Miracle-dz/UniFAR-FTUs huggingface dataset:
Multiplex SILAC Analysis of a Cellular TDP-43 Proteinopathy Model Reveals Protein Inclusions Associated with SUMOylation and Diverse Polyubiquitin Chains*

Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a major protein component within ubiquitin-positive inclusions of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Although TDP-43 is a nuclear DNA/RNA-binding protein, in pathological conditions, TDP-43 has been reported to redistribute to the cytoplasm where it is cleaved and forms insoluble, ubiquitinated, and phosphorylated inclusions. Here we present a cellular model in which full-length human TDP-43 or a splicing isoform (TDP-S6) that lacks the C terminus is overexpressed in a human cell line and mouse primary neurons. Whereas recombinant and endogenous TDP-43 was primarily localized in the nucleus, the shorter TDP-S6 formed highly insoluble cytoplasmic and nuclear inclusions reminiscent of disease-specific pathology. Western blot analysis of detergent-insoluble extracts showed an increase in high molecular weight immunoreactive species for TDP-S6 compared with TDP-43, consistent with ubiquitination or ubiquitin-like modifications. We used a multiplex stable isotope labeling with amino acids in cell culture approach to compare the detergent-insoluble proteome from mock-, TDP-43-, and TDP-S6-transfected cells. TDP-S6 overexpression caused a concomitant increase in both ubiquitin (Ub) and the small Ub-like modifier-2/3 (SUMO-2/3) within the insoluble proteome. Similarly, full-length TDP-43 overexpression also resulted in the elevation of SUMO-2/3. Immunofluorescence showed strong co-localization of endogenous Ub with both cytoplasmic and nuclear TDP-S6 inclusions, whereas SUMO-2/3 was co-localized mainly with the nuclear inclusions. Quantitative mass spectrometry further revealed that mixed Lys-48 and Lys-63 polyUb linkages were associated with the TDP insoluble fractions. Together our data indicate that expression of a TDP-43 splice variant lacking a C terminus recapitulates many of the cellular and biochemical features associated with disease pathology and that the interplay of ubiquitination and SUMOylation may have an important role in TDP-43 regulation.
The application accuracy of the NeuroMate robot--A quantitative comparison with frameless and frame-based surgical localization systems.

The NeuroMatetrade mark robot system (Integrated Surgical Systems, Davis, CA) is a commercially available, image-guided, robotic-assisted system used for stereotactic procedures in neurosurgery. In this article, we present a quantitative comparison of the application accuracy of the NeuroMate with that of standard frame-based and frameless stereotactic techniques. The article discusses a five-way application accuracy comparison study. The variables of our comparison and their mean errors are as follows: (1) with the robot in a frame-based configuration, the RMS was 0.86 +/- 0.32 mm; (2) with the robot in the frameless configuration, the RMS was 1.95 +/- 0.44 mm; (3) in a standard stereotactic (ZD) frame-based approach, the RMS was 1.17 +/- 0.25 mm; (4) with an infrared tracking system using the frame for fiducial registration, the RMS was 1.47 +/- 0.45 mm; (5) with an infrared tracking system using screw markers for registration, the RMS was 0.68 +/- 0.26 mm. The study was performed with 2-mm sections of CT scans. These results show that the application accuracy of the frame-based NeuroMate robot is comparable to that of standard localizing systems, whether they are frame-based or infrared tracked.
Differential induction of tumor necrosis factor α and manganese superoxide dismutase by endotoxin in human monocytes: Role of protein tyrosine kinase, mitogen‐activated protein kinase, and nuclear factor κB

