Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluation of DNA Damage Induced by 2 Polybrominated Diphenyl Ether Flame Retardants (BDE-47 and BDE-209) in SK-N-MC Cells

Polybrominated diphenyl ethers (PBDEs) are a class of flame retardants whose levels have increased in the environment and in human tissues in the past decades. Exposure to PBDEs has been associated with developmental neurotoxicity, endocrine dysfunction, and reproductive disorders. In spite of their widespread distribution and potential adverse health effects, only few studies have addressed the potential neurotoxicity of PBDEs. In the present study, we evaluated the cyto- and genotoxicity of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) and decabrominated diphenyl ether (BDE-209) in human neuroblastoma cells (SK-N-MC). The DNA damage was measured using the alkaline version of the Comet assay, while specific oxidative-generated DNA damage was evaluated by a modified version of the Comet assay with the repair enzyme formamidopyrimidine glycosylase (FPG). The results show that BDE-47 and BDE-209 (5-20 μmol/L) are able to induce DNA damage in human SK-N-MC cells. Pretreatment with the antioxidant melatonin significantly reduced the DNA damage induced by both congeners. The Comet assay carried out in the presence of FPG suggests that both congeners increase purine oxidation. In all cases, BDE-47 was more potent than BDE-209. The results indicate that 2 environmentally relevant PBDEs cause DNA damage which is primarily mediated by the induction of oxidative stress and may contribute to adverse health effects.
Fast Multiparameter Reconstruction of Multicomponent Induction Well-Logging Datum in a Deviated Well in a Horizontally Stratified Anisotropic Formation

In this paper, we advance a fast iterative inversion algorithm of multicomponent induction well-logging (MCIL) datum to simultaneously reconstruct a total model vector in a deviated well in the horizontally stratified transversally isotropic (TI) formation (TI medium) with the case-neglecting borehole. The model vector consists of the horizontal and vertical conductivities, the interface depth of each bed, and a borehole dipping angle. Because an electromagnetic field emitted by a horizontal magnetic dipole is no longer axially symmetrical, we first decompose the horizontal magnetic dipole located at borehole axis as the sum of two harmonics only so that the computation of MCIL responses can be entirely transformed into three axially symmetrical problems. Therefore, we solve them through the numerical mode matching method and obtain the semianalytic (SA) solution of an EM field in an arbitrary bed. Then, based on the perturbation principle and spatial distribution of formation conductivity related to the model vector, we set up an efficient SA algorithm of Frechet derivatives of the MCIL response with respect to the model vector. Then we extract an initial model from synthetic logs for the inversion through a special blocking technique. Finally, we give an iterative process to simultaneously reconstruct all model parameters from the logs through a combination of a normalization and singular value decomposition technique. Numerical tests validate the algorithms.
Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury

Fibrillar carbon nanotubes simultaneously deliver two small interfering RNAs, which safely prevent acute kidney injury and prolong survival in mice. Double trouble for kidney toxicity The kidneys can be damaged by drugs, such as antibiotics and chemotherapy, as well as by surgery, which robs the organs of oxygen. To prevent injury, Alidori et al. devised a nanomedicine treatment approach that delivers two small interfering RNAs (siRNAs) to the main cells of the kidney, the renal proximal tubule cells. siRNAs targeting Mep1b and Trp53 were attached to fibrillar carbon nanotubes and delivered simultaneously to mice before drug-induced kidney insult. With such RNA interference, the kidney cells could not produce meprin-1β and p53—two key proteins involved in kidney injury; the mice lived longer and remained injury-free, but only if given both siRNAs. The nanotube/siRNA complexes were also safe and had favorable pharmacokinetics in monkeys. The next steps will be testing the dual siRNAs in other animal models of kidney injury. RNA interference has tremendous yet unrealized potential to treat a wide range of illnesses. Innovative solutions are needed to protect and selectively deliver small interfering RNA (siRNA) cargo to and within a target cell to fully exploit siRNA as a therapeutic tool in vivo. Herein, we describe ammonium-functionalized carbon nanotube (fCNT)–mediated transport of siRNA selectively and with high efficiency to renal proximal tubule cells in animal models of acute kidney injury (AKI). fCNT enhanced siRNA delivery to tubule cells compared to siRNA alone and effectively knocked down the expression of several target genes, including Trp53, Mep1b, Ctr1, and EGFP. A clinically relevant cisplatin-induced murine model of AKI was used to evaluate the therapeutic potential of fCNT-targeted siRNA to effectively halt the pathogenesis of renal injury. Prophylactic treatment with a combination of fCNT/siMep1b and fCNT/siTrp53 significantly improved progression-free survival compared to controls via a mechanism that required concurrent reduction of meprin-1β and p53 expression. The fCNT/siRNA was well tolerated, and no toxicological consequences were observed in murine models. Toward clinical application of this platform, fCNTs were evaluated for the first time in nonhuman primates. The rapid and kidney-specific pharmacokinetic profile of fCNT in primates was comparable to what was observed in mice and suggests that this approach is amenable for use in humans. The nanocarbon-mediated delivery of siRNA provides a therapeutic means for the prevention of AKI to safely overcome the persistent barrier of nephrotoxicity during medical intervention.
Workshop Proceedings

