Miracle-dz/UniFAR-FTUs huggingface dataset:
The future of low-density lipoprotein cholesterol lowering therapy: An end to statin exceptionalism?

A screen of microbial culture broths led by Akira Endo in the 1970s led to the discovery of compactin, a competitive inhibitor of the rate-limiting enzyme in cholesterol synthesis HMG-CoA reductase (HMGCR). Subsequent development of closely related compounds gave rise to statin medications. Numerous clinical trials of statin therapy demonstrate robust reductions in both low-density lipoprotein cholesterol (LDL-C) and cardiovascular events, reinforcing statins’ role as the pharmacologic backbone of current hyperlipidemia treatment strategies. These striking clinical trial results led researchers to seek evidence for pleiotropic cholesterol-independent effects of statins; the impact of statins on metrics of inflammation, endothelial dysfunction, oxidative stress, and immunomodulation were carefully examined. Favorable results from these studies gave rise to the ‘‘statin exceptionalism’’ hypothesis, the notion that statins exert clinical gain beyond that which would be predicted by the LDL-C reduction achieved. Recent advances in the realms of both clinical trials and human genetics provide an opportunity to test this hypothesis.
Antibody or Antibody Fragments: Implications for Molecular Imaging and Targeted Therapy of Solid Tumors

The use of antibody-based therapeutics has proven very promising for clinical applications in cancer patients, with multiple examples of antibodies and antibody–drug conjugates successfully applied for the treatment of solid tumors and lymphomas. Given reported recurrence rates, improvements are clearly still necessary. A major factor limiting the efficacy of antibody-targeted cancer therapies may be the incomplete penetration of the antibody or antibody–drug conjugate into the tumor. Incomplete tumor penetration also affects the outcome of molecular imaging, when using such targeting agents. From the injection site until they arrive inside the tumor, targeting molecules are faced with several barriers that impact intratumoral distribution. The primary means of antibody transport inside tumors is based on diffusion. The diffusive penetration inside the tumor is influenced by both antibody properties, such as size and binding affinity, as well as tumor properties, such as microenvironment, vascularization, and targeted antigen availability. Engineering smaller antibody fragments has shown to improve the rate of tumor uptake and intratumoral distribution. However, it is often accompanied by more rapid clearance from the body and in several cases also by inherent destabilization and reduction of the binding affinity of the antibody. In this perspective, we discuss different cancer targeting approaches based on antibodies or their fragments. We carefully consider how their size and binding properties influence their intratumoral uptake and distribution, and how this may affect cancer imaging and therapy of solid tumors.
Fear from the Heart: Sensitivity to Fear Stimuli Depends on Individual Heartbeats

Cognitions and emotions can be influenced by bodily physiology. Here, we investigated whether the processing of brief fear stimuli is selectively gated by their timing in relation to individual heartbeats. Emotional and neutral faces were presented to human volunteers at cardiac systole, when ejection of blood from the heart causes arterial baroreceptors to signal centrally the strength and timing of each heartbeat, and at diastole, the period between heartbeats when baroreceptors are quiescent. Participants performed behavioral and neuroimaging tasks to determine whether these interoceptive signals influence the detection of emotional stimuli at the threshold of conscious awareness and alter judgments of emotionality of fearful and neutral faces. Our results show that fearful faces were detected more easily and were rated as more intense at systole than at diastole. Correspondingly, amygdala responses were greater to fearful faces presented at systole relative to diastole. These novel findings highlight a major channel by which short-term interoceptive fluctuations enhance perceptual and evaluative processes specifically related to the processing of fear and threat and counter the view that baroreceptor afferent signaling is always inhibitory to sensory perception.
The Importance of Shear in the Deflection of Bamboo Beams