A mutant Escherichia coli lipopolysaccharide (LPS) lacking myristoyl fatty acid markedly stimulates the activity of manganese superoxide dismutase (MnSOD) without inducing tumor necrosis factor α (TNFα) production by human monocytes (Tian et al., 1998, Am J Physiol 275:C740.), suggesting that induction of MnSOD and TNFα by LPS are regulated through different signal transduction pathways. The protein tyrosine kinase (PTK)/mitogen‐activated protein kinase (MAPK) pathway plays an important role in the LPS‐induced TNFα production. In the current study, we determined the effects of PTK inhibitors, genistein and herbimycin A, on the induction of MnSOD and TNFα in human monocytes. Genistein (10 μg/ml) and herbimycin A (1 μg/ml) markedly inhibited LPS‐induced protein tyrosine phosphorylation, phosphorylation and nuclear translocation of MAPK (p42 ERK, extracellular signal‐regulated kinase), and increases in the steady state level of TNFα mRNA as well as TNFα production. In contrast, at similar concentrations, genistein and herbimycin A had no effect on the LPS‐induced activation of nuclear factor κB (NFκB) and induction of MnSOD (mRNA and enzyme activity) in human monocytes. In addition, inhibition of NFκB activation by gliotoxin and pyrrodiline dithiocarbamate, inhibited LPS induction of TNFα and MnSOD mRNAs. These results suggest that (1) while PTK and MAPK are essential for the production of TNFα, they are not necessary for the induction of MnSOD by LPS, and (2) while activation of NFκB alone is insufficient for the induction of TNFα mRNA by LPS, it is necessary for the induction of TNFα as well as MnSOD mRNAs. J. Cell. Physiol. 182:381–389, 2000. © 2000 Wiley‐Liss, Inc.
Evaluation of Patient Perceptions After Vestibuloplasty Procedure: A Comparison of Diode Laser and Scalpel Techniques.

INTRODUCTION Inadequate vestibular depth results in poor plaque control owing to an insufficient width of keratinized gingiva. Vestibuloplasty provides the necessary vestibular depth and can be performed either with a scalpel, electrocautery or lasers. AIM To evaluate the patient perceptions related to pain and discomfort on the 1(st), 3(rd) and the 7(th) day post vestibuloplasty and also assess the healing outcomes related to the treatment of inadequate vestibular depth either with the diode laser or the scalpel. MATERIALS AND METHODS Twenty patients who had inadequate vestibular depth and required vestibuloplasty were assigned randomly to undergo the procedure either with the scalpel or the laser. The data obtained was analysed for intergroup comparison with an independent paired t-test and intragroup comparison was determined by a paired t-test. RESULTS Intragroup comparison within the laser group for VAS scores of pain and discomfort within all the reported days exhibited a significant difference (p<0.05). Inter group comparison revealed that the patients in the laser group had lower VAS cores for pain and discomfort compared to the scalpel group (p<0.05). Analysis of the three pointer scale for healing revealed that the patients in the laser group exhibited better healing outcomes on the 1(st), 3(rd) and the 7(th) day compared to the scalpel group. CONCLUSION Observations from the study highlight the opinion that laser can be a safe and effective alternative to traditional vestibuloplasty performed with the scalpel.
Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity.

Derivatives of pyridinones were found to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevent the spread of HIV-1 infection in cell culture without an appreciable effect on other retroviral or cellular polymerases. 3-[( (4,7-Dimethyl-1,3-benzoxazol-2-yl) methyl]amino ]-5-ethyl-6-methylpyridin-2(1H)-one (L-697,639) and 3-[[ (4,7-dichloro-1,3-benzoxazol-2-yl) methyl]amino]-5-ethyl-6-methylpyridin-2(1H)-one (L-697,661), two compounds within this series, had HIV-1 RT IC50 values in the range of 20-800 nM, depending upon the template-primer used. The most potent inhibition was obtained with rC.dG and dA.dT as template--primers. With rC.dG, reversible slow-binding non-competitive inhibition was observed. [3H]L-697,639 bound preferentially to enzyme-template-primer complexes. This binding was magnesium-dependent and saturable with a stoichiometry of 1 mol of [3H]L-697,639 per mol of RT heterodimer. Displacement of [3H]L-697,639 was seen with phosphonoformate. In human T-lymphoid-cell culture, L-697,639 and L-697,661 inhibited the spread of HIV-1 infection by at least 95% at concentrations of 12-200 nM. Synergism between 3'-azido-3'-deoxythymidine or dideoxyinosine and either of these compounds was also demonstrated in cell culture. Based upon their specificity for HIV-1 RT activity, template-primer dependence on potency and ability to displace [3H]L-697,639; a tetrahydroimidazo [4,5,1-jk] [1,4]-benzodiazepin-2(1H)-thione derivative R82150 and the dipyridodiazepinone BI-RG-587 appear to inhibit RT activity by the same mechanism as the pyridinones.
Intraspecific divergence of ionoregulatory physiology in the euryhaline teleost Fundulus heteroclitus: possible mechanisms of freshwater adaptation

