time between May 2002 until receipt of a speeding citation than controls. Among penalty groups, significantly shorter times until receipt of another citation were observed among drivers escaping consequences or receiving fines/points compared with drivers receiving fines/PBJ. Conclusions. Drivers who receive speeding citations are at increased risk of receiving subsequent speeding citations, suggesting that speeding citations have limited effects on deterrence in the context of the current traffic enforcement system. When comparing different penalties, PBJ is associated with a reduced rate of recidivism more than stronger penalties; however, it is unclear whether the reduction primarily is attributable to the penalty itself or to characteristics of drivers receiving PBJ. Increasing drivers' perceptions that they are at risk of being caught speeding may improve the effectiveness of speeding law enforcement.
Application of Parameterized Time-Frequency Analysis on Multicomponent Frequency Modulated Signals

Parameterized time-frequency (TF) transforms, with signal-dependent kernel parameters, have been proposed to analyze multicomponent frequency modulated (FM) signals. Usually, the kernel parameters are estimated through recursive approximation of TF representation (TFR) ridge when instantaneous frequency models of the components have the same parameter settings. However, it will be inapplicable if the components have the different FM sources. In this paper, we introduce a novel method that enables the parameterized TF transform to generate the well-concentrated TFR for both the monocomponent signal and a wide class of multicomponent FM signals, whose components are modulated by either the same or the different sources. The proposed method contains two aspects: 1) estimating kernel parameters based on spectrum concentration index and 2) separating components and assembling the parameterized TFRs of the separated components. An advantage of the proposed method is that it avoids the dependence of the TFR while estimating the parameters. Moreover, it is effective at low signal-to-noise rate. The validity and practical utility of the proposed method are demonstrated by both the simulated and real signals. The results show that it outperforms the traditional TF methods in providing the TFR of the improved concentration for various multicomponent FM signals.