According to the traditional theory of elasticity, the total deflection of a beam occurs due to the combined effect of both the bending moment and the shear force. In isotropic materials such as steel and concrete, the deflection due to shear is usually not taken into account since it represents only 1% of the total deformation approximately. However, in anisotropic materials such as bamboo, the deflection due to shear should be taken into account because it may represent more than 20% of the total deformation of the beam. To better predict the influence of the shear effect on the deflection of bamboo beams, the longitudinal Young ́s modulus and the shear modulus of Guadua angustifolia were determined through the application of repeated three-point bending tests of whole culms and small prismatic elements while aligning their length along the axial direction of the culm. In order to determine the value of the shear modulus, each test was carried out using four different spans. The end results for the culms were: the longitudinal modulus of elasticity E equal to 23525 MPa, and the shear modulus G equal to 298 MPa. Thus, the substantial difference between the Young ́s modulus and the shear modulus confirms the high anisotropy of bamboo, and results indicate that shear deformation should always be included for the calculation of deflections of bamboo structures. Furthermore, the significant differences between these values and those obtained with the small prismatic elements may be attributed to the anisotropy and heterogeneity of the material. However, more tests have to be accomplished to further corroborate these results and find other anisotropic elastic properties of the material.
High‐dose tamoxifen and sulindac as first‐line treatment for desmoid tumors

I read with interest the recent article by Volpe et al. on the natural history of 32 incidentally detected small renal masses. The authors stated that small renal masses grow at slow or undetectable rates and that a period of observation may be appropriate for some patients. I would like to point out, however, that the study was somewhat limited in that none of the tumors were analyzed on biopsy and only nine were resected. Tumors were presumed to be renal cell carcinomas (RCCs) on the basis of imaging studies, which are not infallible in distinguishing RCCs from benign tumors such as oncocytomas and angiomyolipomas. In fact, one of the nine resected tumors in the study was confirmed to be an oncocytoma. Volpe and colleagues concluded that tumor growth rate on its own probably was not sufficient for the accurate prediction of the behavior of every small renal mass. Furthermore, they speculated that studies (cytogenetic, immunohistochemical, and other) performed on needle biopsy samples, as well as the investigation of novel radiographic parameters, could help in the identification of patients who had renal lesions exhibiting favorable prognostic characteristics and a long natural history and who therefore could be followed conservatively in most cases. It is worth noting that pathologists, and especially cytopathologists, already use fine-needle aspiration and coreneedle biopsy to distinguish patients who can be followed conservatively from those who should undergo resection. As Volpe et al. point out, recent studies have found that as many as 38.5% of all masses measuring 2 cm are benign. Benign lesions such as angiomyolipomas can be identified on fine-needle aspiration or core-needle biopsy, as can RCC subtypes such as chromophobe RCC and low-grade papillary RCC, which are associated with a significantly lower risk of disease progression compared with conventional RCC. Conventional/clear cell tumors with high Fuhrman grade, in contrast, are associated with a relatively poor prognosis and probably should be resected if at all possible, regardless of their size. Some other minor issues also warrant mentioning. Volpe and colleagues state that the biologic behavior of predominantly cystic RCC is not well known, when it is in fact well documented that these tumors are relatively indolent. It is true that in the past, the term adenoma was used by pathologists to describe renal masses that measured 3 cm, were detected incidentally at autopsy, and were histologically similar to RCC but had lower associated metastasis rates. The current definition of adenoma according to the 1996 American Joint Committee on Cancer Consensus Conference, however, is very different, and based on this definition, adenomas specifically do not include radiographically identified masses. There remain specific settings in which growth rate may be useful in predicting outcome for patients with small, radiographically identified lesions. These settings include Fuhrman Grade 1 or 2 conven650
Identification of single-stranded-DNA-binding proteins that interact with muscle gene elements