SUMMARY We examined intraspecific variation in ionoregulatory physiology within euryhaline killifish, Fundulus heteroclitus, to understand possible mechanisms of freshwater adaptation in fish. Pronounced differences in freshwater tolerance existed between northern (2% mortality) and southern (19% mortality) killifish populations after transfer from brackish water (10 g l-1) to freshwater. Differences in Na+ regulation between each population might partially account for this difference in tolerance, because plasma Na+ was decreased for a longer period in southern survivors than in northerns. Furthermore, northern fish increased Na+/K+-ATPase mRNA expression and activity in their gills to a greater extent 1-14 days after transfer than did southerns, which preceded higher whole-body net flux and unidirectional influx of Na+ at 14 days. All observed differences in Na+ regulation were small, however, and probably cannot account for the large differences in mortality. Differences in Cl- regulation also existed between populations. Plasma Cl- was maintained in northern fish, but in southerns, plasma Cl- decreased rapidly and remained low for the duration of the experiment. Correspondingly, net Cl- loss from southern fish remained high after transfer, while northerns eliminated Cl- loss altogether. Elevated Cl- loss from southern fish in freshwater was possibly due to a persistence of seawater gill morphology, as paracellular permeability (indicated by extrarenal clearance rate of PEG-4000) and apical crypt density in the gills (detected using scanning electron microscopy) were both higher than in northern fish. These large differences in the regulation of Cl- balance probably contributed to the marked differences in mortality after freshwater transfer. Glomerular filtration rate and urination frequency were also lower in southerns. Taken together, these data suggest that northern killifish are better adapted to freshwater environments and that minimizing Cl- imbalance appears to be the key physiological difference accounting for their greater freshwater tolerance.
Cerebral Artery Velocity Determined by Transcranial Doppler Ultrasonography in Patients With β-Thalassemia Intermedia Compared to β-Thalassemia Major

We aimed to compare cerebral artery velocity and relevant clinical factors in patients with β-thalassemia intermedia (β-TI), β-thalassemia major (β-TM), and healthy individuals. For this study, 60 patients with β-TM and 64 with β-TI were randomly selected. Sixty healthy adults comprised the control group. Time average maximum mean velocity (TAMMV) was measured in large cerebral arteries with transcranial Doppler (TCD) ultrasonography. In all arteries, TAMMV was significantly higher in the β-TI group than that of β-TM or controls (P < .001). Patients with β-TM had significantly higher TAMMV than controls in most arteries evaluated (P < .001). Overall, the lack of regular blood transfusions, splenectomy, and lower age (to a lesser extent) was found to be independent influencing factors contributing to high cerebral artery velocities. Further detailed longitudinal studies are needed to confirm these results and to determine the risk of silent infarction and stroke in patients with thalassemia and abnormal TCD, with particular focus on patients with β-TI.
Sociodemographic and hispanic acculturation factors and isolated anotia/microtia.

BACKGROUND It has been observed in several studies that infants with anotia/microtia are more common among Hispanics compared with other racial/ethnic groups. We examined the association between selected Hispanic ethnicity and acculturation factors and anotia/microtia in the National Birth Defects Prevention Study. METHODS We examined data from mothers of 351 infants with isolated anotia/microtia and 8435 unaffected infants from the National Birth Defects Prevention Study with an expected delivery date from 1997 to 2007. Sociodemographic, maternal, and acculturation factors (e.g., age, maternal education, household income, body mass index, gestational diabetes, folic acid, smoking, alcohol intake, study center, parental birthplace, and years lived in the United States, maternal language) were assessed as overall risk factors and also as risk factors among subgroups of Hispanics (United States- and foreign-born) versus non-Hispanic whites. RESULTS Compared with non-Hispanic whites, both United States- and foreign-born Hispanic mothers demonstrated substantially higher odds of delivering infants with anotia/microtia across nearly all strata of sociodemographic and other maternal factors (adjusted odds ratios range: 2.1-11.9). The odds of anotia/microtia was particularly elevated among Hispanic mothers who emigrated from Mexico after age five (adjusted odds ratios = 4.88; 95% confidence interval = 2.93-8.11) or who conducted the interview in Spanish (adjusted odds ratios = 4.97; 95% confidence interval = 3.00-8.24). CONCLUSION We observed that certain sociodemographic and acculturation factors are associated with higher risks of anotia/microtia among offspring of Hispanic mothers.
Macrolide-Resistant Streptococcus pneumoniae and Streptococcus pyogenes in the Pediatric Population in Germany during 2000-2001

