Miracle-dz/UniFAR-FTUs huggingface dataset:
Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 Gene Editing Technique in Xenotransplantation

Genetically modified pigs have been considered favorable resources in xenotransplantation. Microinjection of randomly integrating transgenes into zygotes, somatic cell nuclear transfer, homologous recombination, zinc finger nucleases, transcription activator-like effector nucleases, and most recently, clustered regularly interspaced short palindromic repeats-cas9 (CRISPR/Cas9) are the techniques that have been used to generate these animals. Here, we provide an overview of the CRISPR approaches that have been used to modify genes which are vital in improving xenograft survival rate, including cytidine monophosphate-N-acetylneuraminic acid hydroxylase, B1,4N-acetylgalactosaminyltransferase, isoglobotrihexosylceramide synthase, class I MHC, von Willebrand factor, C3, and porcine endogenous retroviruses. In addition, we will mention the importance of potential candidate genes which could be targeted using CRISPR/Cas9.
Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation

Mutant RAS–selective dependence on the GEF SOS2 reveals tumor cell sensitivity to kinase inhibitors. Finding alternatives to targeting RAS Many tumors have mutations in the guanosine triphosphatases (GTPases) HRAS, NRAS, or KRAS. Pharmacologically targeting these proteins has so far been elusive; hence, targeting critical members of their signaling pathway(s) may be more successful. Sheffels et al. found that the guanine nucleotide exchange factor SOS2, in contrast to its family member SOS1, was dispensable for two-dimensional cell proliferation but mediated oncogenic and stem-like switches in the three-dimensional growth behavior of normal and tumor cells to varying degrees, most critically for cells expressing Gly12/13 mutants of KRAS. Further analysis of the differential downstream pathways suggested that SOS2 dependence and RAS mutant type may indicate whether individual inhibitors of the kinase PI3K, AKT, or MEK may be effective against the tumor. About a third of tumors have activating mutations in HRAS, NRAS, or KRAS, genes encoding guanosine triphosphatases (GTPases) of the RAS family. In these tumors, wild-type RAS cooperates with mutant RAS to promote downstream effector activation and cell proliferation and transformation, suggesting that upstream activators of wild-type RAS are important modulators of mutant RAS-driven oncogenesis. The guanine nucleotide exchange factor (GEF) SOS1 mediates KRAS-driven proliferation, but little is understood about the role of SOS2. We found that RAS family members have a hierarchical requirement for the expression and activity of SOS2 to drive cellular transformation. In mouse embryonic fibroblasts (MEFs), SOS2 critically mediated mutant KRAS-driven, but not HRAS-driven, transformation. Sos2 deletion reduced epidermal growth factor (EGF)–dependent activation of wild-type HRAS and phosphorylation of the kinase AKT in cells expressing mutant RAS isoforms. Assays using pharmacological inhibitors revealed a hierarchical requirement for signaling by phosphoinositide 3-kinase (PI3K) in promoting RAS-driven cellular transformation that mirrored the requirement for SOS2. KRAS-driven transformation required the GEF activity of SOS2 and was restored in Sos2−/− MEFs by expression of constitutively activated PI3K. Finally, CRISPR/Cas9-mediated deletion of SOS2 reduced EGF-stimulated AKT phosphorylation and synergized with MEK inhibition to revert the transformed phenotype of human KRAS mutant pancreatic and lung tumor cells. These results indicate that SOS2-dependent PI3K signaling mediates mutant KRAS-driven transformation, revealing therapeutic targets in KRAS-driven cancers. Our data also reveal the importance of three-dimensional culture systems in investigating the mediators of mutant KRAS.
Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA‐mediated apoptosis