A sequence-specific DNA-binding protein from skeletal-muscle extracts that binds to probes of three muscle gene DNA elements is identified. This protein, referred to as muscle factor 3, forms the predominant nucleoprotein complex with the MCAT gene sequence motif in an electrophoretic mobility shift assay. This protein also binds to the skeletal actin muscle regulatory element, which contains the conserved CArG motif, and to a creatine kinase enhancer probe, which contains the E-box motif, a MyoD-binding site. Muscle factor 3 has a potent sequence-specific, single-stranded-DNA-binding activity. The specificity of this interaction was demonstrated by sequence-specific competition and by mutations that diminished or eliminated detectable complex formation. MyoD, a myogenic determination factor that is distinct from muscle factor 3, also bound to single-stranded-DNA probes in a sequence-specific manner, but other transcription factors did not. Multiple copies of the MCAT motif activated the expression of a heterologous promoter, and a mutation that eliminated expression was correlated with diminished factor binding. Muscle factor 3 and MyoD may be members of a class of DNA-binding proteins that modulate gene expression by their abilities to recognize DNA with unusual secondary structure in addition to specific sequence.
Extensive virologic and immunologic characterization in an HIV-infected individual following allogeneic stem cell transplant and analytic cessation of antiretroviral therapy: A case study

Background Notwithstanding 1 documented case of HIV-1 cure following allogeneic stem cell transplantation (allo-SCT), several subsequent cases of allo-SCT in HIV-1 positive individuals have failed to cure HIV-1 infection. The aim of our study was to describe changes in the HIV reservoir in a single chronically HIV-infected patient on suppressive antiretroviral therapy who underwent allo-SCT for treatment of acute lymphoblastic leukemia. Methods and findings We prospectively collected peripheral blood mononuclear cells (PBMCs) by leukapheresis from a 55-year-old man with chronic HIV infection before and after allo-SCT to measure the size of the HIV-1 reservoir and characterize viral phylogeny and phenotypic changes in immune cells. At day 784 post-transplant, when HIV-1 was undetectable by multiple measures—including PCR measurements of both total and integrated HIV-1 DNA, replication-competent virus measurement by large cell input quantitative viral outgrowth assay, and in situ hybridization of colon tissue—the patient consented to an analytic treatment interruption (ATI) with frequent clinical monitoring. He remained aviremic off antiretroviral therapy until ATI day 288, when a low-level virus rebound of 60 HIV-1 copies/ml occurred, which increased to 1,640 HIV-1 copies/ml 5 days later, prompting reinitiation of ART. Rebounding plasma HIV-1 sequences were phylogenetically distinct from proviral HIV-1 DNA detected in circulating PBMCs before transplantation. The main limitations of this study are the insensitivity of reservoir measurements, and the fact that it describes a single case. Conclusions allo-SCT led to a significant reduction in the size of the HIV-1 reservoir and a >9-month-long ART-free remission from HIV-1 replication. Phylogenetic analyses suggest that the origin of rebound virus was distinct from the viruses identified pre-transplant in the PBMCs.
Waveform Design for Synthetic-Aperture Radar Imaging through Dispersive Media

In this paper we analyze the problem of optimal waveform design for synthetic-aperture radar (SAR) imaging through a dispersive medium. We use a scalar model for wave propagation, together with the single-scattering approximation, and we assume that measurements are polluted with thermal noise whose statistics are known. For image formation, we use a filtered backprojection algorithm in which the filter is determined by knowledge of the power-spectral densities of the scene and noise. In this framework, we derive a waveform which is optimal in the sense of minimizing the mean-square-error of the reconstructed image. We show the results of simulations for the example of imaging point scatterers embedded in a certain dispersive background. We show that for low signal-to-noise ratios, the optimal waveform resembles what is known as a precursor: a wave that is generated from propagating ultrawideband waveforms through the medium.
Nicotinamide Mononucleotide, an Intermediate of NAD+ Synthesis, Protects the Heart from Ischemia and Reperfusion

Nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme for nicotinamide adenine dinucleotide (NAD+) synthesis, and Sirt1, an NAD+-dependent histone deacetylase, protect the heart against ischemia/reperfusion (I/R). It remains unknown whether Nampt mediates the protective effect of ischemic preconditioning (IPC), whether nicotinamide mononucleotide (NMN, 500 mg/kg), a product of Nampt in the NAD+ salvage pathway, mimics the effect of IPC, or whether caloric restriction (CR) upregulates Nampt and protects the heart through a Sirt1-dependent mechanism. IPC upregulated Nampt protein, and the protective effect of IPC against ischemia (30 minutes) and reperfusion (24 hours) was attenuated at both early and late phases in Nampt +/− mice, suggesting that Nampt plays an essential role in mediating the protective effect of IPC. In order to mimic the effect of Nampt, NMN was administered by intraperitoneal injection. NMN significantly increased the level of NAD+ in the heart at baseline and prevented a decrease in NAD+ during ischemia. NMN protected the heart from I/R injury when it was applied once 30 minutes before ischemia or 4 times just before and during reperfusion, suggesting that exogenous NMN protects the heart from I/R injury in both ischemic and reperfusion phases. The protective effect of NMN was accompanied by decreases in acetylation of FoxO1, but it was not obvious in Sirt1 KO mice, suggesting that the effect of NMN is mediated through activation of Sirt1. Compared to control diet (90% calories), CR (60% calories for 6 weeks) in mice led to a significant reduction in I/R injury, accompanied by upregulation of Nampt. The protective effect of CR against I/R injury was not significant in cardiac-specific Sirt1 KO mice, suggesting that the protective effect of CR is in part mediated through the Nampt-Sirt1 pathway. In conclusion, exogenous application of NMN and CR protects the heart by both mimicking IPC and activating Sirt1.
Utility of brachyury in distinction of chordoma from cytomorphologic mimics in fine‐needle aspiration and core needle biopsy

Chordoma is a neoplasm of notochordal differentiation that typically occurs in the axial skeleton. Accurate diagnosis is therapeutically important but can be challenging, especially in fine‐needle aspiration (FNA) and core needle biopsy (CNB). Immunohistochemistry for the transcription factor brachyury (T) has recently proven diagnostically useful in whole‐tissue sections. Our aim was to compare brachyury performance with conventional markers (S‐100, EMA, keratin) and to evaluate its utility in distinguishing chordoma from cytomorphologic mimics. Brachyury immunohistochemistry was performed on chordoma (8 FNA, 12 CNB), chondrosarcoma (10 FNA), and metastatic mucinous adenocarcinoma (12 FNA). Immunohistochemistry performed at the time of diagnosis was also reviewed. Brachyury was positive in 17 (85%) cases of chordoma and typically showed moderate‐to‐strong nuclear staining. Of five sets of concurrent FNA and CNB, four pairs were positive for brachyury in both samples and one pair was positive for brachyury in the CNB and negative in the cell block. S‐100, EMA, and keratin stains were available for 13 chordomas: 9 (69%) cases (including the 3 negative for brachyury) were positive for S‐100 and keratin or EMA; 4 cases were keratin positive but S‐100 negative. No nuclear brachyury staining was seen in chondrosarcoma or adenocarcinoma, though two adenocarcinomas showed cytoplasmic staining. Brachyury separates chordoma from cytomorphologic mimics with high sensitivity and specificity in small biopsies. As a single test, brachyury has higher sensitivity than a combined panel of S‐100 and epithelial markers. When added to the conventional panel, brachyury increases sensitivity to 100% without sacrificing specificity. Diagn. Cytopathol. 2014;42:647–652. © 2014 Wiley Periodicals, Inc.
Polymerase Chain Reaction as a Diagnostic Tool for Six Sexually Transmitted Infections - Preliminary Results

Background and aim Sexually transmitted infections are a very frequent and under-diagnosed cause of illness worldwide. A high number of detection methods and a large range of specimens in which sexually transmitted infections can be determined are available at the moment. Polymerase chain reaction performed on first void urine offers the advantage of being non-invasive, self-collectable and has high sensitivity and specificity. We looked to determine the frequency of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Mycoplasma hominis, Mycoplasma genitalium and Ureaplasma urealyticum in symptomatic and asymptomatic patients. Methods Six sexually transmitted infections were determined in the first void urine of 15 symptomatic and asymptomatic patients by polymerase chain reaction. We used “Epicenter MasterPure™ Complete DNA and RNA Purification Kit” for the DNA purification and “Seeplex® STD6 ACE Detection” for the DNA amplification. The results were examined in UV light. Results A number of 5 patients had positive results for Chlamydia trachomatis or Neisseria gonorrhoeae. Sexually transmitted infections are more frequent in men between 27 and 40 years old. Conclusions Polymerase chain reaction is a good diagnostic tool for sexually transmitted infections because it has a high sensitivity and specificity. Chlamydia trachomatis is the most frequent sexually transmitted infection, followed by Neisseria gonorrhoeae.
Pandinus imperator scorpion venom blocks voltage-gated potassium channels in GH3 cells