ABSTRACT In a nationwide study in Germany covering 13 clinical microbiology laboratories, a total of 307 Streptococcus pyogenes (mainly pharyngitis) and 333 Streptococcus pneumoniae (respiratory tract infections) strains were collected from outpatients less than 16 years of age. The MICs of penicillin G, amoxicillin, cefotaxime, erythromycin A, clindamycin, levofloxacin, and telithromycin were determined by the microdilution method. In S. pyogenes isolates, resistance rates were as follows: penicillin, 0%; erythromycin A, 13.7%; and levofloxacin, 0%. Telithromycin showed good activity against S. pyogenes isolates (MIC90 = 0.25 μg/ml; MIC range, 0.016 to 16 μg/ml). Three strains were found to be telithromycin-resistant (MIC ≥ 4 μg/ml). Erythromycin-resistant strains were characterized for the underlying resistance genotype, with 40.5% having the efflux type mef(A), 38.1% having the erm(A), and 9.5% having the erm(B) genotypes. emm typing of macrolide-resistant S. pyogenes isolates showed emm types 4 (45.2%), 77 (26.2%), and 12 (11.9%) to be predominant. In S. pneumoniae, resistance rates were as follows: penicillin intermediate, 7.5%; penicillin resistant, 0%; erythromycin A, 17.4%; and levofloxacin, 0%. Telithromycin was highly active against pneumococcal isolates (MIC90 ≤ 0.016 μg/ml; range, 0.016 to 0.5 μg/ml). The overall resistance profile of streptococcal respiratory tract isolates is still favorable, but macrolide resistance is of growing concern in Germany.
Exploring the experiences of bereaved families involved in assisted suicide in Southern Switzerland: a qualitative study

Background In Switzerland, helping with assisted suicide under certain conditions is not prosecuted. With approximately 300 cases annually, this leaves behind a large group of bereaved people where its consequences are mostly unknown. The study aimed to explore family involvement in decision making prior to assisted suicide, and to examine their ways of coping during the bereavement period. Methods A qualitative interview study used the principles of Grounded Theory analysis. Eleven relatives of eight patients, who died in Southern Switzerland after assisted suicide, participated in semistructured interviews. Results The large majority of family members faced moral dilemmas during the decision-making phase. Their respect for patient's autonomy was a key justification to resolve dilemmas. Two types of involvement were identified: categorised as ‘passive’ when the decision making was located with the patient, and ‘active’ when assisted suicide was proposed by the family member and/or the relative was involved in some way. The relatives reported feelings of isolation during and after assisted suicide. Family members reported fear of social stigma and did not openly disclose assisted suicide as the cause of death. None of those interviewed received formal psychological support. Conclusions Bereaved families express moral dilemmas, feelings of isolation and secrecy in the management of assisted suicide in Southern Switzerland. These features seem underestimated and not sufficiently recognised by the healthcare professionals. Management of assisted suicide requests should include consideration of family members’ needs, in addition to those of the patient.
Postoperative Radiotherapy is Associated with Better Survival in Non–Small Cell Lung Cancer with Involved N2 Lymph Nodes: Results of an Analysis of the National Cancer Data Base

Introduction: Use of postoperative radiotherapy (PORT) in non–small-cell lung cancer remains controversial. Limited data indicate that PORT may benefit patients with involved N2 nodes. This study evaluates this hypothesis in a large retrospective cohort treated with chemotherapy and contemporary radiation techniques. Methods: The National Cancer Data Base was queried for patients diagnosed 2004–2006 with resected non–small-cell lung cancer and pathologically involved N2 (pN2) nodes also treated with chemotherapy. Multivariable Cox proportional hazards model was used to assess factors associated with overall survival (OS). Inverse probability of treatment weighting (IPTW) using the propensity score was used to reduce selection bias. OS was compared between patients treated with versus without PORT using the adjusted Kaplan–Meier estimator and weighted log-rank test based on IPTW. Results: Two thousand and one hundred and fifteen patients were eligible for analysis. 918 (43.4%) received PORT, 1197 (56.6%) did not. PORT was associated with better OS (median survival time 42 months with PORT versus 38 months without, p = 0.048). This effect was significant in multivariable and IPTW Cox models (hazard ratio: 0.87, 95% confidence interval: 0.78–0.98, p = 0.026, and hazard ratio: 0.89, 95% confidence interval: 0.79–1.00, p = 0.046, respectively). No interaction was seen between the effects of PORT and number of involved lymph nodes (p = 0.615). Conclusions: PORT was associated with better survival for patients with pN2 nodes also treated with chemotherapy. No interaction was seen between benefit of PORT and number of involved nodes. These findings reinforce the benefit of PORT for N2 disease in modern practice using the largest, most recent cohort of chemotherapy-treated pN2 patients to date.
Local Uncoupling of the Cerebrovascular and Metabolic Responses to Somatosensory Stimulation after Neuronal Nitric Oxide Synthase Inhibition

