Miracle-dz/UniFAR-FTUs huggingface dataset:
CriSNPr, a single interface for the curated and de novo design of gRNAs for CRISPR diagnostics using diverse Cas systems

Nucleic acid detection and variant calling through CRISPR-based diagnostics (CRISPRDx) has facilitated clinical decision-making, particularly during the COVID-19 pandemic. This has been further accelerated through the discovery of newer and engineered CRISPR effectors, expanding the portfolio of such diagnostic applications to a wide variety of pathogenic and non-pathogenic conditions. However, each diagnostic CRISPR pipeline requires customized detection schemes originating from fundamental principles of the Cas protein used, its guide RNA (gRNA) design parameters, and the assay readout. This is particularly relevant for variant detection, an attractive low-cost alternative to sequencing-based approaches for which no in silico pipeline for the ready-to-use design of CRISPR-based diagnostics currently exists. In this manuscript, we fill this lacuna using a unified webserver CriSNPr (CRISPR based SNP recognition), which provides the user the opportunity to de-novo design gRNAs based on six CRISPRDx proteins of choice (Fn/enFnCas9, LwCas13a, LbCas12a, AaCas12b, and Cas14a) and query for ready-to-use oligonucleotide sequences for validation on relevant samples. In addition, we provide a database of curated pre-designed gRNAs and target/off-target for all human and SARS-CoV-2 variants reported so far. CriSNPr has been validated on multiple Cas proteins and highlights its broad and immediate scope of utilization across multiple detection platforms. CriSNPr is available at URL http://crisnpr.igib. res.in/.
Predicted structure of the hepatitis B virus polymerase reveals an ancient conserved protein fold

Hepatitis B virus (HBV) replicates by protein-primed reverse transcription. It chronically infects >250 million people, and the dominant anti-HBV drugs are nucleos(t)ide analogs targeting the viral polymerase (P). P has four domains, the terminal protein (TP) that primes DNA synthesis, a spacer, the reverse transcriptase (RT), and the ribonuclease H (RNaseH). Despite being a major drug target and catalyzing a reverse transcription pathway very different from the retroviral pathway, HBV P has resisted structural analysis for decades. Here, we exploited advances in protein structure prediction to model the structure of P. The predicted HBV RT and RNaseH domains aligned to the HIV RT-RNaseH at 3.75 Å RMSD, had a nucleic acid binding groove spanning the two active sites, had DNA polymerase active site motifs in their expected positions, and accommodated two Mg++ ions in both active sites. Surprisingly, the TP domain wrapped around the RT domain, with the priming tyrosine poised over the RT active site. This model was validated using published mutational analyses, and by docking RT and RNaseH inhibitors, RNA:DNA heteroduplexes, and the HBV ε RNA stem-loop that templates DNA priming into the model. The HBV P fold, including the orientation of the TP domain, was conserved among hepadnaviruses from rodents to fish and in P from a fish nackednavirus, but not in other non-retroviral RTs. Therefore, this protein fold has persisted since the hepadnaviruses diverged from nackednaviruses >400 million years ago. This model will guide drug development and mechanistic studies into P’s function. Significance The hepatitis B virus (HBV) polymerase (P) catalyzes an unusual reverse transcription pathway and is a major drug target. However, P’s insolubility and instability have long prevented its structural analyses. This work predicts the structure of P proteins from human to fish viruses, revealing an unanticipated conserved protein fold that is at least 400 million years old. The HBV P model was validated by mechanistically interpreting mutations with strong phenotypes and by computationally docking nucleic acids to P and inhibitors into both of its active sites. The model will advance mechanistic studies into the function of P and enable drug discovery against targets on P other than the reverse transcriptase and ribonuclease H active sites.
Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance

BRAFV600E is prototypical of oncogenic mutations that can be targeted therapeutically and treatment of BRAF-mutant melanomas with RAF and MEK inhibitors results in rapid tumor regression. However, drug-induced rewiring causes BRAFV600E melanoma cells to rapidly acquire a drug-adapted state. In patients this is thought to promote acquisition or selection for resistance mutations and disease recurrence. In this paper we use an energy-based implementation of ordinary differential equations in combination with proteomic, transcriptomic and imaging data from melanoma cells, to model the precise mechanisms responsible for adaptive rewiring. We demonstrate the presence of two parallel MAPK (RAF-MEK-ERK kinase) reaction channels in BRAFV600E melanoma cells that are differentially sensitive to RAF and MEK inhibitors. This arises from differences in protein oligomerization and allosteric regulation induced by oncogenic mutations and drug binding. As a result, the RAS-regulated MAPK channel can be active under conditions in which the BRAFV600E-driven channel is fully inhibited. Causal tracing demonstrates that this provides a sufficient quantitative explanation for initial and acquired responses to multiple different RAF and MEK inhibitors individually and in combination. Highlights A thermodynamic framework enables structure-based description of allosteric interactions in the EGFR and MAPK pathways Causal decomposition of efficacy of targeted drugs elucidates rewiring of MAPK channels Model-based extrapolation from type I½ RAF inhibitors to type II RAF inhibitors A unified mechanistic explanation for adaptive and genetic resistance across BRAF-cancers
Intramuscular mRNA BNT162b2 vaccine against SARS-CoV-2 induces robust neutralizing salivary IgA

Intramuscularly administered vaccines stimulate robust serum neutralizing antibodies, yet they are often less competent in eliciting sustainable ‘sterilizing immunity’ at the mucosal level. Our study uncovers, strong neutralizing mucosal component (NT50 ≤ 50pM), emanating from intramuscular administration of an mRNA vaccine. We show that saliva of BNT162b2 vaccinees contains temporary IgA targeting the Receptor-Binding-Domain (RBD) of SARS-CoV-2 spike protein and demonstrate that these IgAs are key mediators of potent neutralization. RBD-targeting IgAs were found to associate with the Secretory Component, indicating their bona-fide transcytotic origin and their dimeric tetravalent nature. The mechanistic understanding of the exceptionally high neutralizing activity provided by mucosal IgA, acting at the first line of defence, will advance vaccination design and surveillance principles, pointing to novel treatment approaches, and to new routes of vaccine administration and boosting. Significance statement We unveiled powerful mucosal neutralization upon BNT162b2 vaccination, mediated by temporary polymeric IgA and explored its longitudinal properties. We present a model, whereby the molecular architecture of polymeric mucosal IgA and its spatial properties are responsible for the outstanding SARS-CoV-2 neutralization potential. We established a methodology for quantitative comparison of immunoreactivity and neutralization for IgG and IgAs in serum and saliva in molar equivalents for standardization in diagnostics, surveillance of protection and for vaccine evaluations.
Minus one frameshifted puromycin N-acetyltransferase is targeted to the nucleolus: sporadic but reproducible chimera formation by a transfected Lc3b construct

Map1Lc3b is a protein that has pivotal functions in cellular autophagy. At least three groups in the past decade have reported its presence in the nucleoli of cells, but its functions in that organelle remain unknown. We isolated a few clonal populations of cells stably expressing V5-tagged mouse Lc3b highly enriched in the nucleoli, but the frequency of occurrence of such clones was strikingly low. The phenomenon was readily reproducible, though the protein in the nucleolus puzzlingly had varying molecular masses in different clones but consistently displayed a very strong interaction with the mitochondrial protein C1qbp, which has well-documented functions in the nucleolus. We investigated further and discovered that, in at least one of the clones, Lc3b had formed a chimera with the puromycin resistance gene in the plasmid, plausibly by illegitimate recombination during or after integration of the construct into the cellular genomic DNA. The -1 shifted reading frame of puromycin N-acetyltransferase (pac) can encode a protein that is equally long as the one encoded by the complete pac ORF, but is targeted to the nucleoli due to a drastic shift in the isoelectric point (pI). Notably, this set of events again brings into focus the low threshold often reported for recombination events to occur in eukaryotic cells, the multiple factors influencing them, and calls for increased vigilance in experiments involving DNA transfection and gene targeting.
The stationary phase-specific sRNA FimR2 is a multifunctional regulator of bacterial motility, biofilm formation and virulence