We examined the effects of Pandinus imperator scorpion venom on voltage-gated potassium channels in cultured clonal rat anterior pituitary cells (GH3 cells) using the gigohm-seal voltage-clamp method in the whole-cell configuration. We found that Pandinus venom blocks the voltage-gated potassium channels of GH3 cells in a voltage-dependent and dose-dependent manner. Crude venom in concentrations of 50-500 micrograms/ml produced 50-70% block of potassium currents measured at -20 mV, compared with 25-60% block measured at +50 mV. The venom both decreased the peak potassium current and shifted the voltage dependence of potassium current activation to more positive potentials. Pandinus venom affected potassium channel kinetics by slowing channel opening, speeding deactivation slightly, and increasing inactivation rates. Potassium currents in cells exposed to Pandinus venom did not recover control amplitudes or kinetics even after 20-40 min of washing with venom-free solution. The concentration dependence of crude venom block indicates that the toxins it contains are effective in the nanomolar range of concentrations. The effects of Pandinus venom were mimicked by zinc at concentrations less than or equal to 0.2 mM. Block of potassium current by zinc was voltage dependent and resembled Pandinus venom block, except that block by zinc was rapidly reversible. Since zinc is found in crude Pandinus venom, it could be important in the interaction of the venom with the potassium channel. We conclude that Pandinus venom contains toxins that bind tightly to voltage-dependent potassium channels in GH3 cells. Because of its high affinity for voltage-gated potassium channels and its irreversibility, Pandinus venom may be useful in the isolation, mapping, and characterization of voltage-gated potassium channels.
Binding of Mycoplasma arthritidis‐derived mitogen to human MHC class II molecules via its N terminus is modulated by invariant chain expression and its C terminus is required for T cell activation

Mycoplasma arthritidis‐derived mitogen (MAM) is considered to be a member of the superantigen family despite the fact that there is no evidence until now indicating its binding to MHC class II molecules. To demonstrate its direct binding and to determine the regions involved in MHC class II and TCR interactions, we generated a recombinant wild‐type and two truncated forms of the MAM protein. Data obtained in the course of the present investigation show that MAM binds specifically and significantly to human MHC class II molecules. Evidence is also provided that MAM bears two distinct binding regions: one is located within its N terminus and interacts with MHC class II molecules, while the second region which is located in its C terminus mediates its recognition by the TCR. Association of the MHC class II‐associated invariant chain peptide with the peptide binding groove on the cell surface completely abolished MAM binding and presentation. This inhibitory effect is restored by the expression of HLA‐DM molecules, suggesting that the nature of the peptide within the binding groove and / or the stability of the MHC class II molecules on the cell surface may modulate MAM / MHC class II interactions.
Are We One Hop Away from a Better Internet?

The Internet suffers from well-known performance, reliability, and security problems. However, proposed improvements have seen little adoption due to the difficulties of Internet-wide deployment. We observe that, instead of trying to solve these problems in the general case, it may be possible to make substantial progress by focusing on solutions tailored to the paths between popular content providers and their clients, which carry a large share of Internet traffic. In this paper, we identify one property of these paths that may provide a foothold for deployable solutions: they are often very short. Our measurements show that Google connects directly to networks hosting more than 60% of end-user prefixes, and that other large content providers have similar connectivity. These direct paths open the possibility of solutions that sidestep the headache of Internet-wide deployability, and we sketch approaches one might take to improve performance and security in this setting.