It has recently been shown, using either genetically engineered mutant mice (nitric oxide synthase [NOS] knockout) or specific pharmacological tools, that type I NOS (neuronal isoform of NOS, [nNOS]) participates in coupling cerebral blood flow to functional activation. However, it has not been clearly established whether the associated metabolic response was preserved under nNOS inhibition and whether this action was exerted homogeneously within the brain. To address these issues, we analyzed the combined circulatory and metabolic consequences of inhibiting the nNOS both at rest and during functional activation in the rat anesthetized with α-chloralose. Cerebral blood flow and cerebral glucose use (CGU) were measured autoradiographically using [14C]iodoantipyrine and [14C]2-deoxyglucose during trigeminal activation induced by unilateral whiskers stimulation in vehicle- and 7-nitroindazole-treated rats. Our data show that inhibition of nNOS globally decreased CBF without altering CGU, indicating that NO-releasing neurons play a significant role in maintaining a resting cerebrovascular tone in the whole brain. During whisker stimulation, nNOS inhibition totally abolished the cerebrovascular response only in the second order relay stations (thalamus and somatosensory cortex) of the trigeminal relay without altering the metabolic response. These findings provide evidence that the involvement of neurally-derived NO in coupling flow to somatosensory activation is region-dependent, and that under nNOS inhibition, CBF and CGU may vary independently during neuronal activation.
AutoFault: Towards Automatic Construction of Algebraic Fault Attacks

A prototype of the framework AutoFault, which automatically constructs fault-injection attacks for hardware realizations of ciphers, is presented. AutoFault can be used to quickly evaluate the resistance of security-critical hardware blocks to fault attacks and the adequacy of implemented countermeasures. The framework takes as inputs solely the circuit description of the cipher and the fault(s) and produces an algebraic formula that can be handed over to an external solver. In contrast to previous work, attacks constructed by AutoFault do not incorporate any cipher-specific cryptoanalytic derivations, making the framework accessible to users without cryptographic background. We report successful application of AutoFault in combination with a state-of-the-art SAT solver to LED-64 and to small-scale AES. To the best of our knowledge, this is the first time that a state-of-the-art cipher (LED-64) was broken by a fault attack with no prior manual cryptanalysis whatsoever.
MicroRNA-223 Antagonizes Angiogenesis by Targeting &bgr;1 Integrin and Preventing Growth Factor Signaling in Endothelial Cells

Rationale: Endothelial cells in situ are largely quiescent, and their isolation and culture are associated with the switch to a proliferative phenotype. Objective: To identify antiangiogenic microRNAs expressed by native endothelial cells that are altered after isolation and culture, as well as the protein targets that regulate responses to growth factors. Methods and Results: Profiling studies revealed that miR-223 was highly expressed in freshly isolated human, murine, and porcine endothelial cells, but those levels decreased in culture. In primary cultures of endothelial cells, vascular endothelial cell growth factor and basic fibroblast growth factor further decreased miR-223 expression. The overexpression of precursor-miR-223 did not affect basal endothelial cell proliferation but abrogated vascular endothelial cell growth factor–induced and basic fibroblast growth factor–induced proliferation, as well as migration and sprouting. Inhibition of miR-223 in vivo using specific antagomirs potentiated postnatal retinal angiogenesis in wild-type mice, whereas recovery of perfusion after femoral artery ligation and endothelial sprouting from aortic rings from adult miR-223−/y animals were enhanced. MiR-223 overexpression had no effect on the growth factor–induced activation of ERK1/2 but inhibited the vascular endothelial cell growth factor–induced and basic fibroblast growth factor–induced phosphorylation of their receptors and activation of Akt. &bgr;1 integrin was identified as a target of miR-223 and its downregulation reproduced the defects in growth factor receptor phosphorylation and Akt signaling seen after miR-223 overexpression. Reintroduction of &bgr;1 integrin into miR-223–ovexpressing cells was sufficient to rescue growth factor signaling and angiogenesis. Conclusions: These results indicate that miR-223 is an antiangiogenic microRNA that prevents endothelial cell proliferation at least partly by targeting &bgr;1 integrin.