Bacterial pathogens employ a plethora of virulence factors for host invasion, and their use is tightly regulated to maximize infection efficiency and manage resources in a nutrient-limited environment. Here we show that during Escherichia coli stationary phase the small non-coding RNA fimR2 regulates fimbrial and flagellar biosynthesis at the post-transcriptional level, leading to biofilm formation as the dominant mode of survival under conditions of nutrient depletion. fimR2 interacts with the translational regulator CsrA, antagonizing its functions and firmly tightening control over motility and biofilm formation. Generated through RNase E cleavage, fimR2 regulates stationary phase biology independently of the chaperones Hfq and ProQ. The Salmonella enterica version of fimR2 induces effector protein secretion by the type III secretion system and stimulates infection, thus linking the sRNA to virulence. This work reveals the importance of bacterial sRNAs in modulating various aspects of bacterial physiology including stationary phase and virulence. Highlights fimR2 expression causes biofilm formation and alters bacterial outer membrane architecture fimR2 modulates CsrA activity and sequesters it from its targets The Salmonella fimR2 variant is functional in E. coli fimR2 is generated through RNase E processing and enhances infectivity
1 1 Temporal and genetic variation in female aggression after mating 2 3

3 Eleanor Batha*, Edmund Ryan Biscochoa, August Easton-Calabriab, Stuart Wigbya 4 5 a Department of Zoology, 6 University of Oxford, 7 Oxford, UK OX1 3SZ 8 9 b Organismic and Evolutionary Biology Department 10 Harvard University 11 Cambridge, MA 02138 12 13 * Corresponding author: 14 Eleanor Bath: eleanor.bath@zoo.ox. ac.uk 15 Phone number: +441865271161 16 17 Department of Zoology, 18 University of Oxford 19 Zoology Research and Administration Building 20 11a Mansfield Road 21 Oxford OX1 3SZ 22 23
PacJam: Securing Dependencies Continuously via Package-Oriented Debloating

Real-world software is usually built on top of other software provided as packages that are managed by package managers. Package managers facilitate code reusability and programmer productivity but incur significant software bloat by installing excessive dependent packages. This dependency hell increases potential security issues and hampers rapid response to newly discovered vulnerabilities. We propose a package-oriented debloating framework, PacJam, for adaptive and security-aware management of an application's dependent packages. PacJam improves upon existing debloating techniques by providing a configurable fallback mechanism via post-deployment policies. It also elides the need to completely specify the application's usage scenarios and does not require runtime support. Moreover, PacJam enables to rapidly mitigate newly discovered vulnerabilities with minimal impact on the application's functionality. We evaluate PacJam on 10 popular and diverse Linux applications comprising 575K-39M SLOC each. Compared to a state-of-the-art approach, piecewise debloating, PacJam debloats 66% of the packages per application on average, reducing the attack surface by removing 46% of CVEs and 69% (versus 66%) of gadgets, with significantly less runtime overhead and without the need to install a custom loader.
Supplementary Material for Image2Reverb: Cross-Modal Reverb Impulse Response Synthesis

As supplementary material, we present and review a number of input/output examples across several categories with distinct properties1. A summary of these results is shown in Table 1. We additionally present a more detailed diagram of our architecture, shown in Fig. 11. Finally, to gain a qualitative view of intra-scene and adjacent-scene consistency, we plot our test set input images according to the corresponding output audio characteristics by a visualization shown in Figure 12. We produce multiband T60 estimations from all output IRs, and then used t-SNE [3] to reduce the data dimensionality to two dimensions. We then solve a linear assignment problem to transform this into a grid representation. Several instances of within-scene clusters are visible, as well as closeness of related scenes. This suggests that while our method does make errors (outliers are also visible), it learns to treat similar scenes similarly while capturing variation.
Learning robot motor skills with mixed reality