A workshop entitled “Challenges and Opportunities in Evaluating Protein Allergenicity across Biotechnology Industries” was held at the 51st Annual Meeting of the Society of Toxicology (SOT) in San Francisco, California. The workshop was sponsored by the Biotechnology Specialty Section of SOT and was designed to present the science-based approaches used in biotechnology industries to evaluate and regulate protein allergenicity. A panel of experts from industry and government highlighted the allergenicity testing requirements and research in the agricultural, pharmaceutical/biopharma, and vaccine biotechnology industries and addressed challenges and opportunities for advancing the science of protein allergenicity. The main learning from the workshop was that immunoglobulin E-mediated allergenicity of biotechnology-derived products is difficult to assess without human data. The approaches currently being used to evaluate potential for allergenicity across biotechnology industries are very different and range from bioinformatics, in vitro serology, in vivo animal testing, in vitro and in vivo functional assays, and “biosimilar” assessments (ie, biotherapeutic equivalents to innovator products). The challenge remains with regard to the different or lack of regulatory requirements for allergenicity testing across industries, but the novel approaches being used with bioinformatics and biosimilars may lead to opportunities in the future to collaborate across biotechnology industries.
Biocompatibility and Inflammation Profile of B2A-Coated Granules Used in Arthrodesis

The biocompatibility/inflammation profile of B2A-coated ceramic granules was evaluated using a panel of standard biocompatibility protocols (International Organization for Standardization-10993) including skin irritation and delayed-type hypersensitivity (Kligman maximization test), as well as acute, subacute, and chronic toxicity. Additionally, the potential of B2A-coated granules to elicit inflammatory reactions was also assessed using in vivo air pouch models, and B2A was evaluated using in vitro models of leukocyte recruitment and endothelial cell activation. Overall, the findings demonstrate that B2A-coated ceramic granules exhibit good biocompatibility profiles in the murine air pouch model and in standard subcutaneous implant models, and B2A did not demonstrate evidence of leukocyte recruitment or endothelial cell activation. These findings suggest that B2A and B2A-coated granules have little, if any, propensity to initiate inflammation reactions based on leukocyte recruitment. Thus, traditional biocompatibility and specially designed inflammation models indicate a high degree of biocompatibility and a low possibility of toxicity, inflammation, or edema following the implant of B2A-coated granules.
Albuminuria and renal insufficiency prevalence guides population screening: Results from the NHANES III