Increasing evidence suggests that deubiquitinase USP7 participates in tumor progression by various mechanisms and serves as a potential therapeutic target. However, its expression and role in esophageal cancer remains elusive; the anti‐cancer effect by targeting USP7 still needs to be investigated. Here, we reported that USP7 was overexpressed in esophageal squamous cell carcinoma (ESCC) tissues compared with adjacent tissues, implying that USP7 was an attractive anticancer target of ESCC. Pharmaceutical or genetic inactivation of USP7 inhibited esophageal cancer cells growth in vitro and in vivo and induced apoptosis. Mechanistically, inhibition of USP7 accumulated poly‐ubiquitinated proteins, activated endoplasmic reticulum stress, and increased expression of ATF4, which transcriptionally upregulated expression of NOXA and induced NOXA‐mediated apoptosis. These results provide an evidence for clinical investigation of USP7 inhibitors for the treatment of ESCC.
Infants distinguish between leaders and bullies

Significance Prior research indicates that infants can represent power asymmetries and expect them to both endure over time and extend across situations. Building on these efforts, we examined whether 21-month-old infants could distinguish between two different bases of social power. Infants first saw three protagonists interact with a powerful character who was either a leader (with respect-based power) or a bully (with fear-based power). Next, the character gave an order to the protagonists. Infants expected the protagonists to continue to obey the leader’s order after she left the scene, but they expected the protagonists to obey the bully’s order only when she remained present. Thus, by 21 months of age, infants can already distinguish between respect-based and fear-based power relations. We examined whether 21-month-old infants could distinguish between two broad types of social power: respect-based power exerted by a leader (who might be an authority figure with legitimate power, a prestigious individual with merited power, or some combination thereof) and fear-based power exerted by a bully. Infants first saw three protagonists interact with a character who was either a leader (leader condition) or a bully (bully condition). Next, the character gave an order to the protagonists, who initially obeyed; the character then left the scene, and the protagonists either continued to obey (obey event) or no longer did so (disobey event). Infants in the leader condition looked significantly longer at the disobey than at the obey event, suggesting that they expected the protagonists to continue to obey the leader in her absence. In contrast, infants in the bully condition looked equally at the two events, suggesting that they viewed both outcomes as plausible: The protagonists might continue to obey the absent bully to prevent further harm, or they might disobey her because her power over them weakened in her absence. Additional results supported these interpretations: Infants expected obedience when the bully remained in the scene and could harm the protagonists if defied, but they expected disobedience when the order was given by a character with little or no power over the protagonists. Together, these results indicate that by 21 months of age, infants already hold different expectations for subordinates’ responses to individuals with respect-based as opposed to fear-based power.
Autoregulation of ToxR and Its Regulatory Actions on Major Virulence Gene Loci in Vibrio parahaemolyticus

Vibrio parahaemolyticus, the leading causative agent of seafood-associated gastroenteritis, harbors two major virulence gene loci T3SS1 and Vp-PAI (T3SS2 and tdh2). ToxR is a virulence regulator of vibrios. Cell density-dependent transcriptional pattern of toxR and its regulatory actions on T3SS1 and Vp-PAI have been previously reported, but the detailed regulatory mechanisms are still obscure. In the present work, we showed that the highest transcription level of toxR occurs at an OD600 = 0.2–0.4, which may be due to the subtle repression of ToxR and the quorum-sensing (QS) master regulator AphA. We also showed that ToxR is involved in regulating the mouse lethality, enterotoxicity, cytotoxicity, and hemolytic activity of V. parahaemolyticus. ToxR binds to the multiple promoter-proximal DNA regions within the T3SS1 locus to repress their transcription. In addition, ToxR occupies the multiple promoter-proximal DNA regions of Vp-PAI locus to activate their transcription. Thus, ToxR regulates the multiple virulence phenotypes via directly acting on the T3SS1 and Vp-PAI genes. Data presented here provide a deeper understanding of the regulatory patterns of ToxR in V. parahaemolyticus.
Pretreatment Hepatitis C Virus NS5A/NS5B Resistance-Associated Substitutions in Genotype 1 Uruguayan Infected Patients