Mixed Reality (MR) has recently shown great success as an intuitive interface for enabling end-users to teach robots. Related works have used MR interfaces to communicate robot intents and beliefs to a co-located human, as well as developed algorithms for taking multi-modal human input and learning complex motor behaviors. Even with these successes, enabling end-users to teach robots complex motor tasks still poses a challenge because end-user communication is highly task dependent and world knowledge is highly varied. We propose a learning framework where end-users teach robots a) motion demonstrations, b) task constraints, c) planning representations, and d) object information, all of which are integrated into a single motor skill learning framework based on Dynamic Movement Primitives (DMPs). We hypothesize that conveying this world knowledge will be intuitive with an MR interface, and that a sample-efficient motor skill learning framework which incorporates varied modalities of world knowledge will enable robots to effectively solve complex tasks.
Wavelet Neural Network in Underwater Targets Recognition Based on Diagonal Slice Spectrum

Aiming at the dilemma situation of the recognition rate and real-time quality in current underwater target recognition technology,in order to make underwater target recognition more practical in actual combat and achieve high efficiency and instantaneity while getting a stable and reliable target recognition rate,the paper put forward a recognition system based on diagonal slice spectrum and wavelet neural network classifier.The system made full use of the inhibiting ability of higher-order spectrum analysis to the Gaussian noises,the characteristic of containing lots of recognition information,and the strongpoints that wavelet neural network is of adaptiveness,self-learning ability,approximation and automatic contraction and panning function,the simulations on the measure data of three ships show that the average recognition rate can reach to 90.4%,while the convergence rate increases by 16.9% compare with ordinary neural networks,which shows that the underwater target recognition system has a good prospect.
A Distributed Approximate Nearest Neighbor Method for Real-Time Face Recognition

Nowadays, face recognition and more generally image recognition have many applications in the modern world and are widely used in our daily tasks. This paper aims to propose a distributed approximate nearest neighbor (ANN) method for real-time face recognition using a big dataset that involves a lot of classes. The proposed approach is based on using a clustering method to separate the dataset into diﬀerent clusters and on specifying the importance of each cluster by deﬁning cluster weights. To this end, reference instances are selected from each cluster based on the cluster weights using a maximum likelihood approach. This process leads to a more informed selection of instances, so it enhances the performance of the algorithm. Experimental results conﬁrm the eﬃciency of the proposed method and its out-performance in terms of accuracy and the processing time.
Aero-Performance Efficient Noise Reduction for the F404-400 Engine

This paper reports on a technology demonstration test of a GEAE F404-400 engine with low aero-performance impact noise suppression devices. The test was conducted at the Naval Air Warfare Center Aircraft Division at Lakehurst N.J. The engine was mounted on a modified engine support stand that permitted aero-performance assessment and measure of far field acoustics. The noise suppression concepts investigated involved outer divergent flap chevron extension, internal engine corrugated seals, and microjet injection of either nitrogen or water droplet spray. Noise reduction at the peak energy emission angle was 2 dB for chevrons, corrugated engine seals, and water droplet spray. The corrugated seals were found to eliminate shock generated noise. The chevrons decreased thrust between 1½. The water droplet spray did not affect thrust, and the corrugated engine seals enhanced thrust by ½%. Both the water droplet spray and corrugated seals reduced Infra-Red plume emission.
The Association Between Conditional Cash Transfer and Fertility Intention in Indonesia

This study aims to analyze the relationship between conditional cash transfer (PKH in Indonesia)acceptance status and fertility intentions of married women ages 15-49 years who do not use contraception in Indonesia. The data used in this research comes from the results of SUSENAS 2017. The sample was limited to married women aged 15-49 years not currently using a contraceptive method. Ordinal logistic regression was employed to analyze the relationship between PKH acceptance status and fertility intention after controlling for the effects of individual control factors, while a multilevel ordinal logistic model was used to investigate the effects of contextual factors. The study results showed that after controlling for the effects of individual and contextual variables, a high fertility intention was associated with receiving PKH. Women from PKH beneficiary households tended to maximize the assistance received by increasing the number of children (moral hazard behavior ). Moral hazard behavior was more pronounced in women from households that had received PKH or received PKH but could not show their cards.
Comparison of Hartley and Fourier Transforms in Harmonic Modelling of Five-Limb Core Transformer Inrush Current