Albuminuria and renal insufficiency prevalence guides population screening: Results from the NHANES III . Background A number of screening criteria, applied either at a single point in time or serially, can be used for the purpose of identifying individuals at risk of end-stage renal disease (ESRD). This study focused on two such criteria measured on a single occasion, proteinuria and renal insufficiency, and examined their prevalence in a sample representative of the adult U.S. non-institutionalized population. Such knowledge guides the utility of population screening to prevent ESRD. Methods The prevalence of albuminuria (microalbuminuria and macroalbuminuria from a random urine albumin-to-creatinine ratio) and renal insufficiency [glomerular filtration rate (GFR) estimated from serum creatinine] was determined in different age categories in various adult screening groups in the cross-sectional Third National Health and Nutrition Examination Survey (NHANES III). Results A total of 14,622 adult participants were included in the analysis. In the general population, 8.3% and 1.0% of participants demonstrated microalbuminuria and macroalbuminuria, respectively. To identify one case of albuminuria, one would need to screen three persons with diabetes mellitus, seven non-diabetic hypertensive persons, or six persons over the age of 60. When albuminuria and renal insufficiency were considered together, it was clear that these tests were identifying different segments of the population; 37% of participants with a GFR less than 30 mL/min/1.73m 2 demonstrated no albuminuria. Non-albuminuric renal insufficiency was most evident in the ages of 60 to 79; 34% of diabetics, and 63% of non-diabetic hypertensives with a GFR less than 30 mL/min/1.73m 2 demonstrated no albuminuria. Conclusions Albuminuria is prevalent, and when considered together, screening tests of albuminuria and renal insufficiency measured on a single occasion identify different segments of the population. The prevalence of albuminuria and renal insufficiency in populations of interest should be considered, as this knowledge has implications for the effectiveness of screening.
The difficult—and often delayed—diagnosis of CTCL

High-throughput sequencing of T cell receptors to define and quantify T cell populations emerges as a diagnostic tool with the remarkable ability to discriminate between CTCL and benign inflammatory conditions (Kirsch et al., this issue). High-throughput sequencing of T cell receptors to define and quantify T cell populations emerges as a diagnostic tool with the remarkable ability to discriminate between CTCL and benign inflammatory conditions (Kirsch et al., this issue).
Pacemaker-induced transient asynchrony suppresses heart failure progression

Transient asynchrony induced by an implanted pacemaker improves pathobiology of heart failure in large animals. Disruptive technology Healthy and the majority of failing hearts beat synchronously. However, some hearts contract with poor coordination and if they are weak, this worsens clinical outcomes. Pacemakers used to reset a heart’s rhythm can also change the synchrony of contraction, making it better or worse, and current therapy called resynchronization makes it better. Perhaps counterintuitively, Kirk et al. demonstrate that using a pacemaker to purposely induce dyssynchrony—but only for part of each day—makes the synchronous failing heart better. In their process, pacemaker-induced transient asynchrony (PITA), the heart’s right ventricle is paced to induce a 6-hour period of dyssynchrony each day, followed by atrial pacing to resynchronize the heart for the remaining 18 hours. In dogs with heart failure, PITA halted chamber dilation and negative remodeling of the heart tissue, improved cellular signaling and force generation, and resulted in normal muscle fiber structure and function, similar to healthy controls. PITA may help the majority of patients with heart failure who have synchronous contraction and thus are not treated with standard resynchronization pacemakers. Uncoordinated contraction from electromechanical delay worsens heart failure pathophysiology and prognosis, but restoring coordination with biventricular pacing, known as cardiac resynchronization therapy (CRT), improves both. However, not every patient qualifies for CRT. We show that heart failure with synchronous contraction is improved by inducing dyssynchrony for 6 hours daily by right ventricular pacing using an intracardiac pacing device, in a process we call pacemaker-induced transient asynchrony (PITA). In dogs with heart failure induced by 6 weeks of atrial tachypacing, PITA (starting on week 3) suppressed progressive cardiac dilation as well as chamber and myocyte dysfunction. PITA enhanced β-adrenergic responsiveness in vivo and normalized it in myocytes. Myofilament calcium response declined in dogs with synchronous heart failure, which was accompanied by sarcomere disarray and generation of myofibers with severely reduced function, and these changes were absent in PITA-treated hearts. The benefits of PITA were not replicated when the same number of right ventricular paced beats was randomly distributed throughout the day, indicating that continuity of dyssynchrony exposure is necessary to trigger the beneficial biological response upon resynchronization. These results suggest that PITA could bring the benefits of CRT to the many heart failure patients with synchronous contraction who are not CRT candidates.
Clinical Relevance of the Advanced Microbiologic and Biochemical Investigations in Periodontal Diagnosis: A Critical Analysis