Hepatitis C Virus (HCV) infection treatment has dramatically changed with the advent of direct-acting antiviral agents (DAAs). However, the efficacy of DAAs can be attenuated by the presence of resistance-associated substitutions (RASs) before and after treatment. Indeed, RASs detected in DAA treatment-naïve HCV-infected patients could be useful for clinical management and outcome prediction. Although the frequency of naturally occurring HCV NS5A and NS5B RASs has been addressed in many countries, there are only a few reports on their prevalence in the South American region. The aim of this study was to investigate the presence of RASs to NS5A and NS5B inhibitors in a DAA treatment naïve cohort of Uruguayan patients infected with chronic hepatitis C and compare them with reports from other South American countries. Here, we found that naturally occurring substitutions conferring resistance to NS5A and NS5B inhibitors were present in 8% and 19.2%, respectively, of treatment-naïve HCV genotype 1 infected patients. Importantly, the baseline substitutions in NS5A and NS5B herein identified differ from the studies previously reported in Brazil. Furthermore, Uruguayan strains subtype 1a clustered within all major world clades, showing that HCV variants currently circulating in this country are characterized by a remarkable genetic diversity.
Loss in Translation: Learning Bilingual Word Mapping with a Retrieval Criterion

Continuous word representations learned separately on distinct languages can be aligned so that their words become comparable in a common space. Existing works typically solve a quadratic problem to learn a orthogonal matrix aligning a bilingual lexicon, and use a retrieval criterion for inference. In this paper, we propose an unified formulation that directly optimizes a retrieval criterion in an end-to-end fashion. Our experiments on standard benchmarks show that our approach outperforms the state of the art on word translation, with the biggest improvements observed for distant language pairs such as English-Chinese.
Glutamate-activated BK channel complexes formed with NMDA receptors

Significance Large-conductance BK channels are dually activated by voltage and Ca2+ and play a powerful integrative role in regulating cellular excitability and Ca2+ signaling in neurons. However, BK channels have a requirement of high intracellular free Ca2+ concentrations for activation under physiological conditions, and the Ca2+ sources for their activation are not well understood. In this work, we establish that BK channels physically form protein complexes with Ca2+-permeable NMDA receptors via their obligatory BKα and GluN1 subunits. The activation mechanism and function of postsynaptic BK channels at synapses remain largely unknown. We found that postsynaptic BK channels in medial perforant path-dentate gyrus granule cell synapses are activated by NMDA receptor-mediated Ca2+ influx and modulate excitatory synaptic transmission. The large-conductance calcium- and voltage-activated K+ (BK) channel has a requirement of high intracellular free Ca2+ concentrations for its activation in neurons under physiological conditions. The Ca2+ sources for BK channel activation are not well understood. In this study, we showed by coimmunopurification and colocalization analyses that BK channels form complexes with NMDA receptors (NMDARs) in both rodent brains and a heterologous expression system. The BK–NMDAR complexes are broadly present in different brain regions. The complex formation occurs between the obligatory BKα and GluN1 subunits likely via a direct physical interaction of the former’s intracellular S0–S1 loop with the latter’s cytosolic regions. By patch-clamp recording on mouse brain slices, we observed BK channel activation by NMDAR-mediated Ca2+ influx in dentate gyrus granule cells. BK channels modulate excitatory synaptic transmission via functional coupling with NMDARs at postsynaptic sites of medial perforant path-dentate gyrus granule cell synapses. A synthesized peptide of the BKα S0–S1 loop region, when loaded intracellularly via recording pipette, abolished the NMDAR-mediated BK channel activation and effect on synaptic transmission. These findings reveal the broad expression of the BK–NMDAR complexes in brain, the potential mechanism underlying the complex formation, and the NMDAR-mediated activation and function of postsynaptic BK channels in neurons.
Neural Character-based Composition Models for Abuse Detection