ABSTRACT It is well known that the magnitude of transformer inrush current depends on several factors such as transformer construction and the angle of the applied voltage at the time of energization. In this paper, a novel approach is proposed to compute inrush current in both of time and frequency domains taking into consideration the significance of formulas derived based on magnetic circuit of five-limb transformer. Electric circuit nonlinear mathematical equations are applied to solve inrush problem based on iteration via MATLAB code. The comparison of the Harmonic domain simulation results obtained from Hartley transform with that of Fourier transform proves the capability of Hartley transform to accurately assess inrush current requiring less number of computations.
Parametric optimization of steel lattice portal frame with chs structural members

The paper has proposed a mathematical model for parametric optimization problem of the steel lattice portal frame. The design variable vector includes geometrical parameters of the structure (node coordinates), as well as cross-sectional dimensions of the structural members. The system of constraints covers load-carrying capacities constraints formulated for all design sections of structural members of the steel structure subjected to all ultimate load case combinations. The displacements constraints formulated for the specified nodes of the steel structure subjected to all serviceability load case combinations have been also included into the system of constraints. Additional requirements in the form of constraints on lower and upper values of the design variables, constraints on permissible minimal thicknesses, constraints on permissible maximum diameter-to-thickness ratio for the structural members with circle hollow sections, as well as the conditions for designing gusset-less welded joints between structural members with circle hollow sections have been also considered in the scope of the mathematical model. The method of the objective function gradient projection onto the active constraints surface with simultaneous correction of the constraints violations has been used to solve the formulated parametric optimization problem. New optimal layouts of the steel lattice portal frame by the criterion of the minimum weight, as well as minimum costs on manufacturing and erection have been presented.
A Randomized Controlled Trial on Assessment of Analgesia on Using Magnesium Sulphate by Different Routes in Patients Undergoing Arthroscopy of Knee under Spinal Anaesthesia

BACKGROUND Adequate pain management has a great importance for smooth postoperative recovery, early hospital discharge and early rehabilitation. In this study, we compare the analgesic effect and possible side effects of different routes of magnesium sulphate administration in cases of spinal anaesthesia for knee arthroscopy. METHODS This is an experimental prospective randomized control study. 196 patients undergoing knee arthroscopy were divided into 4 groups (49 each): Group A: Given bupivacaine intrathecally during spinal anaesthesia. Group B: Given magnesium sulphate 50 mg with bupivacaine intrathecally. Group C: Given magnesium sulphate IV 10 min after intrathecal injection (30 mg/kg MgSo4). Group D: Given magnesium sulphate intra-articular route, 10 min before the end of surgery (800 mgSo4 diluted in 12 ml normal saline (0.9 % NaCl). Operative time in minutes, VAS at rest and after procedure, time lapse before first analgesic dose after surgery, total dose of rescue analgesics used, pulse rate, mean arterial pressure and side effects were observed and analysed. RESULTS In regards to the lapse of time between end of surgery and first rescue analgesic given, total doses of tramadol used during the 24 hours after the procedure were significantly better in patients given intra-articular magnesium sulphate than other groups (P = 0.001). Patients of Group C who received IV magnesium sulphate were significantly better than patients who were given intrathecal magnesium sulphate in relation to time taken from end of surgery until first analgesic dose. VAS at rest and during the period of first 24 hours followed by surgery was statistically significant in patients who received intra-articular magnesium sulphate (p- 0.001). CONCLUSIONS Intra-articular administration of magnesium sulphate was observed to be superior to other routes of administration or not using at all. Next to intra-articular route, intravenous magnesium sulphate was found to be superior to intrathecal route in providing post operative analgesia in arthroscopy patients. KEY WORDS Analgesia, Knee Arthroscopy, Pain, Magnesium Sulphate, Intrathecal, Intra-articular