New approaches to periodontal diagnosis, including advanced microbiologic, biochemical, and genetic tests, have been shown to provide the clinician with the information not available by traditional means. The purpose of a diagnostic test is to confirm, exclude, classify, or monitor disease to guide treatment. Their clinical value depends on whether the information they provide leads to improved patient outcomes. This can be assessed by randomized trials, which compare patient outcomes from the new diagnostic test versus the old test strategy. Being nonmandatory for marketing approval, such trials are not always feasible because of large sample sizes requirements. So, many diagnostic tests enter the practice without being critically analysed for any additional benefits. Effective diagnosis is just as essential as the selection of effective treatments for the success of periodontal therapy. So, the current paper aims to focus on the practical utility of this rapidly emerging plethora of periodontal diagnostic tools, emphasizing the critical issues surrounding the clinical application of microbiologic and biochemical investigations, employed for periodontal diagnosis.
Delivery delay analysis for roadside unit deployment in intermittently connected VANETs

This paper analyzes the information delivery delay for roadside unit deployment in an intermittently connected vehicular network. An analytical model is developed to describe the relationship between the average information delivery delay and the distance between two neighbor RSUs deployed along a road. The derived model considers a straight highway scenario where two RSUs are deployed at a distance without any direct connection and vehicles are sparsely distributed on the road with road condition information randomly generated between the two neighbor RSUs. Moreover, the model takes into account the vehicle speed, the vehicle density, the likelihood of an incident, and the distance between two RSUs. The effectiveness of the derived analytical model is verified through simulation results. Given the delay requirement of some time-critical applications, this model can be used to estimate the maximum distance allowed between two neighbor RSUs, which can provide a reference basis for the deployment of RSUs in such scenarios.
Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin’s glucose-lowering effects

Inhibition of FABP4 rescues defective apelin signaling, decreases fatty acid accumulation, and promotes insulin sensitivity. An apelin a day keeps the doctor away Apelin is an atheroprotective protein, which promotes insulin sensitivity and metabolic health, but the details of its signaling are not well understood. Hwangbo et al. discovered that the apelin receptor is predominantly localized in endothelial cells of metabolic organs, such as muscle and adipose tissues, and that it functions, in part, by inhibiting fatty acid binding protein 4 (FABP4) activity. The authors also found that inhibition of FABP4 can reverse the metabolic disease phenotype associated with defective apelin signaling and thus improve fatty acid uptake, glucose utilization, and insulin sensitivity. Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue. Conditional endothelial-specific deletion of Aplnr (AplnrECKO) resulted in markedly impaired glucose utilization and abrogation of apelin-induced glucose lowering. Furthermore, we identified inactivation of Forkhead box protein O1 (FOXO1) and inhibition of endothelial expression of fatty acid (FA) binding protein 4 (FABP4) as key downstream signaling targets of apelin/APLNR signaling. Both the Apln−/− and AplnrECKO mice demonstrated increased endothelial FABP4 expression and excess tissue FA accumulation, whereas concurrent endothelial Foxo1 deletion or pharmacologic FABP4 inhibition rescued the excess FA accumulation phenotype of the Apln−/− mice. The impaired glucose utilization in the AplnrECKO mice was associated with excess FA accumulation in the skeletal muscle. Treatment of these mice with an FABP4 inhibitor abrogated these metabolic phenotypes. These findings provide mechanistic insights that could greatly expand the therapeutic repertoire for type 2 diabetes and related metabolic disorders.
Muscle contributions to knee joint stability: Effects of ACL injury and knee brace use.