The advent of social media in recent years has fed into some highly undesirable phenomena such as proliferation of offensive language, hate speech, sexist remarks, etc. on the Internet. In light of this, there have been several efforts to automate the detection and moderation of such abusive content. However, deliberate obfuscation of words by users to evade detection poses a serious challenge to the effectiveness of these efforts. The current state of the art approaches to abusive language detection, based on recurrent neural networks, do not explicitly address this problem and resort to a generic OOV (out of vocabulary) embedding for unseen words. However, in using a single embedding for all unseen words we lose the ability to distinguish between obfuscated and non-obfuscated or rare words. In this paper, we address this problem by designing a model that can compose embeddings for unseen words. We experimentally demonstrate that our approach significantly advances the current state of the art in abuse detection on datasets from two different domains, namely Twitter and Wikipedia talk page.
Enhancing Security and Scalability in Software Defined LTE Core Networks

The rapid development of mobile networks has revolutionized the way of accessing the Internet. The exponential growth of mobile subscribers, devices and various applications frequently brings about excessive traffic in mobile networks. The demand for higher data rates, lower latency and seamless handover further drive the demand for the improved mobile network design. However, traditional methods can no longer offer cost-efficient solutions for better user quality of experience with fast time-to-market. Recent work adopts SDN in LTE core networks to meet the requirement. In these software defined LTE core networks, scalability and security become important design issues that must be considered seriously. In this paper, we propose a scalable channel security scheme for the software defined LTE core network. It applies the VxLAN for scalable tunnel establishment and MACsec for security enhancement. According to our evaluation, the proposed scheme not only enhances the security of the channel communication between different network components, but also improves the flexibility and scalability of the core network with little performance penalty. Moreover, it can also shed light on the design of the next generation cellular network.
Transposase subunit architecture and its relationship to genome size and the rate of transposition in prokaryotes and eukaryotes

Abstract Cut-and-paste transposons are important tools for mutagenesis, gene-delivery and DNA sequencing applications. At the molecular level, the most thoroughly understood are Tn5 and Tn10 in bacteria, and mariner and hAT elements in eukaryotes. All bacterial cut-and-paste transposases characterized to date are monomeric prior to interacting with the transposon end, while all eukaryotic transposases are multimers. Although there is a limited sample size, we proposed that this defines two pathways for transpososome assembly which distinguishes the mechanism of the bacterial and eukaryotic transposons. We predicted that the respective pathways would dictate how the rate of transposition is related to transposase concentration and genome size. Here, we have tested these predictions by creating a single-chain dimer version of the bacterial Tn5 transposase. We show that artificial dimerization switches the transpososome assembly pathway from the bacterial-style to the eukaryotic-style. Although this had no effect in vitro, where the transposase does not have to search far to locate the transposon ends, it increased the rate of transposition in bacterial and HeLa cell assays. However, in contrast to the mariner elements, the Tn5 single-chain dimer remained unaffected by over-production inhibition, which is an emergent property of the transposase subunit structure in the mariner elements.
Towards Accurate Shape Reconstruction of Compact Bionic Handling Arm

Continuum robots can continuously curve to give much more flexibility than rigid robots. Usually, continuum robots are made up of soft flexible material and have complex structures to provide high dexterity of motion. The presence of these factors, i.e., soft material and complex structure, make mathematical modeling of continuum robots a cumbersome task. This paper aims to discuss the Pythagorean Hodograph (PH) based method for shape reconstruction of continuum robots and proposes a methodology for improving this reconstructed shape using experimental data. The method is successfully applied to Compact Bionic Handling Arm (CBHA) manipulator. The results show a clear improvement in the accuracy.
Assessing the Impact of Aging on Burden of Disease

Background: In this study, we presented a theoretical model to measure aging rate in OECD countries, quantitatively measuring the effect of aging rate on disease patterns in each country and explaining how these effects were obtained. The purpose of this study was to investigate how disease burden varies according to the level of medical infrastructure and changes in aging index using OECD aging data and WHO disease burden data. Methods: This study used OECD Health data and global burden of disease data from the WHO in 2000 and 2012. We applied a difference-in-differences (DID) model was used to analyze effects of aging. Results: Disease burdens increased over time, especially in the aging population of middle-aged. In the case of loss of life due to premature death, the number of middle-aged and older population was increased significantly. When we examined the econometric model after controlling related factors, there was a significant increase in loss of life due to illness and premature death. On the other hand, the group of piles at the aging level had a significant positive effect on Years of Life Lost (YLL). Although the interaction effect as an important variable showing double difference effect of aging did not affect Disability adjusted Life Year (DALY), it showed a significant positive effect on YLL. Conclusion: Loss of life due to death of the elderly was relatively higher than that of the elderly. Therefore, the impact of population aging on medical resources and medical expenditures in the future should consider population structure changes, disease burden by age group, and interactions of these two incremental factors.
A Method for Calculating the Purity of Vortex Electromagnetic Waves