MUSCLE CONTRIBUTIONS TO KNEE JOINT STABILITY: EFFECTS OF ACL INJURY AND KNEE BRACE USE Aaron Joseph Derouin University of Windsor, 2006 The purpose of this study was to develop an EMG-based biomechanical model of the lower extremity for the purpose of evaluating the rotational joint stiffness of ACLdeficient (n=9) and reconstructed (n=8) knees, with and without a functional knee brace. Kinematic, EMG, and kinetic data were measured, while subjects performed stable and unstable quasi-static squats, and were incorporated into biomechanical and anatomical models. Individual and total muscle contributions to knee joint rotational stiffness were calculated about the flexion-extension axis, using the method developed by Potvin and Brown (2005) for four independent variables: Squat task; Leg condition (uninjured, unbraced, braced); Knee angle (5-10°, 20-25°, 40-45°); Injury Status. Subjects had significantly higher (p<0.05) total knee joint stiffness values while wearing the brace compared to the control leg. The difference in knee joint stiffness values in the unstable trials compared to stable trials was significantly greater at 5-10° versus 20-25° and 4045°. R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission.
Type 1 diabetes immunotherapy using polyclonal regulatory T cells

Autologous regulatory T cells can be expanded and are well tolerated in patients with recent-onset type 1 diabetes. Regulating type 1 diabetes In patients with type 1 diabetes (T1D), immune cells attack the insulin-producing β cells of the pancreas. The resulting prolonged increase in blood sugar levels can lead to serious complications including heart disease and kidney failure. Regulatory T cells (Tregs) have been shown to be defective in autoimmune diseases. Now, Bluestone et al. report a phase 1 trial of adoptive Treg immunotherapy to repair or replace Tregs in type 1 diabetics. The ex vivo–expanded polyclonal Tregs were long-lived after transfer and retained a broad Treg phenotype long-term. Moreover, the therapy was safe, supporting efficacy testing in further trials. Type 1 diabetes (T1D) is an autoimmune disease that occurs in genetically susceptible individuals. Regulatory T cells (Tregs) have been shown to be defective in the autoimmune disease setting. Thus, efforts to repair or replace Tregs in T1D may reverse autoimmunity and protect the remaining insulin-producing β cells. On the basis of this premise, a robust technique has been developed to isolate and expand Tregs from patients with T1D. The expanded Tregs retained their T cell receptor diversity and demonstrated enhanced functional activity. We report on a phase 1 trial to assess safety of Treg adoptive immunotherapy in T1D. Fourteen adult subjects with T1D, in four dosing cohorts, received ex vivo–expanded autologous CD4+CD127lo/−CD25+ polyclonal Tregs (0.05 × 108 to 26 × 108 cells). A subset of the adoptively transferred Tregs was long-lived, with up to 25% of the peak level remaining in the circulation at 1 year after transfer. Immune studies showed transient increases in Tregs in recipients and retained a broad Treg FOXP3+CD4+CD25hiCD127lo phenotype long-term. There were no infusion reactions or cell therapy–related high-grade adverse events. C-peptide levels persisted out to 2+ years after transfer in several individuals. These results support the development of a phase 2 trial to test efficacy of the Treg therapy.
Optimal multi-slot spectrum sensing in energy harvesting cognitive radio systems

In this paper, we consider a cognitive radio (CR) system operating in slotted mode, where the secondary user (SU) has no wired power supplies and is powered exclusively through extracting energy from ambient environment. Due to hardware limitation, the SU can only perform either of energy harvesting, spectrum sensing or data transmission at the same time and we assume that a timeslot is partitioned into three non-overlapping fractions. Considering a generalized multi-slot spectrum sensing paradigm with data fusion rule, we focus on the "saving-sensing-throughput" tradeoff and joint optimization for save-ratio, sensing duration as well as sensing threshold to maximize the SU's expected achievable throughput while keeping primary users (PUs) sufficiently protected. By translating the original optimization problem into a convex one, we show that the optimal solutions for sample number, mini-slot number as well as sensing threshold are non-unique and single-slot spectrum sensing is more practically preferable. We also investigate the impact of system parameters to the optimal sensing strategy.