This paper describes a criterion and calculation method for the purity of vortex electromagnetic wave modes. The factors affecting the purity are discussed on the basis of orbital angular momentum(OAM) waves generated by a dipole uniform circular array. Simulations show that the property of the vortex electromagnetic wave in the propagation process will distort with the decrease of propagation distance r as well as the increase of θ in spherical coordinate system. In addition, a threshold of variance is defined to judge whether the purity of vortex is acceptable or not.
Fast Incoherent OFDR Interrogation of FBG Arrays Using Sparse Radio Frequency Responses

We present two implementations of fast, discrete incoherent optical frequency-domain reflectometers (I-OFDR) for the interrogation of equally spaced fiber Bragg grating (FBG) arrays, based on the determination of the array's radio frequency (RF) response at a sparse number of frequencies. FBG reflectivities are determined by use of the inverse discrete Fourier transform (IDFT) of the sparse RF response, in a dynamic range limited by crosstalk induced by FBG positioning errors. The first implementation employs the complete, vector RF response at a number of frequencies equal to the number <inline-formula><tex-math notation="LaTeX">${N}$</tex-math></inline-formula> of FBGs in the array. In the second, the introduction of a reference reflector allows for an interrogation using the power (phaseless) RF response in <inline-formula><tex-math notation="LaTeX">${4N-1}$</tex-math></inline-formula> frequencies. Demodulation based on IDFT leads to total interrogation times determined by the network analyzer scan time, which can be as low as 10 <inline-formula><tex-math notation="LaTeX">${\mu }$</tex-math></inline-formula>s per FBG. Depending on the interrogation technique, electrical bandwidth requirements are 1–2 GHz in our array with 10-cm separation. We implemented both techniques in a <inline-formula><tex-math notation="LaTeX">${N=10}$</tex-math></inline-formula> array, inducing decays in reflectivity by 10 dB in one or several FBGs. Unambiguous detection of FBG decays was obtained in both interrogation methods. Additional tests performed on the measured reflectivities also show that measurement linearity is preserved in the 10-dB decay range. As discrete I-OFDR systems, the proposed techniques show the possibility to reach compromises between interrogation time and dynamic range or accuracy in reflectivity measurements, using the number of interrogation frequencies and the sensor topology.
Increased use of security personnel in Irish psychiatric hospitals: 2008–2012

Objectives Little is known about the involvement of security personnel in Irish psychiatric care. Content analysis of inspection reports is a feasible way to investigate this under-researched topic. We aimed to (i) Describe the number of approved centres per year in which we observed comments about the presence of security personnel in published reports of inspections conducted from 2008 to 2012 (ii) Report the main themes of all text relating to security personnel published in these inspection reports. Method We conducted a content analysis of all 349 inspection reports published between 2008 and 2012. Results The number of approved centres in which security personnel were noted increased from 3% to 8% between the years 2008 and 2012. This increase was not statistically significant when the same unique centres were compared between years (p=0.684). Employment details such as contracted employment relationship, location relative to the approved centre and hours of work appeared inconsistent across centres. Role functions of security personnel differed across centres and ranged from monitoring the entrance of a unit to observing, restraining and secluding patients. Contrasting perceptions of suitability were evident in the inspection reports. The extent to which the training needs of security personnel were met was unclear from the reports. Conclusions Activity of security personnel in psychiatric hospitals may not be role appropriate, compliant with legislation or conducive to treatment. Best practice guidelines should be developed in consultation with multiple stakeholders.